1
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Chen T, Li X, Hou P, He H, Wang H. VAPA suppresses BEFV and VSV-induced type I IFNs signaling response by targeting JAK1 for NEDD4-mediated ubiquitin-proteasome degradation. Vet Microbiol 2025; 304:110456. [PMID: 40080976 DOI: 10.1016/j.vetmic.2025.110456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 03/03/2025] [Accepted: 03/03/2025] [Indexed: 03/15/2025]
Abstract
VAMP-associated protein A (VAPA) binds to various proteins involved in multiple cellular processes, however, its role in the regulation of type I interferons (IFN-I) signaling has not been elucidated. In this study, we demonstrate that VAPA negatively regulates the IFN-I signaling during bovine epidemic fever virus (BEFV) and vesicular stomatitis virus (VSV) infection. Upon treatment with IFN-β, VAPA negatively regulates the JAK-STAT signaling pathway. Further studies show that VAPA inhibits the IFN-I signaling by promoting the degradation of JAK1 through the ubiquitin-proteasome system during BEFV and VSV infection. Mechanistically, VAPA facilitates the interaction between the E3 ubiquitin ligase NEDD4 and JAK1, thereby enhancing the ubiquitination and subsequent degradation of JAK1. Furthermore, viral titers are markedly reduced, and the promoting effect of VAPA on VSV or BEFV replication is attenuated in NEDD4-deficient cells. Taken together, our findings reveal a novel role for VAPA in negatively regulating the IFN-I signaling response and provide a molecular basis for the design of targeted antiviral agents.
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Affiliation(s)
- Tianhua Chen
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan 250358, China
| | - Xingyu Li
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan 250358, China
| | - Peili Hou
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan 250358, China.
| | - Hongbin He
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan 250358, China.
| | - Hongmei Wang
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan 250358, China.
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2
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Li R, Zheng W, Xiao Y, Yu X, Sheng J, Zhang H, Chen C, Ma Z, Wang Y. Mycoplasma hyopneumoniae nuclease Mhp597 negatively regulates TBK1-IRF3-IFN-I pathway by targeting vimentin to facilitate infection. Int J Biol Macromol 2025; 306:141351. [PMID: 39988178 DOI: 10.1016/j.ijbiomac.2025.141351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 02/25/2025]
Abstract
Infection with Mycoplasma hyopneumoniae (M. hyopneumoniae) leads to chronic infectious pneumonia in pigs, resulting in significant distress and economic losses in the global pig industry. The pathogen secretes various proteins, including toxins, adhesins, and virulence-related enzymes, which facilitate adhesion, invasion, and immune evasion processes between bacteria and the host. However, the effector proteins of M. hyopneumoniae are predominantly uncharacterized. In this study, we demonstrate that the nuclease Mhp597 functions as a potential effector protein of M. hyopneumoniae, and we elucidate its mechanism of action in facilitating immune evasion. Our findings indicate that Mhp597 exhibits high expression efficiency in host cells and significantly inhibits IFN-α and IFN-β protein expression. Using yeast two-hybrid and co-immunoprecipitation experiments, we established that Mhp597 interacts with porcine alveolar macrophage vimentin (Vim) via specific amino acid residues (Arg 232, Lys 256, Phe 263, and Lys 317). Further analysis revealed that Mhp597 inhibited the phosphorylation of TBK1 and IRF3 via Vim, thereby suppressing type I interferon (IFN-I) production and promoting the proliferation of M. hyopneumoniae within host cells. In conclusion, this study provides the first detailed account of the molecular mechanism by which Mhp597 negatively regulates the TBK1-IRF3-IFN-I signaling pathway through Vim, thus facilitating immune evasion and proliferation of M. hyopneumoniae within host cells. These findings enhance our understanding of the pathogenic mechanisms of M. hyopneumoniae and suggest potential molecular targets for the development of novel therapeutic strategies.
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Affiliation(s)
- Ruirui Li
- College of Animal Science and Technology, Shihezi University, Shihezi, China; Collaborative Innovation Center for Sheep Health Breeding and Zoonotic Disease Prevention and Control, Shihezi, Xinjiang, China; International Joint Research Center for Animal Health, Shihezi, Xinjiang, China
| | - Wei Zheng
- College of Animal Science and Technology, Shihezi University, Shihezi, China; Collaborative Innovation Center for Sheep Health Breeding and Zoonotic Disease Prevention and Control, Shihezi, Xinjiang, China; International Joint Research Center for Animal Health, Shihezi, Xinjiang, China
| | - Yangyang Xiao
- College of Animal Science and Technology, Shihezi University, Shihezi, China; Collaborative Innovation Center for Sheep Health Breeding and Zoonotic Disease Prevention and Control, Shihezi, Xinjiang, China; International Joint Research Center for Animal Health, Shihezi, Xinjiang, China
| | - Xiaojiao Yu
- College of Animal Science and Technology, Shihezi University, Shihezi, China; Collaborative Innovation Center for Sheep Health Breeding and Zoonotic Disease Prevention and Control, Shihezi, Xinjiang, China; International Joint Research Center for Animal Health, Shihezi, Xinjiang, China
| | - Jinliang Sheng
- College of Animal Science and Technology, Shihezi University, Shihezi, China; Collaborative Innovation Center for Sheep Health Breeding and Zoonotic Disease Prevention and Control, Shihezi, Xinjiang, China; International Joint Research Center for Animal Health, Shihezi, Xinjiang, China
| | - Hui Zhang
- College of Animal Science and Technology, Shihezi University, Shihezi, China; Collaborative Innovation Center for Sheep Health Breeding and Zoonotic Disease Prevention and Control, Shihezi, Xinjiang, China; International Joint Research Center for Animal Health, Shihezi, Xinjiang, China
| | - Chuangfu Chen
- College of Animal Science and Technology, Shihezi University, Shihezi, China; Collaborative Innovation Center for Sheep Health Breeding and Zoonotic Disease Prevention and Control, Shihezi, Xinjiang, China; International Joint Research Center for Animal Health, Shihezi, Xinjiang, China.
| | - Zhongchen Ma
- College of Animal Science and Technology, Shihezi University, Shihezi, China; Collaborative Innovation Center for Sheep Health Breeding and Zoonotic Disease Prevention and Control, Shihezi, Xinjiang, China; International Joint Research Center for Animal Health, Shihezi, Xinjiang, China.
| | - Yong Wang
- College of Animal Science and Technology, Shihezi University, Shihezi, China; Collaborative Innovation Center for Sheep Health Breeding and Zoonotic Disease Prevention and Control, Shihezi, Xinjiang, China; International Joint Research Center for Animal Health, Shihezi, Xinjiang, China.
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3
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Fan JH, Zhao YY, Ma YH, Pan XY, Shao HC, Zi MH, Ren H, Zhang Y, Han S, Wan B, Zhang GP, He WR. The African swine fever virus B125R protein antagonizes JAK-STAT signalling by promoting the degradation of IFNAR2. Vet Res 2025; 56:87. [PMID: 40270033 PMCID: PMC12016261 DOI: 10.1186/s13567-025-01523-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 03/14/2025] [Indexed: 04/25/2025] Open
Abstract
African swine fever (ASF) is a highly contagious and severe hemorrhagic disease caused by African swine fever virus (ASFV). Currently, few safe and effective vaccines or antiviral drugs are available for its prevention. Interferon (IFN), a key component of innate antiviral immunity, induces interferon-stimulated genes (ISGs) by activating the JAK-STAT signalling pathway, resulting in antiviral effects. ASFV strains, including ASFV SY18, ASFV HLJ18, and ASFV BA71V, are highly sensitive to IFN-I treatment; however, the mechanisms by which ASFV antagonizes the host type I IFN response have not been fully elucidated. In this study, we identified the ASFV B125R protein (pB125R) as a negative regulator of the JAK-STAT pathway. We observed that ectopically expressed pB125R significantly suppressed the IFN-β-triggered activation of JAK-STAT signalling in HEK293T and PK-15 cells. Mechanistic studies revealed that pB125R binds to IFNAR2 and promotes its autophagic degradation, impairing the signal transduction of the IFN response at an early stage. This ultimately reduces the nuclear translocation of the ISGF3 complex and decreases ISG production. Our findings highlight the immunosuppressive activity of pB125R and reveal a novel mechanism by which ASFV evades the host IFN response, contributing to potential strategies for developing vaccines and therapeutics against ASF.
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Affiliation(s)
- Jun-Hao Fan
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China
| | - Yan-Yan Zhao
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China
| | - Yu-He Ma
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China
| | - Xiao-Ya Pan
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China
| | - Han-Cheng Shao
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China
| | - Meng-Hui Zi
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China
| | - Haojie Ren
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China
| | - Yuhang Zhang
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China
- Longhu Laboratory, Zhengzhou, 450000, Henan, China
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Henan Agricultural University, Zhengzhou, 450000, China
| | - Shichong Han
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China
- Longhu Laboratory, Zhengzhou, 450000, Henan, China
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Henan Agricultural University, Zhengzhou, 450000, China
| | - Bo Wan
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China
- Longhu Laboratory, Zhengzhou, 450000, Henan, China
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Henan Agricultural University, Zhengzhou, 450000, China
| | - Gai-Ping Zhang
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China.
- Longhu Laboratory, Zhengzhou, 450000, Henan, China.
| | - Wen-Rui He
- International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China.
- Longhu Laboratory, Zhengzhou, 450000, Henan, China.
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Henan Agricultural University, Zhengzhou, 450000, China.
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4
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Haycock J, Maehr T, Dastjerdi A, Steinbach F. Asian elephant interferons alpha and beta and their anti-herpes viral activity. Front Immunol 2025; 16:1533038. [PMID: 40201174 PMCID: PMC11975597 DOI: 10.3389/fimmu.2025.1533038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/05/2025] [Indexed: 04/10/2025] Open
Abstract
The type I interferons (IFNs) are a group of key cytokines of the vertebrate innate immune system that induce an antiviral state in uninfected cells. Experimental in-vitro and in-vivo data have proven the fundamental role these cytokines possess in the protective response to a wide variety of pathogens, including herpesviruses. In a clinical setting, IFNs have been an important treatment in humans for several decades and increasing evidence demonstrates their potential in controlling viral haemorrhagic fevers when administered early in disease. In juvenile Asian elephants, elephant endotheliotropic herpesvirus haemorrhagic disease (EEHV-HD) often proves fatal when an effective adaptive immune response cannot be mounted in time, suggesting that an enhancement of the innate immune response could provide protection. This study sequenced six members of the Asian elephant type I IFNs, most closely related to sequences from the African elephant and Florida manatee. Subsequently, recombinant Asian elephant IFNα and IFNβ proteins were expressed and assessed for bioactivity in-vitro, relative to recombinant human IFNs, using a novel infection model incorporating primary Asian elephant fibroblasts and bovine alphaherpesvirus 1 (BoHV-1) as a surrogate for EEHV. In a dose-dependent manner, both Asian elephant IFNs and human IFNα2a protected cells from BoHV-1 infection in this proof-of-concept study, even if applied up to 24 hours post-infection in-vitro.
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Affiliation(s)
- Jonathan Haycock
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
- Department of Virology, Animal and Plant Health Agency, Addlestone, United Kingdom
| | - Tanja Maehr
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
- Department of Virology, Animal and Plant Health Agency, Addlestone, United Kingdom
| | - Akbar Dastjerdi
- Department of Virology, Animal and Plant Health Agency, Addlestone, United Kingdom
| | - Falko Steinbach
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
- Department of Virology, Animal and Plant Health Agency, Addlestone, United Kingdom
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5
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Dong H, Li X, Xu S, Wang Y, Xia T, Li P, Ruan W. Proteomic analysis identifies intracellular targets for avian coronavirus NSP10. Arch Virol 2025; 170:74. [PMID: 40080214 DOI: 10.1007/s00705-025-06255-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 12/08/2024] [Indexed: 03/15/2025]
Abstract
Avian coronavirus, also known as infectious bronchitis virus (IBV), is the causative agent of infectious bronchitis (IB). The non-structural proteins (NSPs) of IBV are critical for viral replication and for evading the host's immune response. The innate immune response serves as the first line of defense against viral infections. The IBV genome codes for 15 NSPs (NSP2-16). In this study, we identified host proteins interacting with IBV NSP10 using co-immunoprecipitation (Co-IP) and liquid chromatography-tandem mass spectrometry (LC/MS/MS). Proteomic analysis revealed that interactions of host proteins with NSP10 are involved in processes such as localization, transport, and metabolism, regulation of the cell cycle, and antiviral responses. We further explored the role of NSP10 in these immune and cellular regulation pathways and also confirmed the interaction between NSP10 and the host protein hnRNPA1. Further investigation showed that hnRNPA1 inhibited IBV replication. It is speculated that the binding of hnRNP A1 to NSP10 interferes with the function of the replication complex, thereby inhibiting virus replication. However, co-overexpression of NSP10 and hnRNP A1 partially restored viral replication, suggesting a complex relationship between these two proteins. These findings demonstrate that IBV NSP10 plays a significant role in viral infection and in modulating host cell processes, highlighting its potential as a target for therapeutic interventions.
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Affiliation(s)
- Hao Dong
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, 102206, China
| | - Xueyan Li
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, 102206, China
- Changping Laboratory, Beijing, 102206, China
| | - Shengkui Xu
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, 102206, China
| | - Yuxin Wang
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, 102206, China
| | - Ting Xia
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, 102206, China
- China Rehabilitation Research Center, School of Rehabilitation, China Rehabilitation Science Institute, Capital Medical University, Beijing, 100069, China
| | - Peng Li
- College of Veterinary Medicine, Iowa State University, Ames, Iowa, 50010, US
| | - Wenke Ruan
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, 102206, China.
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6
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Barboza CM, Zamudio RM, Franco AC, de Carvalho Ruthner Batista HB. In vitro characterization of the antiviral activity of Bat Interferon-Induced protein with tetratricopeptide repeats 5 (bat IFIT5) against bat-associated rabies virus. J Neurovirol 2025:10.1007/s13365-025-01245-y. [PMID: 40021552 DOI: 10.1007/s13365-025-01245-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 03/03/2025]
Abstract
Bats are important reservoirs of zoonotic viruses, including the rabies virus (RABV), which causes rabies, a significant and fatal disease. In Brazil, RABV has been detected in several bat species. Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5) is part of a group of interferon-stimulated genes (ISGs) known for their antiviral activity. This study investigated the interaction between batIFIT5 and different genetic lineages of RABV. The batIFIT5 was expressed in HEK-293T cells, which were infected with RABV genetic lineages isolated from Eptesicus furinalis (IP 964/06) and Tadarida brasiliensis (IP 3214/19), at varying infectious doses (pure, 100, 10, and 1). Direct immunofluorescence was performed to assess the effect of batIFIT5 on virus replication through the counting of fluorescent foci. Subsequently, after the expression of batIFIT5, 1 MOI was selected and used to evaluate the potential antiviral effect. Immunofluorescence was performed 24 and 48 h after infection. As a result, the viral concentration remained similar in the presence of batIFIT5 across distinct infectious doses. After infection with 1 MOI, a 30% reduction in infection rates was observed, particularly for the IP 3214/19 isolate after 24 h. These results highlight the potential antiviral role of IFIT5 against RABV infection.
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Affiliation(s)
- Camila Mosca Barboza
- Universidade Federal do ABC, Santo André, SP, Brazil.
- Instituto Pasteur, São Paulo, SP, Brazil.
| | - Raphaela Mello Zamudio
- Universidade Federal do ABC, Santo André, SP, Brazil
- Instituto Pasteur, São Paulo, SP, Brazil
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7
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Al Qureshah F, Le Pen J, de Weerd NA, Moncada-Velez M, Materna M, Lin DC, Milisavljevic B, Vianna F, Bizien L, Lorenzo L, Lecuit M, Pommier JD, Keles S, Ozcelik T, Pedraza-Sanchez S, de Prost N, El Zein L, Hammoud H, Ng LFP, Halwani R, Saheb Sharif-Askari N, Lau YL, Tam AR, Singh N, Bhattad S, Berkun Y, Chantratita W, Aguilar-López R, Shahrooei M, Abel L, Bastard P, Jouanguy E, Béziat V, Zhang P, Rice CM, Cobat A, Zhang SY, Hertzog PJ, Casanova JL, Zhang Q. A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity. J Exp Med 2025; 222:e20241413. [PMID: 39680367 DOI: 10.1084/jem.20241413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 10/13/2024] [Accepted: 11/20/2024] [Indexed: 12/17/2024] Open
Abstract
Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%). Cells heterozygous for these variants display a dominant phenotype in vitro with impaired responses to IFN-α and -ω, but not -β, and viral susceptibility. Negative dominance, rather than haploinsufficiency, accounts for this dominance. Patients heterozygous for these variants are prone to viral diseases, attesting to both the dominance of these variants clinically and the importance of IFN-α and -ω for protective immunity against some viruses.
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Affiliation(s)
- Fahd Al Qureshah
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Wellness and Preventive Medicine Institute, King Abdulaziz City for Science and Technology , Riyadh, Saudi Arabia
| | - Jérémie Le Pen
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Nicole A de Weerd
- Centre for Innate Immunity and Infectious Diseases, Department of Molecular and Translational Science, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | - Marcela Moncada-Velez
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Marie Materna
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
| | - Daniel C Lin
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Université Paris Cité, Imagine Institute , Paris, France
| | - Baptiste Milisavljevic
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Fernanda Vianna
- Laboratório de Medicina Genômica Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul , Porto Alegre, Brazil
- Graduate Program in Medicine, Medical Sciences, Federal University of Rio Grande do Sul , Porto Alegre, Brazil
- National Institute of Population Medical Genetics (INAGEMP) , Porto Alegre, Brazil
| | - Lucy Bizien
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
| | - Lazaro Lorenzo
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
| | - Marc Lecuit
- Université Paris Cité, Imagine Institute , Paris, France
- Department of Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, APHP, Institut Imagine, Paris, France
- Biology of Infection Unit, Institut Pasteur, Inserm U1117, Université Paris Cité, Paris, France
| | - Jean-David Pommier
- Biology of Infection Unit, Institut Pasteur, Inserm U1117, Université Paris Cité, Paris, France
| | - Sevgi Keles
- Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
| | - Tayfun Ozcelik
- Department of Molecular Biology and Genetics, Bilkent University, Bilkent-Ankara, Turkey
| | - Sigifredo Pedraza-Sanchez
- Unit of Biochemistry, National Institute for Medical Sciences and Nutrition Salvador Zubiran (INCMNSZ) , Mexico City, Mexico
| | - Nicolas de Prost
- Service de Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris, France
- Groupe de Recherche Clinique CARMAS, Faculté de Santé de Créteil, Université Paris Est Créteil , Créteil Cedex, France
- INSERM U955, Team "Viruses, Hepatology, Cancer" , Créteil, France
| | - Loubna El Zein
- Biology Department, Lebanese University, Beirut, Lebanon
| | | | - Lisa F P Ng
- A*STAR Infectious Disease Labs, Agency for Science, Technology and Research , Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technology University , Singapore, Singapore
| | - Rabih Halwani
- Research Institute for Medical and Health Sciences, University of Sharjah , Sharjah, UAE
- Prince Abdullah Bin Khalid Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
| | | | - Yu Lung Lau
- Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Anthony R Tam
- Division of Infectious Diseases, Department of Medicine, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | | | | | - Yackov Berkun
- Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Wasun Chantratita
- Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Raúl Aguilar-López
- Department of Surgery, Maternal and Child Hospital, Social Security Institute of the State of Mexico and Municipalities (ISSEMYM), Toluca, Mexico
| | - Mohammad Shahrooei
- Clinical and Diagnostic Immunology, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium
- Dr. Shahrooei's Laboratory , Tehran, Iran
| | - Laurent Abel
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
| | - Paul Bastard
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris , Paris, France
| | - Emmanuelle Jouanguy
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
| | - Vivien Béziat
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
| | - Peng Zhang
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
| | - Charles M Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Aurélie Cobat
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
| | - Shen-Ying Zhang
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
| | - Paul J Hertzog
- Centre for Innate Immunity and Infectious Diseases, Department of Molecular and Translational Science, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | - Jean-Laurent Casanova
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
- Howard Hughes Medical Institute , New York, NY, USA
- Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
| | - Qian Zhang
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Université Paris Cité, Imagine Institute , Paris, France
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8
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Sirisena DMKP, Kim G, Warnakula WADLR, Jayamali BPMV, Tharanga EMT, Jayasinghe JDHE, Sandeepani RI, Wan Q, Sohn H, Lee J. Interferon regulatory factor 2 of red-spotted grouper (Epinephelus akaara): Insights into its transcriptional profiling, antiviral potential, and function in macrophage polarization. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2025; 163:105323. [PMID: 39848353 DOI: 10.1016/j.dci.2025.105323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 01/19/2025] [Accepted: 01/19/2025] [Indexed: 01/25/2025]
Abstract
Interferon regulatory factor 2 (IRF2) is a member of the IRF family that is specifically involved in diverse immune responses via interferon (IFN)/IRF-dependent signaling pathways. In this study, IRF2 of Epinephelus akaara (EAIRF2) was identified and characterized by evaluating its structural and functional properties. EAIRF2 showed the highest homology with IRF2 of Epinephelus coioides and clustered with teleosts in the phylogenetic tree. The highest level of EAIRF2 mRNA was found in the blood under normal physiological conditions. In the immune challenge experiment, significant transcriptional modulation of EAIRF2 upon lipopolysaccharide (LPS), polyinosinic: polycytidylic acid (poly I:C), and nervous necrosis virus (NNV) challenge were observed. The subcellular localization assay confirmed the role of EAIRF2 as a transcription factor by revealing its specific nuclear localization. To elucidate its functional implications in antiviral defense, EAIRF2 was overexpressed in fathead minnow cells, which were subsequently infected with viral hemorrhagic septicemia virus (VHSV). Notably, cells overexpressing EAIRF2 exhibited a significant reduction in the transcription of VHSV genes. Concurrently, the genes associated with the IFN/IRF signaling pathway were upregulated. Furthermore, the Hoechst and propidium iodide dual staining assay, water-soluble tetrazolium-1 (WST-1) assay, and transcriptional analysis of B-cell lymphoma 2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) indicated that EAIRF2 possesses anti-apoptotic properties during viral infection and poly I:C treatment. Additionally, EAIRF2 overexpression in murine macrophages induced M1 polarization and augmented relative marker gene expression. Collectively, these findings suggest that EAIRF2 is a pivotal immune-related gene, specifically implicated in the IFN/IRF-mediated antiviral defense mechanism, apoptotic signaling pathway, and activation of macrophage-mediated immune responses in Epinephelus akaara. The finding of this study enhances our understanding of IRF2's function in teleost immunity and presents potential avenues for developing therapeutic strategies against viral infections and other immune-related conditions in aquaculture species.
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Affiliation(s)
- D M K P Sirisena
- Department of Marine Life Sciences & Center for Genomic Selection in Korean Aquaculture, Jeju National University, Jeju, 63243, Republic of Korea
| | - Gaeun Kim
- Department of Marine Life Sciences & Center for Genomic Selection in Korean Aquaculture, Jeju National University, Jeju, 63243, Republic of Korea
| | - W A D L R Warnakula
- Department of Marine Life Sciences & Center for Genomic Selection in Korean Aquaculture, Jeju National University, Jeju, 63243, Republic of Korea
| | - B P M Vileka Jayamali
- Department of Marine Life Sciences & Center for Genomic Selection in Korean Aquaculture, Jeju National University, Jeju, 63243, Republic of Korea
| | - E M T Tharanga
- Department of Marine Life Sciences & Center for Genomic Selection in Korean Aquaculture, Jeju National University, Jeju, 63243, Republic of Korea
| | - J D H E Jayasinghe
- Department of Marine Life Sciences & Center for Genomic Selection in Korean Aquaculture, Jeju National University, Jeju, 63243, Republic of Korea
| | - R I Sandeepani
- Department of Marine Life Sciences & Center for Genomic Selection in Korean Aquaculture, Jeju National University, Jeju, 63243, Republic of Korea
| | - Qiang Wan
- Department of Marine Life Sciences & Center for Genomic Selection in Korean Aquaculture, Jeju National University, Jeju, 63243, Republic of Korea; Marine Life Research Institute, Jeju National University, Jeju, 63333, Republic of Korea
| | - Hanchang Sohn
- Department of Marine Life Sciences & Center for Genomic Selection in Korean Aquaculture, Jeju National University, Jeju, 63243, Republic of Korea; Marine Life Research Institute, Jeju National University, Jeju, 63333, Republic of Korea.
| | - Jehee Lee
- Department of Marine Life Sciences & Center for Genomic Selection in Korean Aquaculture, Jeju National University, Jeju, 63243, Republic of Korea; Marine Life Research Institute, Jeju National University, Jeju, 63333, Republic of Korea.
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9
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Duan Y, Liu Z, Zang N, Cong B, Shi Y, Xu L, Jiang M, Wang P, Zou J, Zhang H, Feng Z, Feng L, Ren L, Liu E, Li Y, Zhang Y, Xie Z. Landscape of respiratory syncytial virus. Chin Med J (Engl) 2024; 137:2953-2978. [PMID: 39501814 PMCID: PMC11706595 DOI: 10.1097/cm9.0000000000003354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Indexed: 01/11/2025] Open
Abstract
ABSTRACT Respiratory syncytial virus (RSV) is an enveloped, negative-sense, single-stranded RNA virus of the Orthopneumovirus genus of the Pneumoviridae family in the order Mononegavirales. RSV can cause acute upper and lower respiratory tract infections, sometimes with extrapulmonary complications. The disease burden of RSV infection is enormous, mainly affecting infants and older adults aged 75 years or above. Currently, treatment options for RSV are largely supportive. Prevention strategies remain a critical focus, with efforts centered on vaccine development and the use of prophylactic monoclonal antibodies. To date, three RSV vaccines have been approved for active immunization among individuals aged 60 years and above. For children who are not eligible for these vaccines, passive immunization is recommended. A newly approved prophylactic monoclonal antibody, Nirsevimab, which offers enhanced neutralizing activity and an extended half-life, provides exceptional protection for high-risk infants and young children. This review provides a comprehensive and detailed exploration of RSV's virology, immunology, pathogenesis, epidemiology, clinical manifestations, treatment options, and prevention strategies.
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Affiliation(s)
- Yuping Duan
- School of Population Medicine and Public Health, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
- State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100029, China
| | - Zimeng Liu
- National Health Commission Key Laboratory of Systems Biology of Pathogen, Christophe Mérieux Laboratory, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 102629, China
| | - Na Zang
- Department of Respiratory Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing 400014, China
- Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Key Laboratory of Children’s Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing 400014, China
| | - Bingbing Cong
- Department of Epidemiology, National Vaccine Innovation Platform, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Yuqing Shi
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, NHC Key Laboratory of Medical Virology and Viral Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Lili Xu
- Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics (Capital Medical University), Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences (2019RU016), Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health,Beijing 100045, China
| | - Mingyue Jiang
- School of Population Medicine and Public Health, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
- State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100029, China
| | - Peixin Wang
- National Health Commission Key Laboratory of Systems Biology of Pathogen, Christophe Mérieux Laboratory, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 102629, China
| | - Jing Zou
- Department of Epidemiology, National Vaccine Innovation Platform, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Han Zhang
- Department of Epidemiology, National Vaccine Innovation Platform, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Ziheng Feng
- Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics (Capital Medical University), Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences (2019RU016), Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health,Beijing 100045, China
| | - Luzhao Feng
- School of Population Medicine and Public Health, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
- State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100029, China
| | - Lili Ren
- State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100029, China
- National Health Commission Key Laboratory of Systems Biology of Pathogen, Christophe Mérieux Laboratory, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 102629, China
- Key Laboratory of Respiratory Disease Pathogenomics, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Enmei Liu
- Department of Respiratory Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing 400014, China
- Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Key Laboratory of Children’s Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing 400014, China
| | - You Li
- Department of Epidemiology, National Vaccine Innovation Platform, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh EH8 9AG, UK
- Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu 213000, China
| | - Yan Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, NHC Key Laboratory of Medical Virology and Viral Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Zhengde Xie
- Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics (Capital Medical University), Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences (2019RU016), Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health,Beijing 100045, China
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10
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Huang X, Li Y, Li J, Jiang Y, Cui W, Zhou H, Tang L. The long noncoding RNA loc107053557 acts as a gga-miR-3530-5p sponge to suppress the replication of vvIBDV through regulating STAT1 expression. Virulence 2024; 15:2333237. [PMID: 38528779 PMCID: PMC10984138 DOI: 10.1080/21505594.2024.2333237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 03/16/2024] [Indexed: 03/27/2024] Open
Abstract
Infectious bursal disease virus (IBDV) causes immunosuppression and high mortality in young chickens. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are important regulators during viral infection. However, detailed the regulatory mechanisms of lncRNA-miRNA-mRNA have not yet been described in IBDV infection. Here, we analysed the role of lncRNA53557/gga-miR-3530-5p/STAT1 axis in very virulent IBDV (vvIBDV) infection. Evidently upregulated expression of lncRNA53557 was observed in bursa of Fabricius and DT40 cells. Meanwhile, overexpression of lncRNA53557 promoted STAT1 expression and inhibited vvIBDV replication and vice versa, indicating that the upregulation of lncRNA53557 was part of the host antiviral defence. The subcellular fractionation assay confirmed that lncRNA53557 can be localized in the cytoplasm. Further, dual-luciferase reporter, RNA pulldown, FISH and RT-qPCR assays revealed that lncRNA53557 were directly bound to gga-miR-3530-5p and had a negative regulatory relationship between them. Subsequent mechanistic analysis showed that lncRNA53557 acted as a competing endogenous RNA (ceRNA) of gga-miR-3530-5p to relieve the repressive effect of gga-miR-3530-5p on its target STAT1, as well as Mx1, OASL, and ISG15, thereby suppressing vvIBDV replication. The study reveals that a network of enriched lncRNAs and lncRNA-associated ceRNA is involved in the regulation of IBDV infection, offering new insight into the mechanisms underlying IBDV-host interaction.
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Affiliation(s)
- Xuewei Huang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, P.R. China
| | - Yue Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Jiaxuan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Yanping Jiang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, P.R. China
| | - Wen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, P.R. China
| | - Han Zhou
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, P.R. China
| | - Lijie Tang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, P.R. China
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11
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Mohamed AA, Armanious M, Bedair RW, Amin NS, El Tayebi HM. When less is more: The association between the expression of polymorphic CYPs and AFB1-induced HCC. Eur J Clin Invest 2024; 54:e14297. [PMID: 39099542 DOI: 10.1111/eci.14297] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 07/24/2024] [Indexed: 08/06/2024]
Abstract
BACKGROUND An individual's genetic fingerprint is emerging as a pivotal predictor of numerous disease- and treatment-related factors. Single nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes play key roles in an individual's exposure to a malignancy-associated risk, such as Aflatoxin B1 (AFB1)-induced hepatocellular carcinoma (HCC). AIM This study aimed at reviewing literature on the polymorphisms that exist in CYP enzymes and their possible link with susceptibility to AFB1-induced HCC. MATERIALS & METHODS A set of keywords associated with the study subject of interest was used to search the Google Scholar and the PubMed database. The last ten years' worth of research projects were included in the results filter. The research involved HCC patients and any connection between polymorphic forms of CYP enzymes and their susceptibility to AFB1-induced HCC, including older but significant data. RESULTS Variations in CYP1A2 and CYP3A4 were reported to impact the rate and magnitude of AFB1 bio-activation, thus influencing an individual's vulnerability to develop HCC. In HCC patients, the activity of CYP isoforms varies, where increased activity has been reported with CYP2C9, CYP2D6, and CYP2E1, while CYP1A2, CYP2C8, and CYP2C19 exhibit decreased activity. CYP2D6*10 frequency has been discovered to differ considerably in HCC patients. Rs2740574 (an upstream polymorphism in CYP3A4 as detected in CYP3A4*1B) and rs776746 (which affects CYP3A5 RNA splicing), both of which influence CYP3A expression, thus impacting the variability of AFB1-epoxide adducts in HCC patients. DISCUSSION CYP1A2 is the primary enzyme accountable for the formation of harmful AFBO globally. CYP3A4, CYP3A5, CYP3A7, CYP2B7, and CYP3A3 are also implicated in the bio-activation of AFB1 to mutagenic metabolites. It is thought that CYP3A4 is the protein that interacts with AFB1 metabolism the most. CONCLUSION Polymorphic variants of CYP enzymes have a functional impact on the susceptibility to AFB1-induced HCC. Outlining such variation and their implications may provide deeper insights into approaching HCC in a more personalized manner for guiding future risk-assessment, diagnosis, and treatment.
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Affiliation(s)
- Asmaa Ashraf Mohamed
- Clinical Pharmacology and Pharmacogenomics Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Monica Armanious
- Clinical Pharmacology and Pharmacogenomics Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Rana W Bedair
- Clinical Pharmacology and Pharmacogenomics Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Nada Sherif Amin
- Clinical Pharmacology and Pharmacogenomics Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Hend M El Tayebi
- Clinical Pharmacology and Pharmacogenomics Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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12
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Amoia CF, Chengula AA, Hakizimana JN, Wambura PN, Munir M, Misinzo G, Weger-Lucarelli J. Development of a genotype-matched Newcastle disease DNA vaccine candidate adjuvanted with IL-28b for the control of targeted velogenic strains of Newcastle disease virus in Africa. Vet Res Commun 2024; 49:33. [PMID: 39585481 PMCID: PMC11588948 DOI: 10.1007/s11259-024-10590-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 10/10/2024] [Indexed: 11/26/2024]
Abstract
Newcastle disease virus (NDV) is an extremely contagious and deadly virus that affects numerous bird species, posing serious threats to poultry production on a global scale. In addition to implementing biosecurity practices in farming systems, vaccination remains the most effective means of controlling Newcastle disease (ND). However, while existing commercial vaccines provide some level of protection, the effectiveness of these vaccines can be questionable, particularly in field settings where the complexity of vaccination program implementation poses significant challenges, especially against virulent genotypes of NDV. A genotype-matched NDV DNA vaccine could potentially offer a more effective vaccination approach than currently available live attenuated vaccines. By being specifically tailored to match circulating strains, such a vaccine might improve efficacy and reduce the risk of vaccine failure due to genotype mismatch. To develop an alternative vaccine approach, two ND DNA vaccines were constructed in this study. Each vaccine developed in this study contains the fusion (F) and haemagglutinin-neuraminidase (HN) genes of a virulent NDV genotype VII isolate from Tanzania. Interferon lambda-3 (IFNλ3; IL-28b), which has demonstrated capacity to significantly enhance specific adaptive immune responses and decreased levels of inflammatory cytokines, as well as improved protective responses at a high viral challenge dose, was included in one of the developed vaccines. These plasmids were designated pTwist-F-HN-VII-IL28b and pTwist-F-HN-VII. The two plasmids differed in that pTwist-F-HN-VII-IL28b contained the cytokine adjuvant IL-28b. Transfection of cells and subsequent immunofluorescence assays indicated that both plasmids expressed high levels of NDV F-HN proteins. In vivo immunization demonstrated that chicks intramuscularly immunized with pTwist-F-HN-VII-IL28b exhibited significant immune responses compared to chicks immunized with pTwist-F-HN-VII or the commonly used LaSota vaccine (LaSota), which was used as a control. The protective efficacy of pTwist-F-HN-VII-IL28b was 80% after challenge with the highly virulent NDV strain ON148423, compared to 60% for chicks vaccinated using LaSota, and pTwist-F-HN-VII. The findings of this study indicate that IL-28b can be employed as a molecular adjuvant for NDV vaccines. This study represents a key milestone in Newcastle disease vaccine research, particularly in the development of a genotype-matched DNA vaccine candidate. Additionally, this study demonstrated that the combination of F, HN, and IL-28b elicits an efficacious immune response against virulent NDV strains.
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Affiliation(s)
- Charlie F Amoia
- Department of Veterinary Microbiology, Parasitology and Biotechnology, Sokoine University of Agriculture, P. O. Box 3019, Morogoro, 67125, Tanzania.
- SACIDS Foundation for One Health, SACIDS Africa Centre of Excellence for Infectious Diseases, Sokoine University of Agriculture, P. O. Box 3297, Morogoro, 67125, Tanzania.
- Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, 24061, USA.
| | - Augustino A Chengula
- Department of Veterinary Microbiology, Parasitology and Biotechnology, Sokoine University of Agriculture, P. O. Box 3019, Morogoro, 67125, Tanzania
| | - Jean N Hakizimana
- OR Tambo Africa Research Chair for Viral Epidemics, SACIDS Foundation for One Health, Sokoine University of Agriculture, P. O. Box 3297, Morogoro, 67125, Tanzania
| | - Philemon N Wambura
- Department of Veterinary Microbiology, Parasitology and Biotechnology, Sokoine University of Agriculture, P. O. Box 3019, Morogoro, 67125, Tanzania
| | - Muhammad Munir
- Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YG, UK
| | - Gerald Misinzo
- Department of Veterinary Microbiology, Parasitology and Biotechnology, Sokoine University of Agriculture, P. O. Box 3019, Morogoro, 67125, Tanzania
- SACIDS Foundation for One Health, SACIDS Africa Centre of Excellence for Infectious Diseases, Sokoine University of Agriculture, P. O. Box 3297, Morogoro, 67125, Tanzania
- OR Tambo Africa Research Chair for Viral Epidemics, SACIDS Foundation for One Health, Sokoine University of Agriculture, P. O. Box 3297, Morogoro, 67125, Tanzania
| | - James Weger-Lucarelli
- Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, 24061, USA.
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24060, USA.
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13
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Kiflu AB. The Immune Escape Strategy of Rabies Virus and Its Pathogenicity Mechanisms. Viruses 2024; 16:1774. [PMID: 39599888 PMCID: PMC11598914 DOI: 10.3390/v16111774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 11/01/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024] Open
Abstract
In contrast to most other rhabdoviruses, which spread by insect vectors, the rabies virus (RABV) is a very unusual member of the Rhabdoviridae family, since it has evolved to be fully adapted to warm-blooded hosts and spread directly between them. There are differences in the immune responses to laboratory-attenuated RABV and wild-type rabies virus infections. Various investigations showed that whilst laboratory-attenuated RABV elicits an innate immune response, wild-type RABV evades detection. Pathogenic RABV infection bypasses immune response by antagonizing interferon induction, which prevents downstream signal activation and impairs antiviral proteins and inflammatory cytokines production that could eliminate the virus. On the contrary, non-pathogenic RABV infection leads to immune activation and suppresses the disease. Apart from that, through recruiting leukocytes into the central nervous system (CNS) and enhancing the blood-brain barrier (BBB) permeability, which are vital factors for viral clearance and protection, cytokines/chemokines released during RABV infection play a critical role in suppressing the disease. Furthermore, early apoptosis of neural cells limit replication and spread of avirulent RABV infection, but street RABV strains infection cause delayed apoptosis that help them spread further to healthy cells and circumvent early immune exposure. Similarly, a cellular regulation mechanism called autophagy eliminates unused or damaged cytoplasmic materials and destroy microbes by delivering them to the lysosomes as part of a nonspecific immune defense mechanism. Infection with laboratory fixed RABV strains lead to complete autophagy and the viruses are eliminated. But incomplete autophagy during pathogenic RABV infection failed to destroy the viruses and might aid the virus in dodging detection by antigen-presenting cells, which could otherwise elicit adaptive immune activation. Pathogenic RABV P and M proteins, as well as high concentration of nitric oxide, which is produced during rabies virus infection, inhibits activities of mitochondrial proteins, which triggers the generation of reactive oxygen species, resulting in oxidative stress, contributing to mitochondrial malfunction and, finally, neuron process degeneration.
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Affiliation(s)
- Abraha Bahlbi Kiflu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning 530004, China;
- College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning 530004, China
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14
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Swaraj S, Tripathi S. Interference without interferon: interferon-independent induction of interferon-stimulated genes and its role in cellular innate immunity. mBio 2024; 15:e0258224. [PMID: 39302126 PMCID: PMC11481898 DOI: 10.1128/mbio.02582-24] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2024] Open
Abstract
Interferons (IFNs) are multifaceted proteins that play pivotal roles in orchestrating robust antiviral immune responses and modulating the intricate landscape of host immunity. The major signaling pathway activated by IFNs is the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, which leads to the transcription of a battery of genes, collectively known as IFN-stimulated genes (ISGs). While the well-established role of IFNs in coordinating the innate immune response against viral infections is widely acknowledged, recent years have provided a more distinct comprehension of the functional significance attributed to non-canonical, IFN-independent induction of ISGs. In this review, we summarize the non-conventional signaling pathways of ISG induction. These alternative pathways offer new avenues for developing antiviral strategies or immunomodulation in various diseases.
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Affiliation(s)
- Shachee Swaraj
- Emerging Viral Pathogens Laboratory, Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, India
- Microbiology & Cell Biology Department, Biological Sciences Division, Indian Institute of Science, Bengaluru, India
| | - Shashank Tripathi
- Emerging Viral Pathogens Laboratory, Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, India
- Microbiology & Cell Biology Department, Biological Sciences Division, Indian Institute of Science, Bengaluru, India
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15
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Jiang D, Sui C, Wu X, Jiang P, Bai J, Hu Y, Cong X, Li J, Yoo D, Miller LC, Lee C, Du Y, Qi J. Swine NONO promotes IRF3-mediated antiviral immune response by Detecting PRRSV N protein. PLoS Pathog 2024; 20:e1012622. [PMID: 39413144 PMCID: PMC11482726 DOI: 10.1371/journal.ppat.1012622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 09/27/2024] [Indexed: 10/18/2024] Open
Abstract
Non-POU domain-containing octamer-binding protein (NONO) is a multi-functional nuclear protein which belongs to the Drosophila behavior/human splicing (DBHS) protein family. NONO is known to regulate multiple important biological processes including host antiviral immune response. However, whether NONO can inhibit porcine reproductive and respiratory syndrome virus (PRRSV) replication is less well understood. In this study, we demonstrated that swine NONO (sNONO) inhibited PRRSV replication, via increasing expression of IFN-β, whereas NONO knockdown or knockout in PAM-KNU cells was more susceptible to PRRSV infection. As an IRF3 positive regulation factor, NONO promoted IFN-β expression by enhancing activation of IRF3. During PRRSV infection, NONO further up-regulated IRF3-mediated IFN-β expression by interacting with PRRSV N protein. Mechanistically, NONO functioned as a scaffold protein to detect PRRSV N protein and formed N-NONO-IRF3 complex in the nucleus. Interestingly, it was found that the NONO protein reversed the inhibitory effect of PRRSV N protein on type I IFN signaling pathway. Taken together, our study provides a novel mechanism for NONO to increase the IRF3-mediated IFN-β activation by interacting with the viral N protein to inhibit PRRSV infection.
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Affiliation(s)
- Dandan Jiang
- Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China
| | - Chao Sui
- Laboratory Animal Center, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xiangju Wu
- Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China
| | - Ping Jiang
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Juan Bai
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Yue Hu
- Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China
| | - Xiaoyan Cong
- Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China
| | - Juntong Li
- Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China
| | - Dongwan Yoo
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Laura C. Miller
- Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America
| | - Changhee Lee
- College of Veterinary Medicine and Virus Vaccine Research Center, Gyeongsang National University, Jinju, Republic of Korea
| | - Yijun Du
- Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China
| | - Jing Qi
- Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China
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16
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He Y, Shen M, Wang X, Yin A, Liu B, Zhu J, Zhang Z. Suppression of Interferon Response and Antiviral Strategies of Bunyaviruses. Trop Med Infect Dis 2024; 9:205. [PMID: 39330894 PMCID: PMC11435552 DOI: 10.3390/tropicalmed9090205] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/28/2024] [Accepted: 09/05/2024] [Indexed: 09/28/2024] Open
Abstract
The order Bunyavirales belongs to the class of Ellioviricetes and is classified into fourteen families. Some species of the order Bunyavirales pose potential threats to human health. The continuously increasing research reveals that various viruses within this order achieve immune evasion in the host through suppressing interferon (IFN) response. As the types and nodes of the interferon response pathway are continually updated or enriched, the IFN suppression mechanisms and target points of different virus species within this order are also constantly enriched and exhibit variations. For instance, Puumala virus (PUUV) and Tula virus (TULV) can inhibit IFN response through their functional NSs inhibiting downstream factor IRF3 activity. Nevertheless, the IFN suppression mechanisms of Dabie bandavirus (DBV) and Guertu virus (GTV) are mostly mediated by viral inclusion bodies (IBs) or filamentous structures (FSs). Currently, there are no effective drugs against several viruses belonging to this order that pose significant threats to society and human health. While the discovery, development, and application of antiviral drugs constitute a lengthy process, our focus on key targets in the IFN response suppression process of the virus leads to potential antiviral strategies, which provide references for both basic research and practical applications.
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Affiliation(s)
- Yingying He
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
- Department of Clinical Medicine, Anhui Medical University, Hefei 230032, China
| | - Min Shen
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
- Department of Clinical Medicine, Anhui Medical University, Hefei 230032, China
| | - Xiaohe Wang
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
- Department of Clinical Medicine, Anhui Medical University, Hefei 230032, China
| | - Anqi Yin
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
- Department of Clinical Medicine, Anhui Medical University, Hefei 230032, China
| | - Bingyan Liu
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
| | - Jie Zhu
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
| | - Zhenhua Zhang
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
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17
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Shiffer EM, Oyer JL, Copik AJ, Parks GD. Parainfluenza Virus 5 V Protein Blocks Interferon Gamma-Mediated Upregulation of NK Cell Inhibitory Ligands and Improves NK Cell Killing of Neuroblastoma Cells. Viruses 2024; 16:1270. [PMID: 39205244 PMCID: PMC11359056 DOI: 10.3390/v16081270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/03/2024] [Accepted: 08/05/2024] [Indexed: 09/04/2024] Open
Abstract
Natural killer (NK) cells can be effective immunotherapeutic anti-cancer agents due to their ability to selectively target and kill tumor cells. This activity is modulated by the interaction of NK cell receptors with inhibitory ligands on the surface of target cells. NK cell inhibitory ligands can be upregulated on tumor cell surfaces in response to interferon-gamma (IFN-γ), a cytokine which is produced by activated NK cells. We hypothesized that the resistance of tumor cells to NK cell killing could be overcome by expression of the parainfluenza virus 5 (PIV5) V protein, which has known roles in blocking IFN-γ signaling. This was tested with human PM21-NK cells produced through a previously developed particle-based method which yields superior NK cells for immunotherapeutic applications. Infection of human SK-N-SH neuroblastoma cells with PIV5 blocked IFN-γ-mediated upregulation of three NK cell inhibitory ligands and enhanced in vitro killing of these tumor cells by PM21-NK cells. SK-N-SH cells transduced to constitutively express the V protein alone were resistant to IFN-γ-mediated increases in cell surface expression of NK cell inhibitory ligands. Real-time in vitro cell viability assays demonstrated that V protein expression in SK-N-SH cells was sufficient to increase PM21-NK cell-mediated killing. Toward a potential therapeutic application, transient lentiviral delivery of the V gene also enhanced PM21-NK cell killing in vitro. Our results provide the foundation for novel therapeutic applications of V protein expression in combination with ex vivo NK cell therapy to effectively increase the killing of tumor cells.
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Affiliation(s)
| | | | | | - Griffith D. Parks
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA; (E.M.S.); (J.L.O.); (A.J.C.)
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18
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Jiao Y, Zhao P, Xu LD, Yu JQ, Cai HL, Zhang C, Tong C, Yang YL, Xu P, Sun Q, Chen N, Wang B, Huang YW. Enteric coronavirus nsp2 is a virulence determinant that recruits NBR1 for autophagic targeting of TBK1 to diminish the innate immune response. Autophagy 2024; 20:1762-1779. [PMID: 38597182 PMCID: PMC11262224 DOI: 10.1080/15548627.2024.2340420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 03/30/2024] [Accepted: 04/04/2024] [Indexed: 04/11/2024] Open
Abstract
Non-structural protein 2 (nsp2) exists in all coronaviruses (CoVs), while its primary function in viral pathogenicity, is largely unclear. One such enteric CoV, porcine epidemic diarrhea virus (PEDV), causes high mortality in neonatal piglets worldwide. To determine the biological role of nsp2, we generated a PEDV mutant containing a complete nsp2 deletion (rPEDV-Δnsp2) from a highly pathogenic strain by reverse genetics, showing that nsp2 was dispensable for PEDV infection, while its deficiency reduced viral replication in vitro. Intriguingly, rPEDV-Δnsp2 was entirely avirulent in vivo, with significantly increased productions of IFNB (interferon beta) and IFN-stimulated genes (ISGs) in various intestinal tissues of challenged newborn piglets. Notably, nsp2 targets and degrades TBK1 (TANK binding kinase 1), the critical kinase in the innate immune response. Mechanistically, nsp2 induced the macroautophagy/autophagy process and recruited a selective autophagic receptor, NBR1 (NBR1 autophagy cargo receptor). NBR1 subsequently facilitated the K48-linked ubiquitination of TBK1 and delivered it for autophagosome-mediated degradation. Accordingly, the replication of rPEDV-Δnsp2 CoV was restrained by reduced autophagy and excess productions of type I IFNs and ISGs. Our data collectively define enteric CoV nsp2 as a novel virulence determinant, propose a crucial role of nsp2 in diminishing innate antiviral immunity by targeting TBK1 for NBR1-mediated selective autophagy, and pave the way to develop a new type of nsp2-based attenuated PEDV vaccine. The study also provides new insights into the prevention and treatment of other pathogenic CoVs.Abbreviations: 3-MA: 3-methyladenine; Baf A1: bafilomycin A1; CoV: coronavirus; CQ: chloroquine; dpi: days post-inoculation; DMVs: double-membrane vesicles; GABARAP: GABA type A receptor-associated protein; GFP: green fluorescent protein; GIGYF2: GRB10 interacting GYF protein 2; hpi: hours post-infection; IFA: immunofluorescence assay; IFIH1: interferon induced with helicase C domain 1; IFIT2: interferon induced protein with tetratricopeptide repeats 2; IFITM1: interferon induced transmembrane protein 1; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISGs: interferon-stimulated genes; mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; NBR1: NBR1 autophagy cargo receptor; nsp2: non-structural protein 2; OAS1: 2'-5'-oligoadenylate synthetase 1; PEDV: porcine epidemic diarrhea virus; PRRs: pattern recognition receptors; RIGI: RNA sensor RIG-I; RT-qPCR: reverse transcription quantitative polymerase chain reaction; SQSTM1: sequestosome 1; TBK1: TANK binding kinase 1; TCID50: 50% tissue culture infectious doses; VSV: vesicular stomatitis virus.
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Affiliation(s)
- Yajuan Jiao
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Pengwei Zhao
- Department of Biochemistry and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ling-Dong Xu
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Jia-Qi Yu
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
| | - Hou-Li Cai
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
| | - Chong Zhang
- Boehringer Ingelheim Vetmedica (China) Co. Ltd, Taizhou, China
| | - Chao Tong
- Boehringer Ingelheim Vetmedica (China) Co. Ltd, Taizhou, China
| | - Yong-Le Yang
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
| | - Pinglong Xu
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Qiming Sun
- Department of Biochemistry and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ning Chen
- Boehringer Ingelheim Vetmedica (China) Co. Ltd, Taizhou, China
| | - Bin Wang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Yao-Wei Huang
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China
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Sabir AJ, Rong L, Broder CC, Amaya M. Cedar virus biology and its applications as a surrogate for highly pathogenic henipaviruses. CELL INSIGHT 2024; 3:100181. [PMID: 39967899 PMCID: PMC11832809 DOI: 10.1016/j.cellin.2024.100181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 06/28/2024] [Accepted: 06/28/2024] [Indexed: 02/20/2025]
Abstract
Nipah Virus (NiV) and Hendra Virus (HeV), are the prototype species of the genus Henipavirus and are highly pathogenic agents capable of causing fatal diseases in both animals and humans. Both NiV and HeV are classified as biosafety level-4 (BSL-4) restricted pathogens and remain the only henipaviruses within the genus known to cause systemic, severe respiratory and encephalitic henipaviral disease, and represent substantial transboundary threats. There are no approved prophylactic or therapeutic treatments for human henipavirus infections, and the World Health Organization acknowledges them as priority pathogens needing urgent research. The discovery of Cedar virus (CedV), the only recognized non-pathogenic henipavirus, has provided a number of unique opportunities to study henipavirus and host interactions and also facilitate countermeasure development research at lower BSL-2 containment. This review will highlight the unique aspects of CedV biology and how it has been exploited as a model for developing therapeutic strategies against more virulent henipavirus species.
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Affiliation(s)
- Ahmad Jawad Sabir
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL, 60612, USA
| | - Lijun Rong
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL, 60612, USA
| | - Christopher C. Broder
- Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, 20814, USA
| | - Moushimi Amaya
- Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, 20814, USA
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20
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Sarkar P, Gopi P, Pandya P, Paria S, Hossain M, Siddiqui MH, Alamri S, Bhadra K. Insights on the comparative affinity of ribonucleic acids with plant-based beta carboline alkaloid, harmine: Spectroscopic, calorimetric and computational evaluation. Heliyon 2024; 10:e34183. [PMID: 39100473 PMCID: PMC11295990 DOI: 10.1016/j.heliyon.2024.e34183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 07/04/2024] [Accepted: 07/04/2024] [Indexed: 08/06/2024] Open
Abstract
Small molecules as ligands target multifunctional ribonucleic acids (RNA) for therapeutic engagement. This study explores how the anticancer DNA intercalator harmine interacts various motifs of RNAs, including the single-stranded A-form poly (rA), the clover leaf tRNAphe, and the double-stranded A-form poly (rC)-poly (rG). Harmine showed the affinity to the polynucleotides in the order, poly (rA) > tRNAphe > poly (rC)·poly (rG). While no induced circular dichroism change was detected with poly (rC)poly (rG), significant structural alterations of poly (rA) followed by tRNAphe and occurrence of concurrent initiation of optical activity in the attached achiral molecule of alkaloid was reported. At 25 °C, the affinity further showed exothermic and entropy-driven binding. The interaction also highlighted heat capacity (ΔC o p ) and Gibbs energy contribution from the hydrophobic transfer (ΔG hyd) of binding with harmine. Molecular docking calculations indicated that harmine exhibits higher affinity for poly (rA) compared to tRNAphe and poly (rC)·poly (rG). Subsequent molecular dynamics simulations were conducted to investigate the binding mode and stability of harmine with poly(A), tRNAphe, and poly (rC)·poly (rG). The results revealed that harmine adopts a partial intercalative binding with poly (rA) and tRNAphe, characterized by pronounced stacking forces and stronger binding free energy observed with poly (rA), while a comparatively weaker binding free energy was observed with tRNAphe. In contrast, the stacking forces with poly (rC)·poly (rG) were comparatively less pronounced and adopts a groove binding mode. It was also supported by ferrocyanide quenching analysis. All these findings univocally provide detailed insight into the binding specificity of harmine, to single stranded poly (rA) over other RNA motifs, probably suggesting a self-structure formation in poly (rA) with harmine and its potential as a lead compound for RNA based drug targeting.
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Affiliation(s)
- Paromita Sarkar
- University of Kalyani, Department of Zoology, Nadia, W. Bengal, 741235, India
| | - Priyanka Gopi
- Amity Institute of Forensic Sciences, Amity University, Noida, Uttar Pradesh, India
| | - Prateek Pandya
- Amity Institute of Forensic Sciences, Amity University, Noida, Uttar Pradesh, India
| | - Samaresh Paria
- Vidyasagar University, Department of Chemistry, Midnapore 721 102, West Bengal, India
| | - Maidul Hossain
- Vidyasagar University, Department of Chemistry, Midnapore 721 102, West Bengal, India
| | - Manzer H. Siddiqui
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Saud Alamri
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Kakali Bhadra
- University of Kalyani, Department of Zoology, Nadia, W. Bengal, 741235, India
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21
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Lukoszek R, Inesta-Vaquera F, Brett NJM, Liang S, Hepburn LA, Hughes DJ, Pirillo C, Roberts EW, Cowling VH. CK2 phosphorylation of CMTR1 promotes RNA cap formation and influenza virus infection. Cell Rep 2024; 43:114405. [PMID: 38923463 PMCID: PMC11290353 DOI: 10.1016/j.celrep.2024.114405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/12/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
The RNA cap methyltransferase CMTR1 methylates the first transcribed nucleotide of RNA polymerase II transcripts, impacting gene expression mechanisms, including during innate immune responses. Using mass spectrometry, we identify a multiply phosphorylated region of CMTR1 (phospho-patch [P-Patch]), which is a substrate for the kinase CK2 (casein kinase II). CMTR1 phosphorylation alters intramolecular interactions, increases recruitment to RNA polymerase II, and promotes RNA cap methylation. P-Patch phosphorylation occurs during the G1 phase of the cell cycle, recruiting CMTR1 to RNA polymerase II during a period of rapid transcription and RNA cap formation. CMTR1 phosphorylation is required for the expression of specific RNAs, including ribosomal protein gene transcripts, and promotes cell proliferation. CMTR1 phosphorylation is also required for interferon-stimulated gene expression. The cap-snatching virus, influenza A, utilizes host CMTR1 phosphorylation to produce the caps required for virus production and infection. We present an RNA cap methylation control mechanism whereby CK2 controls CMTR1, enhancing co-transcriptional capping.
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Affiliation(s)
| | - Francisco Inesta-Vaquera
- School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK; Department of Biochemistry and Molecular Biology and Genetics, School of Sciences, Universidad de Extremadura, Avenida de Elvas, s/n, 06006 Badajoz, Spain
| | - Natasha J M Brett
- School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK; Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK
| | - Shang Liang
- Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Lydia A Hepburn
- Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - David J Hughes
- School of Biology, University of St Andrews, Biomedical Sciences Research Complex, St Andrews KY16 9ST, UK
| | - Chiara Pirillo
- Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Edward W Roberts
- Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK
| | - Victoria H Cowling
- School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK; Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK.
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22
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Geng Y, Jiang C, Yang H, Xia Q, Xu X, Yang K, Yuan X, Chen J, Chen Y, Chen X, Zhang L, Hu C, Guo A. Construction of an IFNAR1 knockout MDBK cell line using CRISPR/Cas9 and its effect on bovine virus replication. Front Immunol 2024; 15:1404649. [PMID: 39100665 PMCID: PMC11294105 DOI: 10.3389/fimmu.2024.1404649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 07/08/2024] [Indexed: 08/06/2024] Open
Abstract
The type I interferon (IFN) pathway is important for eukaryotic cells to resist viral infection, as well as an impediment to efficient virus replication. Therefore, this study aims to create an IFNAR1 knockout (KO) Madin-Darby bovine kidney (MDBK) cell line using CRISPR/Cas9 and investigate its application and potential mechanism in increasing viral replication of bovines. The IFNAR1 KO cells showed increased titers of bovine viral diarrhea virus (BVDV) (1.5 log10), with bovine enterovirus and bovine parainfluenza virus type 3 (0.5-0.8 log10). RNA-seq revealed reduced expression of the genes related IFN-I pathways including IFNAR1, STAT3, IRF9, and SOCS3 in IFNAR1 KO cells compared with WT cells. In WT cells, 306 differentially expressed genes (DEGs) were identified between BVDV-infected and -uninfected cells. Of these, 128 up- and 178 down-regulated genes were mainly associated with growth cycle and biosynthesis, respectively. In IFNAR1 KO cells, 286 DEGs were identified, with 82 up-regulated genes were associated with signaling pathways, and 204 down-regulated genes. Further, 92 DEGs were overlapped between WT and IFNAR1 KO cells including ESM1, IL13RA2, and SLC25A34. Unique DEGs in WT cells were related to inflammation and immune regulation, whereas those unique in IFNAR1 KO cells involved in cell cycle regulation through pathways such as MAPK. Knocking down SLC25A34 and IL13RA2 in IFNAR1 KO cells increased BVDV replication by 0.3 log10 and 0.4 log10, respectively. Additionally, we constructed an IFNAR1/IFNAR2 double-knockout MDBK cell line, which further increased BVDV viral titers compared with IFNAR1 KO cells (0.6 log10). Overall, the IFNAR1 KO MDBK cell line can support better replication of bovine viruses and therefore provides a valuable tool for bovine virus research on viral pathogenesis and host innate immune response.
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Affiliation(s)
- Yuanchen Geng
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Chuanwen Jiang
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Hao Yang
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Qing Xia
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Xiaowen Xu
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Kaihui Yang
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Xinwei Yuan
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Jianguo Chen
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Yingyu Chen
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Xi Chen
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Lei Zhang
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Changmin Hu
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
| | - Aizhen Guo
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture and Rural Affair, Wuhan, China
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23
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Wu CC, Tam EH, Shih YY, Lin YR, Hsueh PC, Shen HY, Woung CH, Wang LT, Tsai JC, Lin SJ, Chang CR, Ke PY, Kuo RL. Exploration of influenza A virus PA protein-associated cellular proteins discloses its impact on mitochondrial function. Virus Res 2024; 345:199387. [PMID: 38719025 PMCID: PMC11109008 DOI: 10.1016/j.virusres.2024.199387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/08/2024] [Accepted: 05/02/2024] [Indexed: 05/16/2024]
Abstract
Influenza A virus can infect respiratory tracts and may cause severe illness in humans. Proteins encoded by influenza A virus can interact with cellular factors and dysregulate host biological processes to support viral replication and cause pathogenicity. The influenza viral PA protein is not only a subunit of influenza viral polymerase but also a virulence factor involved in pathogenicity during infection. To explore the role of the influenza virus PA protein in regulating host biological processes, we performed immunoprecipitation and LC‒MS/MS to globally identify cellular factors that interact with the PA proteins of the influenza A H1N1, 2009 pandemic H1N1, and H3N2 viruses. The results demonstrated that proteins located in the mitochondrion, proteasome, and nucleus are associated with the PA protein. We further discovered that the PA protein is partly located in mitochondria by immunofluorescence and mitochondrial fractionation and that overexpression of the PA protein reduces mitochondrial respiration. In addition, our results revealed the interaction between PA and the mitochondrial matrix protein PYCR2 and the antiviral role of PYCR2 during influenza A virus replication. Moreover, we found that the PA protein could also trigger autophagy and disrupt mitochondrial homeostasis. Overall, our research revealed the impacts of the influenza A virus PA protein on mitochondrial function and autophagy.
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Affiliation(s)
- Chih-Ching Wu
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Otolaryngology-Head & Neck Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ee-Hong Tam
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Yin Shih
- Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Ru Lin
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Pei-Chun Hsueh
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hsiang-Yi Shen
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chian-Huey Woung
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Li-Ting Wang
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jia-Chen Tsai
- Department of Medical Science, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Syh-Jae Lin
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chuang-Rung Chang
- Department of Medical Science, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Po-Yuan Ke
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rei-Lin Kuo
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
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24
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Wallace R, Bliss CM, Parker AL. The Immune System-A Double-Edged Sword for Adenovirus-Based Therapies. Viruses 2024; 16:973. [PMID: 38932265 PMCID: PMC11209478 DOI: 10.3390/v16060973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/12/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Pathogenic adenovirus (Ad) infections are widespread but typically mild and transient, except in the immunocompromised. As vectors for gene therapy, vaccine, and oncology applications, Ad-based platforms offer advantages, including ease of genetic manipulation, scale of production, and well-established safety profiles, making them attractive tools for therapeutic development. However, the immune system often poses a significant challenge that must be overcome for adenovirus-based therapies to be truly efficacious. Both pre-existing anti-Ad immunity in the population as well as the rapid development of an immune response against engineered adenoviral vectors can have detrimental effects on the downstream impact of an adenovirus-based therapeutic. This review focuses on the different challenges posed, including pre-existing natural immunity and anti-vector immunity induced by a therapeutic, in the context of innate and adaptive immune responses. We summarise different approaches developed with the aim of tackling these problems, as well as their outcomes and potential future applications.
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Affiliation(s)
- Rebecca Wallace
- Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; (R.W.); (C.M.B.)
| | - Carly M. Bliss
- Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; (R.W.); (C.M.B.)
- Systems Immunity University Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Alan L. Parker
- Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; (R.W.); (C.M.B.)
- Systems Immunity University Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
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25
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Efstathiou C, Zhang Y, Kandwal S, Fayne D, Molloy EJ, Stevenson NJ. Respiratory syncytial virus NS1 inhibits anti-viral Interferon-α-induced JAK/STAT signaling, by limiting the nuclear translocation of STAT1. Front Immunol 2024; 15:1395809. [PMID: 38938568 PMCID: PMC11208467 DOI: 10.3389/fimmu.2024.1395809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/06/2024] [Indexed: 06/29/2024] Open
Abstract
Human respiratory viruses are the most prevalent cause of disease in humans, with the highly infectious RSV being the leading cause of infant bronchiolitis and viral pneumonia. Responses to type I IFNs are the primary defense against viral infection. However, RSV proteins have been shown to antagonize type I IFN-mediated antiviral innate immunity, specifically dampening intracellular IFN signaling. Respiratory epithelial cells are the main target for RSV infection. In this study, we found RSV-NS1 interfered with the IFN-α JAK/STAT signaling pathway of epithelial cells. RSV-NS1 expression significantly enhanced IFN-α-mediated phosphorylation of STAT1, but not pSTAT2; and neither STAT1 nor STAT2 total protein levels were affected by RSV-NS1. However, expression of RSV-NS1 significantly reduced ISRE and GAS promoter activity and anti-viral IRG expression. Further mechanistic studies demonstrated RSV-NS1 bound STAT1, with protein modeling indicating a possible interaction site between STAT1 and RSV-NS1. Nuclear translocation of STAT1 was reduced in the presence of RSV-NS1. Additionally, STAT1's interaction with the nuclear transport adapter protein, KPNA1, was also reduced, suggesting a mechanism by which RSV blocks STAT1 nuclear translocation. Indeed, reducing STAT1's access to the nucleus may explain RSV's suppression of IFN JAK/STAT promoter activation and antiviral gene induction. Taken together these results describe a novel mechanism by which RSV controls antiviral IFN-α JAK/STAT responses, which enhances our understanding of RSV's respiratory disease progression.
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Affiliation(s)
- Claudia Efstathiou
- Viral Immunology Group, Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Yamei Zhang
- Viral Immunology Group, Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Shubhangi Kandwal
- Molecular Design Group, School of Chemical Sciences, Dublin City University, Glasnevin, Ireland
- Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Darren Fayne
- Molecular Design Group, School of Chemical Sciences, Dublin City University, Glasnevin, Ireland
- DCU Life Sciences Institute, Dublin City University, Dublin, Ireland
| | - Eleanor J. Molloy
- Paediatrics, Trinity College, Dublin, Ireland
- Neonatology, Children’s Hospital Ireland at Tallaght, Dublin, Ireland
- Neonatology, Coombe Women’s and Infants University Hospital, Dublin, Ireland
| | - Nigel J. Stevenson
- Viral Immunology Group, Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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26
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Kamel R, Aman R, Mahfouz MM. Viperin-like proteins interfere with RNA viruses in plants. FRONTIERS IN PLANT SCIENCE 2024; 15:1385169. [PMID: 38895613 PMCID: PMC11185175 DOI: 10.3389/fpls.2024.1385169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024]
Abstract
Plant viruses cause substantial losses in crop yield and quality; therefore, devising new, robust strategies to counter viral infections has important implications for agriculture. Virus inhibitory protein endoplasmic reticulum-associated interferon-inducible (Viperin) proteins are conserved antiviral proteins. Here, we identified a set of Viperin and Viperin-like proteins from multiple species and tested whether they could interfere with RNA viruses in planta. Our data from transient and stable overexpression of these proteins in Nicotiana benthamiana reveal varying levels of interference against the RNA viruses tobacco mosaic virus (TMV), turnip mosaic virus (TuMV), and potato virus x (PVX). Harnessing the potential of these proteins represents a novel avenue in plant antiviral approaches, offering a broader and more effective spectrum for application in plant biotechnology and agriculture. Identifying these proteins opens new avenues for engineering a broad range of resistance to protect crop plants against viral pathogens.
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Affiliation(s)
| | | | - Magdy M. Mahfouz
- Laboratory for Genome Engineering and Synthetic Biology, Division of Biological Sciences, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
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27
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Lo Cigno I, Calati F, Girone C, Catozzo M, Gariglio M. High-risk HPV oncoproteins E6 and E7 and their interplay with the innate immune response: Uncovering mechanisms of immune evasion and therapeutic prospects. J Med Virol 2024; 96:e29685. [PMID: 38783790 DOI: 10.1002/jmv.29685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/22/2024] [Accepted: 05/10/2024] [Indexed: 05/25/2024]
Abstract
Human papillomaviruses (HPVs) are double-stranded DNA (dsDNA) tumor viruses causally associated with 5% of human cancers, comprising both anogenital and upper aerodigestive tract carcinomas. Despite the availability of prophylactic vaccines, HPVs continue to pose a significant global health challenge, primarily due to inadequate vaccine access and coverage. These viruses can establish persistent infections by evading both the intrinsic defenses of infected tissues and the extrinsic defenses provided by professional innate immune cells. Crucial for their evasion strategies is their unique intraepithelial life cycle, which effectively shields them from host detection. Thus, strategies aimed at reactivating the innate immune response within infected or transformed epithelial cells, particularly through the production of type I interferons (IFNs) and lymphocyte-recruiting chemokines, are considered viable solutions to counteract the adverse effects of persistent infections by these oncogenic viruses. This review focuses on the complex interplay between the high-risk HPV oncoproteins E6 and E7 and the innate immune response in epithelial cells and HPV-associated cancers. In particular, it details the molecular mechanisms by which E6 and E7 modulate the innate immune response, highlighting significant progress in our comprehension of these processes. It also examines forward-looking strategies that exploit the innate immune system to ameliorate existing anticancer therapies, thereby providing crucial insights into future therapeutic developments.
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Affiliation(s)
- Irene Lo Cigno
- Virology Unit, Department of Translational Medicine, Eastern Piedmont University, Novara, Italy
| | - Federica Calati
- Virology Unit, Department of Translational Medicine, Eastern Piedmont University, Novara, Italy
| | - Carlo Girone
- Virology Unit, Department of Translational Medicine, Eastern Piedmont University, Novara, Italy
| | - Marta Catozzo
- Virology Unit, Department of Translational Medicine, Eastern Piedmont University, Novara, Italy
| | - Marisa Gariglio
- Virology Unit, Department of Translational Medicine, Eastern Piedmont University, Novara, Italy
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28
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Li W, Wang Z, Liang J, Xia B, Chen R, Chen T. Role of Medaka ( Oryzias latipes) Foxo3 in Resistance to Nervous Necrosis Virus Infection. Animals (Basel) 2024; 14:1587. [PMID: 38891634 PMCID: PMC11171044 DOI: 10.3390/ani14111587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 05/24/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
Upon encountering a virus, fish initiate an innate immune response, guided by IFNs. Foxo3 plays a part in the body's immune response; however, its specific role in the IFN-guided immune response in fish is yet to be clarified. In this study, we characterized foxo3 in Japanese medaka (Oryzias latipes) and examined its role in the IFN-dependent immune response upon infection with the RGNNV. The results show that the coding region of the medaka foxo3 gene is 2007 base pairs long, encoding 668 amino acids, and possesses a typical forkhead protein family structural domain. The product of this gene shares high homology with foxo3 in other fish species and is widely expressed, especially in the brain, eyes, testes, and heart. Upon RGNNV infection, foxo3-/- mutant larvae showed a lower mortality rate, and adults exhibited a significant reduction in virus replication. Moreover, the absence of foxo3 expression led to an increase in the expression of irf3, and a decrease in the expression of other IFN-related genes such as tbk1 and mapk9, implying that foxo3 may function as a negative regulator in the antiviral signaling pathway. These findings provide crucial insights for disease-resistant breeding in the aquaculture industry.
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Affiliation(s)
- Wen Li
- State Key Laboratory of Mariculture Breeding, Fisheries College of Jimei University, Xiamen 361021, China; (W.L.); (J.L.); (R.C.)
- Engineering Research Center of the Modern Technology for Eel Industry, Xiamen 361021, China
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Xiamen 361021, China
| | - Zhi Wang
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (Z.W.); (B.X.)
| | - Jingjie Liang
- State Key Laboratory of Mariculture Breeding, Fisheries College of Jimei University, Xiamen 361021, China; (W.L.); (J.L.); (R.C.)
- Engineering Research Center of the Modern Technology for Eel Industry, Xiamen 361021, China
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Xiamen 361021, China
| | - Bilin Xia
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (Z.W.); (B.X.)
| | - Ruoxue Chen
- State Key Laboratory of Mariculture Breeding, Fisheries College of Jimei University, Xiamen 361021, China; (W.L.); (J.L.); (R.C.)
- Engineering Research Center of the Modern Technology for Eel Industry, Xiamen 361021, China
| | - Tiansheng Chen
- State Key Laboratory of Mariculture Breeding, Fisheries College of Jimei University, Xiamen 361021, China; (W.L.); (J.L.); (R.C.)
- Engineering Research Center of the Modern Technology for Eel Industry, Xiamen 361021, China
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Xiamen 361021, China
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29
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Velderrain-Armenta F, González-Ochoa G, Tamez-Guerra P, Romero-Arguelles R, Romo-Sáenz CI, Gomez-Flores R, Flores-Mendoza L, Icedo-García R, Soñanez-Organis JG. Bifidobacterium longum and Chlorella sorokiniana Combination Modulates IFN-γ, IL-10, and SOCS3 in Rotavirus-Infected Cells. Int J Mol Sci 2024; 25:5514. [PMID: 38791551 PMCID: PMC11122607 DOI: 10.3390/ijms25105514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/14/2024] [Accepted: 05/17/2024] [Indexed: 05/26/2024] Open
Abstract
Rotavirus is the main cause of acute diarrhea in children up to five years of age. In this regard, probiotics are commonly used to treat or prevent gastroenteritis including viral infections. The anti-rotavirus effect of Bifidobacterium longum and Chlorella sorokiniana, by reducing viral infectivity and improving IFN-type I response, has been previously reported. The present study aimed to study the effect of B. longum and/or C. sorokiniana on modulating the antiviral cellular immune response mediated by IFN-γ, IL-10, SOCS3, STAT1, and STAT2 genes in rotavirus-infected cells. To determine the mRNA relative expression of these genes, HT-29 cells were treated with B. longum and C. sorokiniana alone or in combination, followed by rotavirus infection. In addition, infected cells were treated with B. longum and/or C. sorokiniana. Cellular RNA was purified, used for cDNA synthesis, and amplified by qPCR. Our results demonstrated that the combination of B. longum and C. sorokiniana stimulates the antiviral cellular immune response by upregulating IFN-γ and may block pro-inflammatory cytokines by upregulating IL-10 and SOCS3. The results of our study indicated that B. longum, C. sorokiniana, or their combination improve antiviral cellular immune response and might modulate pro-inflammatory responses.
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Affiliation(s)
- Felizardo Velderrain-Armenta
- Department of Chemistry-Biology and Agriculture, Interdisciplinary Faculty of Biology Sciences and Health, University of Sonora, Navojoa C.P. 85880, Mexico; (F.V.-A.); (L.F.-M.); (R.I.-G.); (J.G.S.-O.)
| | - Guadalupe González-Ochoa
- Department of Chemistry-Biology and Agriculture, Interdisciplinary Faculty of Biology Sciences and Health, University of Sonora, Navojoa C.P. 85880, Mexico; (F.V.-A.); (L.F.-M.); (R.I.-G.); (J.G.S.-O.)
| | - Patricia Tamez-Guerra
- Laboratory of Immunology and Virology, Falculty of Biological Sciences, Autonomous University of Nuevo Leon, San Nicolás de los Garza C.P. 66455, Mexico; (R.R.-A.); (C.I.R.-S.); (R.G.-F.)
| | - Ricardo Romero-Arguelles
- Laboratory of Immunology and Virology, Falculty of Biological Sciences, Autonomous University of Nuevo Leon, San Nicolás de los Garza C.P. 66455, Mexico; (R.R.-A.); (C.I.R.-S.); (R.G.-F.)
| | - César I. Romo-Sáenz
- Laboratory of Immunology and Virology, Falculty of Biological Sciences, Autonomous University of Nuevo Leon, San Nicolás de los Garza C.P. 66455, Mexico; (R.R.-A.); (C.I.R.-S.); (R.G.-F.)
| | - Ricardo Gomez-Flores
- Laboratory of Immunology and Virology, Falculty of Biological Sciences, Autonomous University of Nuevo Leon, San Nicolás de los Garza C.P. 66455, Mexico; (R.R.-A.); (C.I.R.-S.); (R.G.-F.)
| | - Lilian Flores-Mendoza
- Department of Chemistry-Biology and Agriculture, Interdisciplinary Faculty of Biology Sciences and Health, University of Sonora, Navojoa C.P. 85880, Mexico; (F.V.-A.); (L.F.-M.); (R.I.-G.); (J.G.S.-O.)
| | - Ramona Icedo-García
- Department of Chemistry-Biology and Agriculture, Interdisciplinary Faculty of Biology Sciences and Health, University of Sonora, Navojoa C.P. 85880, Mexico; (F.V.-A.); (L.F.-M.); (R.I.-G.); (J.G.S.-O.)
| | - José G. Soñanez-Organis
- Department of Chemistry-Biology and Agriculture, Interdisciplinary Faculty of Biology Sciences and Health, University of Sonora, Navojoa C.P. 85880, Mexico; (F.V.-A.); (L.F.-M.); (R.I.-G.); (J.G.S.-O.)
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30
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Giessler KS, Goehring LS, Jacob SI, Davis A, Esser MM, Lee Y, Zarski LM, Weber PSD, Hussey GS. Impact of the host immune response on the development of equine herpesvirus myeloencephalopathy in horses. J Gen Virol 2024; 105:001987. [PMID: 38767608 PMCID: PMC11170125 DOI: 10.1099/jgv.0.001987] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 04/25/2024] [Indexed: 05/22/2024] Open
Abstract
Herpesviruses establish a well-adapted balance with their host's immune system. Despite this co-evolutionary balance, infections can lead to severe disease including neurological disorders in their natural host. In horses, equine herpesvirus 1 (EHV-1) causes respiratory disease, abortions, neonatal foal death and myeloencephalopathy (EHM) in ~10 % of acute infections worldwide. Many aspects of EHM pathogenesis and protection from EHM are still poorly understood. However, it has been shown that the incidence of EHM increases to >70 % in female horses >20 years of age. In this study we used old mares as an experimental equine EHV-1 model of EHM to identify host-specific factors contributing to EHM. Following experimental infection with the neuropathogenic strain EHV-1 Ab4, old mares and yearling horses were studied for 21 days post-infection. Nasal viral shedding and cell-associated viremia were assessed by quantitative PCR. Cytokine/chemokine responses were evaluated in nasal secretions and cerebrospinal fluid (CSF) by Luminex assay and in whole blood by quantitative real-time PCR. EHV-1-specific IgG sub-isotype responses were measured by ELISA. All young horses developed respiratory disease and a bi-phasic fever post-infection, but only 1/9 horses exhibited ataxia. In contrast, respiratory disease was absent in old mares, but all old mares developed EHM that resulted in euthanasia in 6/9 old mares. Old mares also presented significantly decreased nasal viral shedding but higher viremia coinciding with a single fever peak at the onset of viremia. According to clinical disease manifestation, horses were sorted into an EHM group (nine old horses and one young horse) and a non-EHM group (eight young horses) for assessment of host immune responses. Non-EHM horses showed an early upregulation of IFN-α (nasal secretions), IRF7/IRF9, IL-1β, CXCL10 and TBET (blood) in addition to an IFN-γ upregulation during viremia (blood). In contrast, IFN-α levels in nasal secretions of EHM horses were low and peak levels of IRF7, IRF9, CXCL10 and TGF-β (blood) coincided with viremia. Moreover, EHM horses showed significantly higher IL-10 levels in nasal secretions, peripheral blood mononuclear cells and CSF and higher serum IgG3/5 antibody titres compared to non-EHM horses. These results suggest that protection from EHM depends on timely induction of type 1 IFN and upregulation cytokines and chemokines that are representative of cellular immunity. In contrast, induction of regulatory or TH-2 type immunity appeared to correlate with an increased risk for EHM. It is likely that future vaccine development for protection from EHM must target shifting this 'at-risk' immunophenotype.
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Affiliation(s)
- K. S. Giessler
- Department of Pathobiology & Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
- Bavarian Health and Food Safety Authority, Oberschleissheim, Germany
| | - L. S. Goehring
- MH Gluck Equine Research Center, College of Agriculture, Food & Environment, University of Kentucky, Lexington, KY, USA
| | - S. I. Jacob
- Department of Pathobiology & Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Allison Davis
- Department of Pathobiology & Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - M. M. Esser
- Department of Pathobiology & Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Y. Lee
- Pathology Core, Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - L. M. Zarski
- Department of Pathobiology & Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - P. S. D. Weber
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - G. S. Hussey
- Department of Pathobiology & Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
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31
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Winther K, Kristensen C, Henriksen BL, Hansen LHB, Ryt-Hansen P, Vestergaard G, Skovgaard K, Sandvang D, Boll EJ, Williams AR, Larsen LE. Bacillus subtilis-597 induces changes in lung pathology and inflammation during influenza A virus infection in pigs. Vet Microbiol 2024; 291:110032. [PMID: 38430715 DOI: 10.1016/j.vetmic.2024.110032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 02/15/2024] [Accepted: 02/20/2024] [Indexed: 03/05/2024]
Abstract
In recent years, it has become apparent that imbalances in the gastrointestinal system can impact organs beyond the intestine such as the lungs. Given the established ability of probiotics to modulate the immune system by interacting with gastrointestinal cells, our research aimed to investigate whether administering the probiotic strain Bacillus subtilis-597 could mitigate the outcome of influenza virus infection in pigs. Pigs were fed a diet either with or without the probiotic strain B. subtilis-597 for 14 days before being intranasally inoculated with a swine influenza A H1N2 strain (1 C.2 lineage). Throughout the study, we collected fecal samples, blood samples, and nasal swabs to examine viral shedding and immune gene expression. After seven days of infection, the pigs were euthanized, and lung and ileum tissues were collected for gene expression analysis and pathological examination. Our findings indicate that the administration of B. subtilis-597 exhibit potential in reducing lung lesions, possibly attributable to a general suppression of the immune system as indicated by reduced C-reactive protein (CRP) levels in serum, decreased expression of interferon-stimulated genes (ISGs), and localized reduction of the inflammatory marker serum amyloid A (SAA) in ileum tissue. Notably, the immune-modulatory effects of B. subtilis-597 appeared to be unrelated to the gastrointestinal microbiota, as the composition remained unaltered by both the influenza infection and the administration of B. subtilis-597.
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Affiliation(s)
- Katrine Winther
- Animal and Plant Health & Nutrition, Chr. Hansen A/S, Hoersholm, Denmark; Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Charlotte Kristensen
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | | | | | - Pia Ryt-Hansen
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Gisle Vestergaard
- Animal and Plant Health & Nutrition, Chr. Hansen A/S, Hoersholm, Denmark
| | - Kerstin Skovgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs Lyngby, Denmark
| | - Dorthe Sandvang
- Animal and Plant Health & Nutrition, Chr. Hansen A/S, Hoersholm, Denmark
| | - Erik Juncker Boll
- Animal and Plant Health & Nutrition, Chr. Hansen A/S, Hoersholm, Denmark
| | - Andrew R Williams
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark.
| | - Lars E Larsen
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
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Sengupta P, Chattopadhyay S. Interferons in Viral Infections. Viruses 2024; 16:451. [PMID: 38543816 PMCID: PMC10974426 DOI: 10.3390/v16030451] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 03/12/2024] [Indexed: 05/23/2024] Open
Abstract
Interferons (IFNs) are cytokines that inhibit viral replication in host cells by triggering innate immune responses through the transcriptional induction of various IFN-stimulated genes (ISGs) [...].
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Affiliation(s)
| | - Saurabh Chattopadhyay
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY 40536, USA;
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Dupré J, Le Dimna M, Hutet E, Dujardin P, Fablet A, Leroy A, Fleurot I, Karadjian G, Roesch F, Caballero I, Bourry O, Vitour D, Le Potier MF, Caignard G. Exploring type I interferon pathway: virulent vs. attenuated strain of African swine fever virus revealing a novel function carried by MGF505-4R. Front Immunol 2024; 15:1358219. [PMID: 38529285 PMCID: PMC10961335 DOI: 10.3389/fimmu.2024.1358219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 02/15/2024] [Indexed: 03/27/2024] Open
Abstract
African swine fever virus represents a significant reemerging threat to livestock populations, as its incidence and geographic distribution have surged over the past decade in Europe, Asia, and Caribbean, resulting in substantial socio-economic burdens and adverse effects on animal health and welfare. In a previous report, we described the protective properties of our newly thermo-attenuated strain (ASFV-989) in pigs against an experimental infection of its parental Georgia 2007/1 virulent strain. In this new study, our objective was to characterize the molecular mechanisms underlying the attenuation of ASFV-989. We first compared the activation of type I interferon pathway in response to ASFV-989 and Georgia 2007/1 infections, employing both in vivo and in vitro models. Expression of IFN-α was significantly increased in porcine alveolar macrophages infected with ASFV-989 while pigs infected with Georgia 2007/1 showed higher IFN-α than those infected by ASFV-989. We also used a medium-throughput transcriptomic approach to study the expression of viral genes by both strains, and identified several patterns of gene expression. Subsequently, we investigated whether proteins encoded by the eight genes deleted in ASFV-989 contribute to the modulation of the type I interferon signaling pathway. Using different strategies, we showed that MGF505-4R interfered with the induction of IFN-α/β pathway, likely through interaction with TRAF3. Altogether, our data reveal key differences between ASFV-989 and Georgia 2007/1 in their ability to control IFN-α/β signaling and provide molecular mechanisms underlying the role of MGF505-4R as a virulence factor.
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Affiliation(s)
- Juliette Dupré
- Unité Mixte de Recherche (UMR) VIROLOGIE, Institut National Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École Nationale Vétérinaire d’Alfort (ENVA), Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail (ANSES) Laboratoire de Santé Animale, Université Paris-Est, Maisons-Alfort, France
- Unité Virologie Immunologie Porcines, Laboratoire de Ploufragan-Plouzané-Niort, ANSES, Ploufragan, France
| | - Mireille Le Dimna
- Unité Virologie Immunologie Porcines, Laboratoire de Ploufragan-Plouzané-Niort, ANSES, Ploufragan, France
| | - Evelyne Hutet
- Unité Virologie Immunologie Porcines, Laboratoire de Ploufragan-Plouzané-Niort, ANSES, Ploufragan, France
| | - Pascal Dujardin
- Unité Mixte de Recherche (UMR) VIROLOGIE, Institut National Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École Nationale Vétérinaire d’Alfort (ENVA), Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail (ANSES) Laboratoire de Santé Animale, Université Paris-Est, Maisons-Alfort, France
| | - Aurore Fablet
- Unité Mixte de Recherche (UMR) VIROLOGIE, Institut National Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École Nationale Vétérinaire d’Alfort (ENVA), Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail (ANSES) Laboratoire de Santé Animale, Université Paris-Est, Maisons-Alfort, France
| | - Aurélien Leroy
- UMR 1282 Infectiologie et santé publique (ISP), INRAE Centre Val de Loire, Nouzilly, France
| | - Isabelle Fleurot
- UMR 1282 Infectiologie et santé publique (ISP), INRAE Centre Val de Loire, Nouzilly, France
| | - Grégory Karadjian
- UMR Biologie moléculaire et Immunologie Parasitaires (BIPAR), ENVA-INRAE-ANSES, Laboratoire de Santé Animale, Maisons-Alfort, France
| | - Ferdinand Roesch
- UMR 1282 Infectiologie et santé publique (ISP), INRAE Centre Val de Loire, Nouzilly, France
| | - Ignacio Caballero
- UMR 1282 Infectiologie et santé publique (ISP), INRAE Centre Val de Loire, Nouzilly, France
| | - Olivier Bourry
- Unité Virologie Immunologie Porcines, Laboratoire de Ploufragan-Plouzané-Niort, ANSES, Ploufragan, France
| | - Damien Vitour
- Unité Mixte de Recherche (UMR) VIROLOGIE, Institut National Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École Nationale Vétérinaire d’Alfort (ENVA), Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail (ANSES) Laboratoire de Santé Animale, Université Paris-Est, Maisons-Alfort, France
| | - Marie-Frédérique Le Potier
- Unité Virologie Immunologie Porcines, Laboratoire de Ploufragan-Plouzané-Niort, ANSES, Ploufragan, France
| | - Grégory Caignard
- Unité Mixte de Recherche (UMR) VIROLOGIE, Institut National Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École Nationale Vétérinaire d’Alfort (ENVA), Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail (ANSES) Laboratoire de Santé Animale, Université Paris-Est, Maisons-Alfort, France
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Alakunle E, Kolawole D, Diaz-Cánova D, Alele F, Adegboye O, Moens U, Okeke MI. A comprehensive review of monkeypox virus and mpox characteristics. Front Cell Infect Microbiol 2024; 14:1360586. [PMID: 38510963 PMCID: PMC10952103 DOI: 10.3389/fcimb.2024.1360586] [Citation(s) in RCA: 36] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 02/20/2024] [Indexed: 03/22/2024] Open
Abstract
Monkeypox virus (MPXV) is the etiological agent of monkeypox (mpox), a zoonotic disease. MPXV is endemic in the forested regions of West and Central Africa, but the virus has recently spread globally, causing outbreaks in multiple non-endemic countries. In this paper, we review the characteristics of the virus, including its ecology, genomics, infection biology, and evolution. We estimate by phylogenomic molecular clock that the B.1 lineage responsible for the 2022 mpox outbreaks has been in circulation since 2016. We interrogate the host-virus interactions that modulate the virus infection biology, signal transduction, pathogenesis, and host immune responses. We highlight the changing pathophysiology and epidemiology of MPXV and summarize recent advances in the prevention and treatment of mpox. In addition, this review identifies knowledge gaps with respect to the virus and the disease, suggests future research directions to address the knowledge gaps, and proposes a One Health approach as an effective strategy to prevent current and future epidemics of mpox.
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Affiliation(s)
- Emmanuel Alakunle
- Department of Natural and Environmental Sciences, American University of Nigeria, Yola, Nigeria
| | - Daniel Kolawole
- Department of Natural and Environmental Sciences, American University of Nigeria, Yola, Nigeria
| | - Diana Diaz-Cánova
- Department of Medical Biology, UIT – The Arctic University of Norway, Tromsø, Norway
| | - Faith Alele
- School of Health, University of the Sunshine Coast, Sippy Downs, QLD, Australia
| | - Oyelola Adegboye
- Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia
| | - Ugo Moens
- Department of Medical Biology, UIT – The Arctic University of Norway, Tromsø, Norway
| | - Malachy Ifeanyi Okeke
- Department of Natural and Environmental Sciences, American University of Nigeria, Yola, Nigeria
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Clayton E, Atasoy MO, Naggar RFE, Franco AC, Rohaim MA, Munir M. Interferon-induced protein with tetratricopeptide repeats 5 of black fruit bat ( Pteropus alecto) displays a broad inhibition of RNA viruses. Front Immunol 2024; 15:1284056. [PMID: 38440728 PMCID: PMC10909918 DOI: 10.3389/fimmu.2024.1284056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 01/24/2024] [Indexed: 03/06/2024] Open
Abstract
Bats are natural host reservoirs and have adapted a unique innate immune system that permits them to host many viruses without exhibiting symptoms. Notably, bat interferon stimulated genes (ISGs) have been shown to play antiviral roles. Interferon induced protein with tetratricopeptide repeats 5 (IFIT5) is a well-characterised ISG in humans with antiviral activities against negative-sense RNA viruses via inhibiting viral transcription. Here, we aim to investigate if Pteropus alecto (pa) IFIT5 (paIFIT5) possess the ability to inhibit negative-sense RNA viruses. Initially, gene syntenic and comparative structural analyses of multiple animals highlighted a high level of similarity between Pteropus alecto and human IFIT5 proteins. Our results showed that paIFIT5 was significantly inducible by viral and dsRNA stimulation. Transient overexpression of paIFIT5 inhibited the replication of vesicular stomatitis virus (VSV). Using minireplicon and transcription reporter assays, we demonstrated the ability of paIFIT5 specifically to inhibit H17N10 polymerase activity. Mechanistically, we noticed that the antiviral potential of paIFIT5 against negative sense RNA viruses was retributed to its interaction with 5'ppp containing RNA. Taken together, these findings highlight the genetic and functional conservation of IFIT5 among mammals.
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Affiliation(s)
| | | | | | | | | | - Muhammad Munir
- Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom
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36
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Yang S, Fan Z, Lu X, Liu H, Zhou Z, Qi H, Zeng J, Zheng M, Zou X, Fang S, Zhang G. Response of Human Retinal Microvascular Endothelial Cells to Influenza A (H1N1) Infection and the Underlying Molecular Mechanism. Invest Ophthalmol Vis Sci 2024; 65:38. [PMID: 38252524 PMCID: PMC10810132 DOI: 10.1167/iovs.65.1.38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Purpose Whether H1N1 infection-associated ocular manifestations result from direct viral infections or systemic complications remains unclear. This study aimed to comprehensively elucidate the underlying causes and mechanism. Method TCID50 assays was performed at 24, 48, and 72 hours to verify the infection of H1N1 in human retinal microvascular endothelial cells (HRMECs). The changes in gene expression profiles of HRMECs at 24, 48, and 72 hours were characterized using RNA sequencing technology. Differentially expressed genes (DEGs) were validated using real-time quantitative polymerase chain reaction and Western blotting. CCK-8 assay and scratch assay were performed to evaluate whether there was a potential improvement of proliferation and migration in H1N1-infected cells after oseltamivir intervention. Results H1N1 can infect and replicate within HRMECs, leading to cell rounding and detachment. After H1N1 infection of HRMECs, 2562 DEGs were identified, including 1748 upregulated ones and 814 downregulated ones. These DEGs primarily involved in processes such as inflammation and immune response, cytokine-cytokine receptor interaction, signal transduction regulation, and cell adhesion. The elevated expression levels of CXCL10, CXCL11, CCL5, TLR3, C3, IFNB1, IFNG, STAT1, HLA, and TNFSF10 after H1N1 infection were reduced by oseltamivir intervention, reaching levels comparable to those in the uninfected group. The impaired cell proliferation and migration after H1N1 infection was improved by oseltamivir intervention. Conclusions This study confirmed that H1N1 can infect HRMECs, leading to the upregulation of chemokines, which may cause inflammation and destruction of the blood-retina barrier. Moreover, early oseltamivir administration may reduce retinal inflammation and hemorrhage in patients infected with H1N1.
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Affiliation(s)
- Shuo Yang
- Jinzhou Medical University, Jinzhou, Liaoning, China
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Zixin Fan
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Xiaofeng Lu
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Hui Liu
- Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China
| | - Ziying Zhou
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Hui Qi
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Jian Zeng
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Mianying Zheng
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Xuan Zou
- Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China
| | - Shisong Fang
- Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China
| | - Guoming Zhang
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
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Xu Z, Tian M, Tan Q, Hao P, Gao Z, Li C, Jin N. FHL2 Inhibits SARS-CoV-2 Replication by Enhancing IFN-β Expression through Regulating IRF-3. Int J Mol Sci 2023; 25:353. [PMID: 38203523 PMCID: PMC10778585 DOI: 10.3390/ijms25010353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/14/2023] [Accepted: 12/16/2023] [Indexed: 01/12/2024] Open
Abstract
SARS-CoV-2 triggered the global COVID-19 pandemic, posing a severe threat to public health worldwide. The innate immune response in cells infected by SARS-CoV-2 is primarily orchestrated by type I interferon (IFN), with IFN-β exhibiting a notable inhibitory impact on SARS-CoV-2 replication. FHL2, acting as a docking site, facilitates the assembly of multiprotein complexes and regulates the transcription of diverse genes. However, the association between SARS-CoV-2 and FHL2 remains unclear. In this study, we report for the first time that SARS-CoV-2 infection in Caco2 cells results in the upregulation of FHL2 expression, while the virus's N proteins can enhance FHL2 expression. Notably, the knockdown of FHL2 significantly amplifies SARS-CoV-2 replication in vitro. Conversely, the overexpression of FHL2 leads to a marked reduction in SARS-CoV-2 replication, with the antiviral property of FHL2 being independent of the cell or virus type. Subsequent experiments reveal that FHL2 supports IFN-β transcription by upregulating the expression and phosphorylation of IRF-3, thereby impeding SARS-CoV-2 replication in cells. These findings highlight FHL2 as a potential antiviral target for treating SARS-CoV-2 infections.
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Affiliation(s)
- Zhiqiang Xu
- Agricultural College, Yanbian University, Yanji 133002, China; (Z.X.)
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China; (M.T.)
| | - Mingyao Tian
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China; (M.T.)
| | - Qihan Tan
- Agricultural College, Yanbian University, Yanji 133002, China; (Z.X.)
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China; (M.T.)
| | - Pengfei Hao
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China; (M.T.)
| | - Zihan Gao
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China; (M.T.)
| | - Chang Li
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China; (M.T.)
| | - Ningyi Jin
- Agricultural College, Yanbian University, Yanji 133002, China; (Z.X.)
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China; (M.T.)
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Wang F, Song H, Xu F, Xu J, Wang L, Yang F, Zhu Y, Tan G. Role of hepatitis B virus non-structural protein HBx on HBV replication, interferon signaling, and hepatocarcinogenesis. Front Microbiol 2023; 14:1322892. [PMID: 38188582 PMCID: PMC10767994 DOI: 10.3389/fmicb.2023.1322892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/07/2023] [Indexed: 01/09/2024] Open
Abstract
Hepatitis B, a global health concern caused by the hepatitis B virus (HBV), infects nearly 2 billion individuals worldwide, as reported by the World Health Organization (WHO). HBV, a hepatotropic DNA virus, predominantly targets and replicates within hepatocytes. Those carrying the virus are at increased risk of liver cirrhosis and hepatocellular carcinoma, resulting in nearly 900,000 fatalities annually. The HBV X protein (HBx), encoded by the virus's open reading frame x, plays a key role in its virulence. This protein is integral to viral replication, immune modulation, and liver cancer progression. Despite its significance, the precise molecular mechanisms underlying HBx remain elusive. This review investigates the HBx protein's roles in HBV replication, interferon signaling regulation, and hepatocellular carcinoma progression. By understanding the complex interactions between the virus and its host mediated by HBx, we aim to establish a solid foundation for future research and the development of HBx-targeted therapeutics.
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Affiliation(s)
- Fei Wang
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Hongxiao Song
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Fengchao Xu
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jing Xu
- Health Examination Center, The First Hospital of Jilin University, Changchun, China
| | - Le Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Fan Yang
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yujia Zhu
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Guangyun Tan
- Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
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Boylan BT, Hwang M, Bergmann CC. The Impact of Innate Components on Viral Pathogenesis in the Neurotropic Coronavirus Encephalomyelitis Mouse Model. Viruses 2023; 15:2400. [PMID: 38140641 PMCID: PMC10747027 DOI: 10.3390/v15122400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/04/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Recognition of viruses invading the central nervous system (CNS) by pattern recognition receptors (PRRs) is crucial to elicit early innate responses that stem dissemination. These innate responses comprise both type I interferon (IFN-I)-mediated defenses as well as signals recruiting leukocytes to control the infection. Focusing on insights from the neurotropic mouse CoV model, this review discusses how early IFN-I, fibroblast, and myeloid signals can influence protective anti-viral adaptive responses. Emphasis is placed on three main areas: the importance of coordinating the distinct capacities of resident CNS cells to induce and respond to IFN-I, the effects of select IFN-stimulated genes (ISGs) on host immune responses versus viral control, and the contribution of fibroblast activation and myeloid cells in aiding the access of T cells to the parenchyma. By unraveling how the dysregulation of early innate components influences adaptive immunity and viral control, this review illustrates the combined effort of resident CNS cells to achieve viral control.
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Affiliation(s)
- Brendan T. Boylan
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44196, USA; (B.T.B.); (M.H.)
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Mihyun Hwang
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44196, USA; (B.T.B.); (M.H.)
- Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Cornelia C. Bergmann
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44196, USA; (B.T.B.); (M.H.)
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
- Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
- School of Biological Sciences, Kent State University, Kent, OH 44242, USA
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Feng L, Li W, Li X, Li X, Ran Y, Yang X, Deng Z, Li H. N-MYC-interacting protein enhances type II interferon signaling by inhibiting STAT1 sumoylation. FASEB J 2023; 37:e23281. [PMID: 37933920 DOI: 10.1096/fj.202301450rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 10/04/2023] [Accepted: 10/16/2023] [Indexed: 11/08/2023]
Abstract
Signaling desensitization is key to limiting signal transduction duration and intensity. Signal transducer and activator of transcription 1 (STAT1) can mediate type II interferon (IFNγ)-induced immune responses, which are enhanced and inhibited by STAT1 phosphorylation and sumoylation, respectively. Here, we identified an N-MYC interacting protein, NMI, which can enhance STAT1 phosphorylation and STAT1-mediated IFNγ immune responses by binding and sequestering the E2 SUMO conjugation enzyme, UBC9, and blocking STAT1 sumoylation. NMI facilitates UBC9 nucleus-to-cytoplasm translocation in response to IFNγ, thereby inhibiting STAT1 sumoylation. STAT1 phosphorylation at Y701 and sumoylation at K703 are mutually exclusive modifications that regulate IFNγ-dependent transcriptional responses. NMI could not alter the phosphorylation level of sumoylation-deficient STAT1 after IFNγ treatment. Thus, IFNγ signaling is modulated by NMI through sequestration of UBC9 in the cytoplasm, leading to inhibition of STAT1 sumoylation. Hence, NMI functions as a switch for STAT1 activation/inactivation cycles by modulating an IFNγ-induced desensitization mechanism.
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Affiliation(s)
- Linyuan Feng
- Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Wanwei Li
- Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Xiaowen Li
- Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Xiaotian Li
- Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yanhong Ran
- Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Xiaoping Yang
- Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Zemin Deng
- Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Hongjian Li
- Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China
- Stat Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
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Tang Q, Meng C, Liu Y, Cheng Y, Liu Y, Long Y, Sun S, Feng F. Silencing SIRT1 promotes the anti-HBV action of IFN-α by regulating Pol expression and activating the JAK-STAT signaling pathway. Int Immunopharmacol 2023; 124:110939. [PMID: 37741128 DOI: 10.1016/j.intimp.2023.110939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 09/01/2023] [Accepted: 09/11/2023] [Indexed: 09/25/2023]
Abstract
PURPOSE The purpose this study is to investigate the impact of SIRT1 on the anti-HBV activity of IFN-α and further elucidate its underlying mechanism. METHODS HepG2.2.15 cells stably transfected with HBV virus were chosen as the primary study subject. IFN-α was used to stimulate the cells and regulate the expression of SIRT1, and the JAK-STAT pathway and HBV-related indices were measured by qRT-PCR, Western blotting and ELISA. Immunofluorescence (IF) was used to detect the nuclear translocation of STAT1 and STAT2. Coimmunoprecipitation (Co-IP) was used to detect the binding of SIRT1 to HBV Polymerase (Pol). RESULTS In HepG2.2.15 cells, we found changes in SIRT1 expression. We show that silencing SIRT1 promotes the IFN-α-triggered Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway and consequently enhances the antiviral effects of IFN-α against HBV replication. Importantly, SIRT1 can interact with Pol and increase JAK-STAT activity by regulating Pol expression. Additionally, the inhibition of SIRT1 activity by treatment with the SIRT1 inhibitor selisistat enhanced the anti-HBV effect of IFN-α and JAK-STAT pathway activity. CONCLUSION In conclusion, our results demonstrate that silencing SIRT1 activates the JAK-STAT pathway and enhances the anti-HBV activity of IFN-α by inhibiting Pol expression. This would be a promising therapeutic target to improve the efficacy of IFN-α in the treatment of CHB.
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Affiliation(s)
- Qinyan Tang
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China.
| | - Chunyan Meng
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China.
| | - Yue Liu
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China.
| | - Yanlin Cheng
- School of Life Science, North China University of Science and Technology, Tangshan, Hebei Province, China.
| | - Yang Liu
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China.
| | - Yifei Long
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China.
| | - Shufeng Sun
- School of Nursing and Rehabilitation, North China University of Science and Technology, Tangshan, Hebei Province, China.
| | - Fumin Feng
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China.
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42
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Olmos Liceaga D, Nunes SF, Saenz RA. Ex Vivo Experiments Shed Light on the Innate Immune Response from Influenza Virus. Bull Math Biol 2023; 85:115. [PMID: 37833614 DOI: 10.1007/s11538-023-01217-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 09/21/2023] [Indexed: 10/15/2023]
Abstract
The innate immune response is recognized as a key driver in controlling an influenza virus infection in a host. However, the mechanistic action of such innate response is not fully understood. Infection experiments on ex vivo explants from swine trachea represent an efficient alternative to animal experiments, as the explants conserved key characteristics of an organ from an animal. In the present work we compare three cellular automata models of influenza virus dynamics. The models are fitted to free virus and infected cells data from ex vivo swine trachea experiments. Our findings suggest that the presence of an immune response is necessary to explain the observed dynamics in ex vivo organ culture. Moreover, such immune response should include a refractory state for epithelial cells, and not just a reduced infection rate. Our results may shed light on how the immune system responds to an infection event.
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Affiliation(s)
- Daniel Olmos Liceaga
- Departamento de Matemáticas, Universidad de Sonora, Blvd. Rosales y Luis Encinas S/N, Col Centro, 83000, Hermosillo, SON, Mexico
| | - Sandro Filipe Nunes
- Cambridge Infectious Disease Consortium, Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK
- Animal Sciences and Technologies, Clinical Pharmacology and Safety Sciences, AstraZeneca Biopharmaceuticals R &D, Pepparedsleden 1, SE-43183, Mölndal, Sweden
| | - Roberto A Saenz
- Facultad de Ciencias, Universidad de Colima, Bernal Díaz del Castillo 340, Col Villas de San Sebastián, 28045, Colima, COL, Mexico.
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43
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Jain J, Chaudhary Y, Gaur SK, Tembhurne P, Sekar SC, Dhanavelu M, Sehrawat S, Kaul R. Peste des petits ruminants virus non-structural V and C proteins interact with the NF-κB p65 subunit and modulate pro-inflammatory cytokine gene induction. J Gen Virol 2023; 104. [PMID: 37831061 DOI: 10.1099/jgv.0.001907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2023] Open
Abstract
Peste des petits ruminants virus (PPRV) is known to induce transient immunosuppression in infected small ruminants by modulating several cellular pathways involved in the antiviral immune response. Our study shows that the PPRV-coded non-structural proteins C and V can interact with the cellular NF-κB p65 subunit. The PPRV-C protein interacts with the transactivation domain (TAD) while PPRV-V interacts with the Rel homology domain (RHD) of the NF-κB p65 subunit. Both viral proteins can suppress the NF-κB transcriptional activity and NF-κB-mediated transcription of cellular genes. PPRV-V protein expression can significantly inhibit the nuclear translocation of NF-κB p65 upon TNF-α stimulation, whereas PPRV-C does not affect it. The NF-κB-mediated pro-inflammatory cytokine gene expression is significantly downregulated in cells expressing PPRV-C or PPRV-V protein. Our study provides evidence suggesting a role of PPRV non-structural proteins V and C in the modulation of NF-κB signalling through interaction with the NF-κB p65 subunit.
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Affiliation(s)
- Juhi Jain
- Department of Microbiology, University of Delhi, South Campus, New Delhi, India
| | - Yash Chaudhary
- Department of Microbiology, University of Delhi, South Campus, New Delhi, India
| | - Sharad Kumar Gaur
- Department of Microbiology, University of Delhi, South Campus, New Delhi, India
| | | | | | | | - Sharvan Sehrawat
- Indian Institute of Science Education and Research, Mohali, India
| | - Rajeev Kaul
- Department of Microbiology, University of Delhi, South Campus, New Delhi, India
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44
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Zhao Z, Zhang L, Zhang X, Yue Y, Liu S, Li Y, Ban X, Zhao C, Jin P. Coixendide efficacy in combination with temozolomide in glioblastoma and transcriptome analysis of the mechanism. Sci Rep 2023; 13:15484. [PMID: 37726303 PMCID: PMC10509239 DOI: 10.1038/s41598-023-41421-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 08/26/2023] [Indexed: 09/21/2023] Open
Abstract
The purpose of this study was to explore the role of coixendide (Coix) combine with temozolomide (TMZ) in the treatment of Glioblastoma (GBM) and explore its possible mechanism. CCK-8 was used to determine the inhibitory rate of Coix group, TMZ group and drug combination group on GBM cells, and the combination index (CI) was calculated to determine whether they had synergistic effect. Then RNA was extracted from each group, transcriptome sequencing was performed, and differentially expressed genes (DEGs) were identified. The possible mechanism was analyzed by GO enrichment analysis and KEGG enrichment analysis. The CI of Coix and TMZ indicating a synergistic effect when TMZ concentration is 0.1 mg/ml and Coix concentration is 2 mg/ml. Transcriptome sequencing analysis showed that interferon (IFN) related genes were down-regulated by Coix and up-regulated by TMZ and combined drugs, however, the up-regulation induced by combined drugs was less than that of TMZ. Besides IFN related genes, cholesterol metabolism pathway were also been regulated. Coix and TMZ have synergistic effects in the treatment of GBM at certain doses. RNA-Seq results suggested that the abnormal on genetic materials caused by DNA damage induced by TMZ treatment can be sensed by IFN related genes and activates antiviral IFN signaling, causing the activation of repairing mechanism and drug resistance. Coix inhibits IFN related genes, thereby inhibits drug resistance of TMZ. In addition, the activation of ferroptosis and the regulation of DEGs in cholesterol metabolism pathway were also contributed to the synergistic effects of Coix and TMZ.
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Affiliation(s)
- Zhenran Zhao
- Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
- Neurosurgery, Linyi Traditional Chinese Medical Hospital, Linyi, 276000, Shandong, China
| | - Lei Zhang
- Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Xiaohan Zhang
- Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Yong Yue
- Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Shengchen Liu
- Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Yanan Li
- College of Agronomy, Northwest A&F University, Yangling, Xianyang, 712100, Shaanxi, China
| | - Xiang Ban
- College of Agronomy, Northwest A&F University, Yangling, Xianyang, 712100, Shaanxi, China
| | - Cuizhu Zhao
- College of Agronomy, Northwest A&F University, Yangling, Xianyang, 712100, Shaanxi, China.
| | - Peng Jin
- Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
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45
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Jung KI, McKenna S, Vijayamahantesh V, He Y, Hahm B. Protective versus Pathogenic Type I Interferon Responses during Virus Infections. Viruses 2023; 15:1916. [PMID: 37766322 PMCID: PMC10538102 DOI: 10.3390/v15091916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Following virus infections, type I interferons are synthesized to induce the expression of antiviral molecules and interfere with virus replication. The importance of early antiviral type I IFN response against virus invasion has been emphasized during COVID-19 as well as in studies on the microbiome. Further, type I IFNs can directly act on various immune cells to enhance protective host immune responses to viral infections. However, accumulating data indicate that IFN responses can be harmful to the host by instigating inflammatory responses or inducing T cell suppression during virus infections. Also, inhibition of lymphocyte and dendritic cell development can be caused by type I IFN, which is independent of the traditional signal transducer and activator of transcription 1 signaling. Additionally, IFNs were shown to impair airway epithelial cell proliferation, which may affect late-stage lung tissue recovery from the infection. As such, type I IFN-virus interaction research is diverse, including host antiviral innate immune mechanisms in cells, viral strategies of IFN evasion, protective immunity, excessive inflammation, immune suppression, and regulation of tissue repair. In this report, these IFN activities are summarized with an emphasis placed on the functions of type I IFNs recently observed during acute or chronic virus infections.
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Affiliation(s)
| | | | | | | | - Bumsuk Hahm
- Departments of Surgery & Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212, USA; (K.I.J.); (S.M.); (V.V.); (Y.H.)
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46
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de Andrade Vieira Alves F, Nunes PCG, Arruda LV, Salomão NG, Rabelo K. The Innate Immune Response in DENV- and CHIKV-Infected Placentas and the Consequences for the Fetuses: A Minireview. Viruses 2023; 15:1885. [PMID: 37766291 PMCID: PMC10535478 DOI: 10.3390/v15091885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/25/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Dengue virus (DENV) and chikungunya (CHIKV) are arthropod-borne viruses belonging to the Flaviviridae and Togaviridae families, respectively. Infection by both viruses can lead to a mild indistinct fever or even lead to more severe forms of the diseases, which are characterized by a generalized inflammatory state and multiorgan involvement. Infected mothers are considered a high-risk group due to their immunosuppressed state and the possibility of vertical transmission. Thereby, infection by arboviruses during pregnancy portrays a major public health concern, especially in countries where epidemics of both diseases are regular and public health policies are left aside. Placental involvement during both infections has been already described and the presence of either DENV or CHIKV has been observed in constituent cells of the placenta. In spite of that, there is little knowledge regarding the intrinsic earlier immunological mechanisms that are developed by placental cells in response to infection by both arboviruses. Here, we approach some of the current information available in the literature about the exacerbated presence of cells involved in the innate immune defense of the placenta during DENV and CHIKV infections.
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Affiliation(s)
- Felipe de Andrade Vieira Alves
- Laboratório de Ultraestrutura e Biologia Tecidual, Universidade do Estado do Rio de Janeiro/UERJ, Rio de Janeiro 20550170, RJ, Brazil; (F.d.A.V.A.); (L.V.A.)
- Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040900, RJ, Brazil
| | - Priscila Conrado Guerra Nunes
- Laboratório de Imunologia Viral, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040900, RJ, Brazil;
| | - Laíza Vianna Arruda
- Laboratório de Ultraestrutura e Biologia Tecidual, Universidade do Estado do Rio de Janeiro/UERJ, Rio de Janeiro 20550170, RJ, Brazil; (F.d.A.V.A.); (L.V.A.)
- Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040900, RJ, Brazil
| | - Natália Gedeão Salomão
- Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040900, RJ, Brazil
- Laboratório de Imunologia Viral, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040900, RJ, Brazil;
| | - Kíssila Rabelo
- Laboratório de Ultraestrutura e Biologia Tecidual, Universidade do Estado do Rio de Janeiro/UERJ, Rio de Janeiro 20550170, RJ, Brazil; (F.d.A.V.A.); (L.V.A.)
- Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040900, RJ, Brazil
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47
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McDougal MB, De Maria AM, Ohlson MB, Kumar A, Xing C, Schoggins JW. Interferon inhibits a model RNA virus via a limited set of inducible effector genes. EMBO Rep 2023; 24:e56901. [PMID: 37497756 PMCID: PMC10481653 DOI: 10.15252/embr.202356901] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/29/2023] [Accepted: 07/04/2023] [Indexed: 07/28/2023] Open
Abstract
Interferons control viral infection by inducing the expression of antiviral effector proteins encoded by interferon-stimulated genes (ISGs). The field has mostly focused on identifying individual antiviral ISG effectors and defining their mechanisms of action. However, fundamental gaps in knowledge about the interferon response remain. For example, it is not known how many ISGs are required to protect cells from a particular virus, though it is theorized that numerous ISGs act in concert to achieve viral inhibition. Here, we used CRISPR-based loss-of-function screens to identify a markedly limited set of ISGs that confer interferon-mediated suppression of a model alphavirus, Venezuelan equine encephalitis virus (VEEV). We show via combinatorial gene targeting that three antiviral effectors-ZAP, IFIT3, and IFIT1-together constitute the majority of interferon-mediated restriction of VEEV, while accounting for < 0.5% of the interferon-induced transcriptome. Together, our data suggest a refined model of the antiviral interferon response in which a small subset of "dominant" ISGs may confer the bulk of the inhibition of a given virus.
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Affiliation(s)
- Matthew B McDougal
- Department of MicrobiologyUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - Anthony M De Maria
- Department of MicrobiologyUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - Maikke B Ohlson
- Department of MicrobiologyUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - Ashwani Kumar
- Bioinformatics Core, McDermott CenterUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - Chao Xing
- Bioinformatics Core, McDermott CenterUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - John W Schoggins
- Department of MicrobiologyUniversity of Texas Southwestern Medical CenterDallasTXUSA
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48
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Giorgakoudi K, Schley D, Juleff N, Gubbins S, Ward J. The role of Type I interferons in the pathogenesis of foot-and-mouth disease virus in cattle: A mathematical modelling analysis. Math Biosci 2023; 363:109052. [PMID: 37495013 DOI: 10.1016/j.mbs.2023.109052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 06/16/2023] [Accepted: 07/18/2023] [Indexed: 07/28/2023]
Abstract
Type I interferons (IFN) are the first line of immune response against infection. In this study, we explore the interaction between Type I IFN and foot-and-mouth disease virus (FMDV), focusing on the effect of this interaction on epithelial cell death. While several mathematical models have explored the interaction between interferon and viruses at a systemic level, with most of the work undertaken on influenza and hepatitis C, these cannot investigate why a virus such as FMDV causes extensive cell death in some epithelial tissues leading to the development of lesions, while other infected epithelial tissues exhibit negligible cell death. Our study shows how a model that includes epithelial tissue structure can explain the development of lesions in some tissues and their absence in others. Furthermore, we show how the site of viral entry in an epithelial tissue, the viral replication rate, IFN production, suppression of viral replication by IFN and IFN release by live cells, all have a major impact on results.
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Affiliation(s)
- Kyriaki Giorgakoudi
- The Pirbright Institute, Ash Road, Pirbright, Surrey, GU24 0NF, UK; Department of Mathematical Sciences, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK.
| | - David Schley
- The Pirbright Institute, Ash Road, Pirbright, Surrey, GU24 0NF, UK.
| | - Nicholas Juleff
- The Pirbright Institute, Ash Road, Pirbright, Surrey, GU24 0NF, UK.
| | - Simon Gubbins
- The Pirbright Institute, Ash Road, Pirbright, Surrey, GU24 0NF, UK.
| | - John Ward
- Department of Mathematical Sciences, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK.
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49
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Manríquez RA, Sandoval M, Loncoman C, Tafalla C, Avendaño-Herrera R, Cárcamo JG. Epigenetic reprogramming around IFN1 and IFNy2 promoters in rainbow trout cells inoculated with infectious pancreatic necrosis virus (IPNV). FISH & SHELLFISH IMMUNOLOGY 2023; 140:108947. [PMID: 37454879 DOI: 10.1016/j.fsi.2023.108947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 07/18/2023]
Abstract
Infectious pancreatic necrosis virus (IPNV) has proven to effectively evade the host antiviral responses. This study clarifies whether the modulation of the antiviral immune response exerted by IPNV involves epigenetic mechanisms. An in-silico characterization of the rainbow trout IFN1 and IFNγ2 promoters was performed, identifying the islands or sequences rich in CpG dinucleotides and the putative transcription factor binding sites (TBS) for both gene promoters. RTS11 cells (rainbow trout monocyte/macrophage) were infected with IPNV, and the course of viral infection was followed up to 48 h post infection (hpi). Infected cells showed increased IFN1 and IFNγ2 transcriptional expression at 6 and 24 hpi, respectively. IPNV infection caused increases and decreases in global IFNγ2 promoter methylation at 6 and 24 hpi, respectively. The CpG dinucleotides at positions -392 and + 38 of this promoter were the most sensitive to methylation changes. The IFN1 promoter remained fully unmethylated during the course of the infection, similar to the control. The changes in the methylation pattern observed for the IFNγ2 promoter were coincident with the changes in DNA methyltransferase (DNMT) expression levels, increasing at 6 hpi and decreasing below basal level at 24 hpi. Similarly, the H4 histones associated with the IFN1 and IFNγ2 promoters were hyperacetylated at 6 hpi, subsequently decreasing their acetylation below basal levels at 24 hpi, in both promoters. Coincidentally with the above, overexpression of histone acetyltransferase (HAT) was observed at 6 hpi and of histone deacetylase (HDAC) at 24 hpi, with return to baseline of HAT. These results suggest that IPNV would epigenetically modulate the expression of IFN1 by changing acetylation levels of the histones H4 associated with its promoter. Also, the modulation of the expression of IFNy2 would be by switching methylation/demethylation levels of its promoter, in addition to changes in acetylation levels of histones H4 associated with this promoter. This study is the first to demonstrate the effect of epigenetic reprogramming after IPNV infection in salmonid cells, demonstrating that promoter methylation/demethylation level and changes in the histone code associated with promoters may play a role in the modulation of the immune response induced by the virus.
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Affiliation(s)
- René A Manríquez
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile; Interdisciplinary Center for Aquaculture Research (INCAR), Valdivia, Chile
| | - Moisés Sandoval
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile; Interdisciplinary Center for Aquaculture Research (INCAR), Valdivia, Chile
| | - Carlos Loncoman
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Carolina Tafalla
- Animal Health Research Center (CISA), INIA-CSIC, Valdeolmos-Alalpardo, 28130, Madrid, Spain
| | - R Avendaño-Herrera
- Interdisciplinary Center for Aquaculture Research (INCAR), Valdivia, Chile; Laboratorio de Patología de Organismos Acuáticos y Biotecnología Acuícola, Universidad Andrés Bello, Viña del Mar, Chile; Centro de Investigación Marina Quintay (CIMARQ), Universidad Andrés Bello, Quintay, Chile
| | - Juan G Cárcamo
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile; Interdisciplinary Center for Aquaculture Research (INCAR), Valdivia, Chile.
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50
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Zhang M, Liu WQ, Wang Y, Yan X, Wang B, Wang GH. Identification, expression pattern and functional characterization of IFN-γ involved in activating JAK-STAT pathway in Sebastes schlegeli. FISH & SHELLFISH IMMUNOLOGY 2023; 140:108936. [PMID: 37423401 DOI: 10.1016/j.fsi.2023.108936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/04/2023] [Accepted: 07/06/2023] [Indexed: 07/11/2023]
Abstract
IFN-γ (interferon gamma) is a critical cytokine in the immune system involved both directly and indirectly in antiviral activity, stimulation of bactericidal activity, antigen presentation and activation of macrophages via the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. The IFN-γ function is best described in cell defense against intracellular pathogens in mammals, but IFN-γ cytokine-induced metabolic change and its role in anti-infection remain unknown in teleost fish. In this study, a novel IFN-γ (SsIFN-γ) was identified from black rockfish (Sebastes schlegeli) by rapid amplification of cDNA ends (RACE). The open reading frame (ORF) of SsIFN-γ encoded a putative protein of 215 amino acids and shares 60.2%-93.5% overall sequence identities with other teleost IFN-γ. SsIFN-γ was distributed ubiquitously in all the detected tissues and immune cells, which was highly expressed in the spleen, gills, head kidney by quantitative real-time PCR. The mRNA expression of SsIFN-γ was significantly upregulated in the spleen, head kidney, head kidney (HK) macrophages and peripheral blood lymphocytes (PBLs) during pathogen infection. Meanwhile, the recombinant protein (rSsIFN-γ) exhibited an immunomodulatory function to enhance respiratory burst activity and nitric oxide response of HK macrophages. Furthermore, rSsIFN-γ could effectively upregulate the expression of macrophage proinflammatory cytokine, the expression of JAK-STAT signaling pathway related genes and interferon-related downstream genes in the head kidney and spleen. Luciferase assays showed ISRE and GAS activity were obviously enhanced after rSsIFN-γ treatment. These results indicated that SsIFN-γ possessed apparent immunoregulatory properties and played a role in fighting pathogen infection which will be helpful to further understanding of the immunologic mechanism of teleosts IFN-γ in innate immunity.
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Affiliation(s)
- Min Zhang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, Shandong Province, 266109, China; Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong Province, 266109, China
| | - Wen-Qing Liu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, Shandong Province, 266109, China
| | - Yue Wang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, Shandong Province, 266109, China
| | - Xue Yan
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, Shandong Province, 266109, China
| | - Bing Wang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, Shandong Province, 266109, China
| | - Guang-Hua Wang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, Shandong Province, 266109, China.
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