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Zhang H, Li C, Sun R, Zhang X, Li Z, Hua D, Yin B, Yang L, Zhang L, Huang J. NEIL1 block IFN-β production and enhance vRNP function to facilitate influenza A virus proliferation. NPJ VIRUSES 2024; 2:57. [PMID: 40295715 PMCID: PMC11721407 DOI: 10.1038/s44298-024-00065-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 10/14/2024] [Indexed: 04/30/2025]
Abstract
Influenza A virus (IAV) has developed multiple tactics to hinder the innate immune response including the epigenetic regulation during IAV infection, but the novel epigenetic factors and their mechanism in innate immunity remain well studied. Here, through a non-biased high-throughput sgRNA screening of 1041 known epigenetic modifiers in a cellular model of IAV-induced interferon-beta (IFN-β) production, we identified nei endonuclease VIII-like 1 (NEIL1) as a critical regulator of IFN-β in response to viral infection. Further studies showed that NEIL1 promoted the replication of the influenza virus by regulating the methylation of cytonuclear IFN-β promoter (mainly CpG-345), inhibiting the expression of IFN-β and IFN-stimulating genes. The structural domains of NEIL1, especially the catalytic domain, were critical for the suppression of IFN-β production, but the enzymatic activity of NEIL1 was dispensable. Furthermore, our results revealed that NEIL1 relied on interactions with the N- and C-terminus of the nucleoprotein (NP) of IAV, and NEIL1 expression facilitated the entry of the NP into the nucleus, which further enhanced the stability of the viral ribonucleoprotein (vRNP) complex and thus contributed to IAV replication and transcription. These findings reveal an enzyme-independent mechanism of host NEIL1 that negatively regulates IFN-β expression, thereby facilitating IAV propagation. Our study provides new insights into the roles of NEIL1, both in directly promoting virus replication and in evading innate immunity in IAV infection.
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Affiliation(s)
- Huixia Zhang
- School of Life Sciences, Tianjin University, Tianjin, China
| | - Changyan Li
- School of Life Sciences, Tianjin University, Tianjin, China
| | - Ruiqi Sun
- School of Life Sciences, Tianjin University, Tianjin, China
| | - Xinyi Zhang
- School of Life Sciences, Tianjin University, Tianjin, China
| | - Zexing Li
- School of Life Sciences, Tianjin University, Tianjin, China
| | - Deping Hua
- School of Life Sciences, Tianjin University, Tianjin, China
| | - Boxuan Yin
- School of Life Sciences, Tianjin University, Tianjin, China
| | - Liu Yang
- School of Life Sciences, Tianjin University, Tianjin, China
| | - Lilin Zhang
- School of Life Sciences, Tianjin University, Tianjin, China.
| | - Jinhai Huang
- School of Life Sciences, Tianjin University, Tianjin, China.
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2
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Tu S, Zou J, Xiong C, Dai C, Sun H, Luo D, Jin M, Chen H, Zhou H. Zinc-finger CCHC-type containing protein 8 promotes RNA virus replication by suppressing the type-I interferon responses. J Virol 2024; 98:e0079624. [PMID: 39115433 PMCID: PMC11406956 DOI: 10.1128/jvi.00796-24] [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: 05/07/2024] [Accepted: 06/18/2024] [Indexed: 09/18/2024] Open
Abstract
Host cells have evolved an intricate regulatory network to fine tune the type-I interferon responses. However, the full picture of this regulatory network remains to be depicted. In this study, we found that knock out of zinc-finger CCHC-type containing protein 8 (ZCCHC8) impairs the replication of influenza A virus (IAV), Sendai virus (Sev), Japanese encephalitis virus (JEV), and vesicular stomatitis virus (VSV). Further investigation unveiled that ZCCHC8 suppresses the type-I interferon responses by targeting the interferon regulatory factor 3 (IRF3) signaling pathway. Mechanistically, ZCCHC8 associates with phosphorylated IRF3 and disrupts the interaction of IRF3 with the co-activator CREB-binding protein (CBP). Additionally, the direct binding of ZCCHC8 with the IFN-stimulated response element (ISRE) impairs the ISRE-binding of IRF3. Our study contributes to the comprehensive understanding for the negative regulatory network of the type-I interferon responses and provides valuable insights for the control of multiple viruses from a host-centric perspective.IMPORTANCEThe innate immune responses serve as the initial line of defense against invading pathogens and harmful substances. Negative regulation of the innate immune responses plays an essential role in avoiding auto-immune diseases and over-activated immune responses. Hence, the comprehensive understanding of the negative regulation network for innate immune responses could provide novel therapeutic insights for the control of viral infections and immune dysfunction. In this study, we report that ZCCHC8 negatively regulates the type-I interferon responses. We illustrate that ZCCHC8 impedes the IRF3-CBP association by interacting with phosphorylated IRF3 and competes with IRF3 for binding to ISRE. Our study demonstrates the role of ZCCHC8 in the replication of multiple RNA viruses and contributes to a deeper understanding of the negative regulation system for the type-I interferon responses.
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Affiliation(s)
- Shaoyu Tu
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Jiahui Zou
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Chuhan Xiong
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Chao Dai
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Huimin Sun
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Didan Luo
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Meilin Jin
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, China
| | - Huanchun Chen
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, China
- Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, Hubei, China
- Hubei Hongshan Laboratory, Wuhan, Hubei, China
| | - Hongbo Zhou
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, China
- Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, Hubei, China
- Hubei Hongshan Laboratory, Wuhan, Hubei, China
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3
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Gu Y, Jia XM. Stealth strategies of Candida albicans to evade host immunity. Cell Host Microbe 2024; 32:1459-1461. [PMID: 39265531 DOI: 10.1016/j.chom.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/05/2024] [Indexed: 09/14/2024]
Abstract
During opportunistic pathogenic episodes, Candida albicans employs classical strategies such as the yeast-to-hyphae transition and immunogenic masking. In this issue of Cell Host & Microbe, Luo et al. unveil that the effector protein Cmi1 can be translocated into host cells and targets TBK1, thereby negatively regulating the host's antifungal immune responses.
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Affiliation(s)
- Yebo Gu
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China
| | - Xin-Ming Jia
- Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China; Key Laboratory of Pathogen-Host Interactions of the Ministry of Education of China, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China.
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4
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Subbarayudu S, Namasivayam SKR, Arockiaraj J. Immunomodulation in Non-traditional Therapies for Methicillin-resistant Staphylococcus aureus (MRSA) Management. Curr Microbiol 2024; 81:346. [PMID: 39240286 DOI: 10.1007/s00284-024-03875-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/26/2024] [Indexed: 09/07/2024]
Abstract
The rise of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant challenge in clinical settings due to its ability to evade conventional antibiotic treatments. This overview explores the potential of immunomodulatory strategies as alternative therapeutic approaches to combat MRSA infections. Traditional antibiotics are becoming less effective, necessitating innovative solutions that harness the body's immune system to enhance pathogen clearance. Recent advancements in immunotherapy, including the use of antimicrobial peptides, phage therapy, and mechanisms of immune cells, demonstrate promise in enhancing the body's ability to clear MRSA infections. However, the exact interactions between these therapies and immunomodulation are not fully understood, underscoring the need for further research. Hence, this review aims to provide a broad overview of the current understanding of non-traditional therapeutics and their impact on immune responses, which could lead to more effective MRSA treatment strategies. Additionally, combining immunomodulatory agents with existing antibiotics may improve outcomes, particularly for immunocompromised patients or those with chronic infections. As the landscape of antibiotic resistance evolves, the development of effective immunotherapeutic strategies could play a vital role in managing MRSA infections and reducing reliance on traditional antibiotics. Future research must focus on optimizing these approaches and validating their efficacy in diverse clinical populations to address the urgent need for effective MRSA management strategies.
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Affiliation(s)
- Suthi Subbarayudu
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu, 603203, India
| | - S Karthick Raja Namasivayam
- Centre for Applied Research, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, 602105, India.
| | - Jesu Arockiaraj
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu, 603203, India.
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5
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Calvo-Apalategi A, Nevado ML, Bravo-Gallego LY, González-Granado LI, Allende LM, Pena RR, López-Granados E, Reyburn HT. The lack of either IRF9, or STAT2, has surprisingly little effect on human natural killer cell development and function. Immunology 2024; 172:440-450. [PMID: 38514903 DOI: 10.1111/imm.13779] [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: 05/11/2022] [Accepted: 03/01/2024] [Indexed: 03/23/2024] Open
Abstract
Analysis of genetically defined immunodeficient patients allows study of the effect of the absence of specific proteins on human immune function in real-world conditions. Here we have addressed the importance of type I interferon signalling for human NK cell development by studying the phenotype and function of circulating NK cells isolated from patients suffering primary immunodeficiency disease due to mutation of either the human interferon regulatory factor 9 (IRF9) or the signal transducer and activator of transcription 2 (STAT2) genes. IRF9, together with phosphorylated STAT1 and STAT2, form a heterotrimer called interferon stimulated gene factor 3 (ISGF3) which promotes the expression of hundreds of IFN-stimulated genes that mediate antiviral function triggered by exposure to type I interferons. IRF9- and STAT2-deficient patients are unable to respond efficiently to stimulation by type I interferons and so our experiments provide insights into the importance of type I interferon signalling and the consequences of its impairment on human NK cell biology. Surprisingly, the NK cells of these patients display essentially normal phenotype and function.
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Affiliation(s)
| | - Marta López Nevado
- Immunology Department, University Hospital 12 de Octubre, Madrid, Spain
- Hospital 12 Octubre Research Institute (Imas12), Madrid, Spain
| | | | - Luis Ignacio González-Granado
- Immunology Department, University Hospital 12 de Octubre, Madrid, Spain
- Immunodeficiency Unit, Department of Pediatrics, University Hospital 12 de Octubre, Madrid, Spain
| | - Luis M Allende
- Immunology Department, University Hospital 12 de Octubre, Madrid, Spain
- Hospital 12 Octubre Research Institute (Imas12), Madrid, Spain
- School of Medicine, Complutense University of Madrid, Madrid, Spain
| | | | - Eduardo López-Granados
- Department of Immunology, La Paz University Hospital, Madrid, Spain
- Lymphocyte Pathophysiology Group, La Paz Institute of Biomedical Research, IdiPAZ, Madrid, Spain
| | - Hugh T Reyburn
- Department of Immunology and Oncology, CNB-CSIC, Madrid, Spain
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6
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Nigam M, Devi K, Coutinho HDM, Mishra AP. Exploration of gut microbiome and inflammation: A review on key signalling pathways. Cell Signal 2024; 118:111140. [PMID: 38492625 DOI: 10.1016/j.cellsig.2024.111140] [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: 02/27/2024] [Revised: 03/09/2024] [Accepted: 03/11/2024] [Indexed: 03/18/2024]
Abstract
The gut microbiome, a crucial component of the human system, is a diverse collection of microbes that belong to the gut of human beings as well as other animals. These microbial communities continue to coexist harmoniously with their host organisms and perform various functions that affect the host's general health. Each person's gut microbiota has a unique makeup. The gut microbiota is well acknowledged to have a part in the local as well as systemic inflammation that underlies a number of inflammatory disorders (e.g., atherosclerosis, diabetes mellitus, obesity, and inflammatory bowel disease).The gut microbiota's metabolic products, such as short-chain fatty acids (butyrate, propionate, and acetate) inhibit inflammation by preventing immune system cells like macrophages and neutrophils from producing pro-inflammatory factors, which are triggered by the structural elements of bacteria (like lipopolysaccharide). The review's primary goal is to provide comprehensive and compiled data regarding the contribution of gut microbiota to inflammation and the associated signalling pathways.
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Affiliation(s)
- Manisha Nigam
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India.
| | - Kanchan Devi
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | | | - Abhay Prakash Mishra
- Department of Pharmacology, University of Free State, Bloemfontein 9300, South Africa.
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7
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Li L, Liu Z, Liang R, Yang M, Yan Y, Jiao Y, Jiao Z, Hu X, Li M, Shen Z, Peng G. Novel mutation N588 residue in the NS1 protein of feline parvovirus greatly augments viral replication. J Virol 2024; 98:e0009324. [PMID: 38591899 PMCID: PMC11092363 DOI: 10.1128/jvi.00093-24] [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] [Accepted: 03/19/2024] [Indexed: 04/10/2024] Open
Abstract
Feline parvovirus (FPV) infection is highly fatal in felines. NS1, which is a key nonstructural protein of FPV, can inhibit host innate immunity and promote viral replication, which is the main reason for the severe pathogenicity of FPV. However, the mechanism by which the NS1 protein disrupts host immunity and regulates viral replication is still unclear. Here, we identified an FPV M1 strain that is regulated by the NS1 protein and has more pronounced suppression of innate immunity, resulting in robust replication. We found that the neutralization titer of the FPV M1 strain was significantly lower than that of the other strains. Moreover, FPV M1 had powerful replication ability, and the FPV M1-NS1 protein had heightened efficacy in repressing interferon-stimulated genes (ISGs) expression. Subsequently, we constructed an FPV reverse genetic system, which confirmed that the N588 residue of FPV M1-NS1 protein is a key amino acid that bolsters viral proliferation. Recombinant virus containing N588 also had stronger ability to inhibit ISGs, and lower ISGs levels promoted viral replication and reduced the neutralization titer of the positive control serum. Finally, we confirmed that the difference in viral replication was abolished in type I IFN receptor knockout cell lines. In conclusion, our results demonstrate that the N588 residue of the NS1 protein is a critical amino acid that promotes viral proliferation by increasing the inhibition of ISGs expression. These insights provide a reference for studying the relationship between parvovirus-mediated inhibition of host innate immunity and viral replication while facilitating improved FPV vaccine production.IMPORTANCEFPV infection is a viral infectious disease with the highest mortality rate in felines. A universal feature of parvovirus is its ability to inhibit host innate immunity, and its ability to suppress innate immunity is mainly accomplished by the NS1 protein. In the present study, FPV was used as a viral model to explore the mechanism by which the NS1 protein inhibits innate immunity and regulates viral replication. Studies have shown that the FPV-NS1 protein containing the N588 residue strongly inhibits the expression of host ISGs, thereby increasing the viral proliferation titer. In addition, the presence of the N588 residue can increase the proliferation titer of the strain 5- to 10-fold without affecting its virulence and immunogenicity. In conclusion, our findings provide new insights and guidance for studying the mechanisms by which parvoviruses suppress innate immunity and for developing high-yielding FPV vaccines.
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Affiliation(s)
- Lisha Li
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Zirui Liu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Rui Liang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Mengfang Yang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Yuanyuan Yan
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Yuzhou Jiao
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Zhe Jiao
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Xiaoshuai Hu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Mengxia Li
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Zhou Shen
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Guiqing Peng
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
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8
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Korangath P, Jin L, Yang CT, Healy S, Guo X, Ke S, Grüttner C, Hu C, Gabrielson K, Foote J, Clarke R, Ivkov R. Iron Oxide Nanoparticles Inhibit Tumor Progression and Suppress Lung Metastases in Mouse Models of Breast Cancer. ACS NANO 2024; 18:10509-10526. [PMID: 38564478 PMCID: PMC11025112 DOI: 10.1021/acsnano.3c12064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 03/07/2024] [Accepted: 03/13/2024] [Indexed: 04/04/2024]
Abstract
Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape, leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed the activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 receptor domain-containing adaptor-inducing IFN-β (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent, induced significant antitumor effects, suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases supports a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anticancer immune (nano)adjuvant properties to generate a therapeutic benefit without requiring uptake by cancer cells.
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Affiliation(s)
- Preethi Korangath
- Department
of Radiation Oncology and Molecular Radiation Sciences, School of
Medicine, Johns Hopkins University, Baltimore, Maryland 21231, United States
| | - Lu Jin
- The
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, United States
| | - Chun-Ting Yang
- Department
of Radiation Oncology and Molecular Radiation Sciences, School of
Medicine, Johns Hopkins University, Baltimore, Maryland 21231, United States
| | - Sean Healy
- Department
of Radiation Oncology and Molecular Radiation Sciences, School of
Medicine, Johns Hopkins University, Baltimore, Maryland 21231, United States
| | - Xin Guo
- Department
of Molecular and Comparative Pathobiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States
| | - Suqi Ke
- Department
of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer
Centre, School of Medicine, Johns Hopkins
University, Baltimore, Maryland 21231, United States
| | | | - Chen Hu
- Department
of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer
Centre, School of Medicine, Johns Hopkins
University, Baltimore, Maryland 21231, United States
| | - Kathleen Gabrielson
- Department
of Molecular and Comparative Pathobiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States
| | - Jeremy Foote
- Department
of Microbiology, School of Medicine, University
of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Robert Clarke
- The
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, United States
| | - Robert Ivkov
- Department
of Radiation Oncology and Molecular Radiation Sciences, School of
Medicine, Johns Hopkins University, Baltimore, Maryland 21231, United States
- Department
of Oncology, Sidney Kimmel Comprehensive Cancer Centre, School of
Medicine, Johns Hopkins University, Baltimore, Maryland 21231, United States
- Department
of Mechanical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States
- Department
of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States
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9
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Cheng R, Zhou C, Zhao M, Zhang S, Wan W, Yu Y, Wen B, Jiao J, Xiong X, Xu Q, OuYang X. TRIM56-mediated production of type I interferon inhibits intracellular replication of Rickettsia rickettsii. Microbiol Spectr 2024; 12:e0369523. [PMID: 38358243 PMCID: PMC10986528 DOI: 10.1128/spectrum.03695-23] [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: 10/17/2023] [Accepted: 01/18/2024] [Indexed: 02/16/2024] Open
Abstract
Rickettsia rickettsii (R. rickettsii), the causative agent of Rocky Mountain spotted fever (RMSF), is the most pathogenic member among Rickettsia spp. Previous studies have shown that tripartite motif-containing 56 (TRIM56) E3 ligase-induced ubiquitination of STING is important for cytosolic DNA sensing and type I interferon production to induce anti-DNA viral immunity, but whether it affects intracellular replication of R. rickettsii remains uncharacterized. Here, we investigated the effect of TRIM56 on HeLa and THP-1 cells infected with R. rickettsii. We found that the expression of TRIM56 was upregulated in the R. rickettsii-infected cells, and the overexpression of TRIM56 inhibited the intracellular replication of R. rickettsii, while R. rickettsii replication was enhanced in the TRIM56-silenced host cells with the reduced phosphorylation of IRF3 and STING and the increased production of interferon-β. In addition, the mutation of the TRIM56 E3 ligase catalytic site impairs the inhibitory function against R. rickettsii in HeLa cells. Altogether, our study discovers that TRIM56 is a host restriction factor of R. rickettsii by regulating the cGAS-STING-mediated signaling pathway. This study gives new evidence for the role of TRIM56 in the innate immune response against intracellular bacterial infection and provides new therapeutic targets for RMSF. IMPORTANCE Given that Rickettsia rickettsii (R. rickettsii) is the most pathogenic member within the Rickettsia genus and serves as the causative agent of Rocky Mountain spotted fever, there is a growing need to explore host targets. In this study, we examined the impact of host TRIM56 on R. rickettsii infection in HeLa and THP-1 cells. We observed a significant upregulation of TRIM56 expression in R. rickettsii-infected cells. Remarkably, the overexpression of TRIM56 inhibited the intracellular replication of R. rickettsii, while silencing TRIM56 enhanced bacterial replication accompanied by reduced phosphorylation of IRF3 and STING, along with increased interferon-β production. Notably, the mutation of the TRIM56's E3 ligase catalytic site did not impede R. rickettsii replication in HeLa cells. Collectively, our findings provide novel insights into the role of TRIM56 as a host restriction factor against R. rickettsii through the modulation of the cGAS-STING signaling pathway.
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Affiliation(s)
- Ruxi Cheng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Chunyu Zhou
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Mingliang Zhao
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Shan Zhang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Weiqiang Wan
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Yonghui Yu
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Bohai Wen
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Jun Jiao
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Xiaolu Xiong
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Qin Xu
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xuan OuYang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
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10
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Ruedas-Torres I, Sánchez-Carvajal JM, Salguero FJ, Pallarés FJ, Carrasco L, Mateu E, Gómez-Laguna J, Rodríguez-Gómez IM. The scene of lung pathology during PRRSV-1 infection. Front Vet Sci 2024; 11:1330990. [PMID: 38566751 PMCID: PMC10985324 DOI: 10.3389/fvets.2024.1330990] [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: 10/31/2023] [Accepted: 02/22/2024] [Indexed: 04/04/2024] Open
Abstract
Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically important infectious diseases for the pig industry worldwide. The disease was firstly reported in 1987 and became endemic in many countries. Since then, outbreaks caused by strains of high virulence have been reported several times in Asia, America and Europe. Interstitial pneumonia, microscopically characterised by thickened alveolar septa, is the hallmark lesion of PRRS. However, suppurative bronchopneumonia and proliferative and necrotising pneumonia are also observed, particularly when a virulent strain is involved. This raises the question of whether the infection by certain strains results in an overstimulation of the proinflammatory response and whether there is some degree of correlation between the strain involved and a particular pattern of lung injury. Thus, it is of interest to know how the inflammatory response is modulated in these cases due to the interplay between virus and host factors. This review provides an overview of the macroscopic, microscopic, and molecular pathology of PRRSV-1 strains in the lung, emphasising the differences between strains of different virulence.
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Affiliation(s)
- Inés Ruedas-Torres
- United Kingdom Health Security Agency (UKHSA Porton Down), Salisbury, United Kingdom
- Department of Anatomy and Comparative Pathology and Toxicology, Pathology and Immunology Group (UCO-PIG), UIC Zoonosis y Enfermedades Emergentes ENZOEM, International Agrifood Campus of Excellence (CeiA3), Faculty of Veterinary Medicine, University of Córdoba, Córdoba, Spain
| | - José María Sánchez-Carvajal
- Department of Anatomy and Comparative Pathology and Toxicology, Pathology and Immunology Group (UCO-PIG), UIC Zoonosis y Enfermedades Emergentes ENZOEM, International Agrifood Campus of Excellence (CeiA3), Faculty of Veterinary Medicine, University of Córdoba, Córdoba, Spain
| | | | - Francisco José Pallarés
- Department of Anatomy and Comparative Pathology and Toxicology, Pathology and Immunology Group (UCO-PIG), UIC Zoonosis y Enfermedades Emergentes ENZOEM, International Agrifood Campus of Excellence (CeiA3), Faculty of Veterinary Medicine, University of Córdoba, Córdoba, Spain
| | - Librado Carrasco
- Department of Anatomy and Comparative Pathology and Toxicology, Pathology and Immunology Group (UCO-PIG), UIC Zoonosis y Enfermedades Emergentes ENZOEM, International Agrifood Campus of Excellence (CeiA3), Faculty of Veterinary Medicine, University of Córdoba, Córdoba, Spain
| | - Enric Mateu
- Department of Animal Health and Anatomy, Autonomous University of Barcelona, Barcelona, Spain
| | - Jaime Gómez-Laguna
- Department of Anatomy and Comparative Pathology and Toxicology, Pathology and Immunology Group (UCO-PIG), UIC Zoonosis y Enfermedades Emergentes ENZOEM, International Agrifood Campus of Excellence (CeiA3), Faculty of Veterinary Medicine, University of Córdoba, Córdoba, Spain
| | - Irene Magdalena Rodríguez-Gómez
- Department of Anatomy and Comparative Pathology and Toxicology, Pathology and Immunology Group (UCO-PIG), UIC Zoonosis y Enfermedades Emergentes ENZOEM, International Agrifood Campus of Excellence (CeiA3), Faculty of Veterinary Medicine, University of Córdoba, Córdoba, Spain
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11
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Covill LE, Sendel A, Campbell TM, Piiroinen I, Enoksson SL, Borgström EW, Hansen S, Ma K, Marits P, Norlin AC, Smith CIE, Kåhlin J, Eriksson LI, Bergman P, Bryceson YT. Evaluation of Genetic or Cellular Impairments in Type I IFN Immunity in a Cohort of Young Adults with Critical COVID-19. J Clin Immunol 2024; 44:50. [PMID: 38231281 PMCID: PMC10794435 DOI: 10.1007/s10875-023-01641-1] [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: 11/23/2023] [Accepted: 12/13/2023] [Indexed: 01/18/2024]
Abstract
Several genetic and immunological risk factors for severe COVID-19 have been identified, with monogenic conditions relating to 13 genes of type I interferon (IFN) immunity proposed to explain 4.8% of critical cases. However, previous cohorts have been clinically heterogeneous and were not subjected to thorough genetic and immunological analyses. We therefore aimed to systematically investigate the prevalence of rare genetic variants causing inborn errors of immunity (IEI) and functionally interrogate the type I IFN pathway in young adults that suffered from critical COVID-19 yet lacked comorbidities. We selected and clinically characterized a cohort of 38 previously healthy individuals under 50 years of age who were treated in intensive care units due to critical COVID-19. Blood samples were collected after convalescence. Two patients had IFN-α autoantibodies. Genome sequencing revealed very rare variants in the type I IFN pathway in 31.6% of the patients, which was similar to controls. Analyses of cryopreserved leukocytes did not indicate any defect in plasmacytoid dendritic cell sensing of TLR7 and TLR9 agonists in patients carrying variants in these pathways. However, lymphocyte STAT phosphorylation and protein upregulation upon IFN-α stimulation revealed three possible cases of impaired type I IFN signaling in carriers of rare variants. Together, our results suggest a strategy of functional screening followed by genome analyses and biochemical validation to uncover undiagnosed causes of critical COVID-19.
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Affiliation(s)
- L E Covill
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - A Sendel
- Division of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - T M Campbell
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - I Piiroinen
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - S Lind Enoksson
- Division of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - E Wahren Borgström
- Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - S Hansen
- Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - K Ma
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - P Marits
- Division of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - A C Norlin
- Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - C I E Smith
- Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - J Kåhlin
- Division of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
| | - L I Eriksson
- Division of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
| | - P Bergman
- Division of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
- Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Y T Bryceson
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
- Division of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
- Broegelmann Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
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12
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Wang X, Ding G, Yang P, Cheng G, Kong W, Xu Z. Teleost Eye Is the Portal of IHNV Entry and Contributes to a Robust Mucosal Immune Response. Int J Mol Sci 2023; 25:160. [PMID: 38203332 PMCID: PMC10778588 DOI: 10.3390/ijms25010160] [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: 11/13/2023] [Revised: 12/14/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
The ocular mucosa (OM) is an important and unique part of the vertebrate mucosal immune system. The OM plays an important role in maintaining visual function and defending against foreign antigens or microorganisms, while maintaining a balance between the two through complex regulatory mechanisms. However, the function of ocular mucosal defense against foreign pathogens and mucosal immune response in bony fish are still less studied. To acquire deeper understanding into the mucosal immunity of the OM in teleost fish, we established a study of the immune response of rainbow trout (Oncorhynchus mykiss) infected with the infectious hematopoietic necrosis virus (IHNV). Our findings revealed that IHNV could successfully infiltrate the trout's OM, indicating that the OM could be an important portal for the IHNV. Furthermore, qPCR and RNA-Seq analysis results showed that a large number of immune-related genes were significantly upregulated in the OM of trout with IHNV infection. Critically, the results of our RNA-Seq analysis demonstrated that viral infection triggered a robust immune response, as evidenced by the substantial induction of antiviral, innate, and adaptive immune-related genes in the OM of infected fish, which underscored the essential role of the OM in viral infection. Overall, our findings revealed a previously unknown function of teleost OM in antiviral defense, and provided a theoretical basis for the study of the mucosal immunity of fish.
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Affiliation(s)
- Xinyou Wang
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China;
| | - Guangyi Ding
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; (G.D.); (G.C.); (W.K.)
| | - Peng Yang
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; (G.D.); (G.C.); (W.K.)
| | - Gaofeng Cheng
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; (G.D.); (G.C.); (W.K.)
| | - Weiguang Kong
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; (G.D.); (G.C.); (W.K.)
| | - Zhen Xu
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; (G.D.); (G.C.); (W.K.)
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13
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Solomon G, Love AC, Vaziri GJ, Harvey J, Verrett T, Chernicky K, Simons S, Albert L, Chaves JA, Knutie SA. Effect of urbanization and parasitism on the gut microbiota of Darwin's finch nestlings. Mol Ecol 2023; 32:6059-6069. [PMID: 37837269 DOI: 10.1111/mec.17164] [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: 07/03/2023] [Revised: 09/20/2023] [Accepted: 10/02/2023] [Indexed: 10/15/2023]
Abstract
Host-associated microbiota can be affected by factors related to environmental change, such as urbanization and invasive species. For example, urban areas often affect food availability for animals, which can change their gut microbiota. Invasive parasites can also influence microbiota through competition or indirectly through a change in the host immune response. These interacting factors can have complex effects on host fitness, but few studies have disentangled the relationship between urbanization and parasitism on an organism's gut microbiota. To address this gap in knowledge, we investigated the effects of urbanization and parasitism by the invasive avian vampire fly (Philornis downsi) on the gut microbiota of nestling small ground finches (Geospiza fuliginosa) on San Cristóbal Island, Galápagos. We conducted a factorial study in which we experimentally manipulated parasite presence in an urban and nonurban area. Faeces were then collected from nestlings to characterize the gut microbiota (i.e. bacterial diversity and community composition). Although we did not find an interactive effect of urbanization and parasitism on the microbiota, we did find main effects of each variable. We found that urban nestlings had lower bacterial diversity and different relative abundances of taxa compared to nonurban nestlings, which could be mediated by introduction of the microbiota of the food items or changes in host physiology. Additionally, parasitized nestlings had lower bacterial richness than nonparasitized nestlings, which could be mediated by a change in the immune system. Overall, this study advances our understanding of the complex effects of anthropogenic stressors on the gut microbiota of birds.
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Affiliation(s)
- Gabrielle Solomon
- Department of Ecology and Evolutionary Biology, University of Connecticut, Connecticut, Storrs, USA
| | - Ashley C Love
- Department of Ecology and Evolutionary Biology, University of Connecticut, Connecticut, Storrs, USA
| | - Grace J Vaziri
- Department of Ecology and Evolutionary Biology, University of Connecticut, Connecticut, Storrs, USA
| | - Johanna Harvey
- Department of Ecology and Evolutionary Biology, University of Connecticut, Connecticut, Storrs, USA
| | - Taylor Verrett
- Department of Ecology and Evolutionary Biology, University of Connecticut, Connecticut, Storrs, USA
| | - Kiley Chernicky
- Department of Ecology and Evolutionary Biology, University of Connecticut, Connecticut, Storrs, USA
| | - Shelby Simons
- Department of Ecology and Evolutionary Biology, University of Connecticut, Connecticut, Storrs, USA
| | - Lauren Albert
- Department of Ecology and Evolutionary Biology, University of Connecticut, Connecticut, Storrs, USA
| | - Jaime A Chaves
- Colegio de Ciencias Biológicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador
- Galapagos Science Center, Puerto Baquerizo Moreno, Galapagos, Ecuador
- Department of Biology, San Francisco State University, California, San Francisco, USA
| | - Sarah A Knutie
- Department of Ecology and Evolutionary Biology, University of Connecticut, Connecticut, Storrs, USA
- Colegio de Ciencias Biológicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador
- Institute for Systems Genomics, University of Connecticut, Connecticut, Storrs, USA
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14
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Wu Y, Li M, Tian J, Yan H, Pan Y, Shi H, Shi D, Chen J, Guo L, Feng L. Broad antagonism of coronaviruses nsp5 to evade the host antiviral responses by cleaving POLDIP3. PLoS Pathog 2023; 19:e1011702. [PMID: 37801439 PMCID: PMC10602385 DOI: 10.1371/journal.ppat.1011702] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 10/26/2023] [Accepted: 09/22/2023] [Indexed: 10/08/2023] Open
Abstract
Coronaviruses (CoVs) are a family of the largest RNA viruses that typically cause respiratory, enteric, and hepatic diseases in animals and humans, imposing great threats to the public safety and animal health. Porcine deltacoronavirus (PDCoV), a newly emerging enteropathogenic coronavirus, causes severe diarrhea in suckling piglets all over the world and poses potential risks of cross-species transmission. Here, we use PDCoV as a model of CoVs to illustrate the reciprocal regulation between CoVs infection and host antiviral responses. In this study, downregulation of DNA polymerase delta interacting protein 3 (POLDIP3) was confirmed in PDCoV infected IPEC-J2 cells by isobaric tags for relative and absolute quantification (iTRAQ) and Western blotting analysis. Overexpression of POLDIP3 inhibits PDCoV infection, whereas POLDIP3 knockout (POLDIP3-/-) by CRISPR-Cas9 editing significantly promotes PDCoV infection, indicating POLDIP3 as a novel antiviral regulator against PDCoV infection. Surprisingly, an antagonistic strategy was revealed that PDCoV encoded nonstructural protein 5 (nsp5) was responsible for POLDIP3 reduction via its 3C-like protease cleavage of POLDIP3 at the glutamine acid 176 (Q176), facilitating PDCoV infection due to the loss of antiviral effects of the cleaved fragments. Consistent with the obtained data in IPEC-J2 cell model in vitro, POLDIP3 reduction by cleavage was also corroborated in PDCoV infected-SPF piglets in vivo. Collectively, we unveiled a new antagonistic strategy evolved by PDCoV to counteract antiviral innate immunity by nsp5-mediated POLDIP3 cleavage, eventually ensuring productive virus replication. Importantly, we further demonstrated that nsp5s from PEDV and TGEV harbor the conserved function to cleave porcine POLDIP3 at the Q176 to despair POLDIP3-mediated antiviral effects. In addition, nsp5 from SARS-CoV-2 also cleaves human POLDIP3. Therefore, we speculate that coronaviruses employ similar POLDIP3 cleavage mechanisms mediated by nsp5 to antagonize the host antiviral responses to sustain efficient virus infection.
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Affiliation(s)
- Yang Wu
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Mingwei Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Jin Tian
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Haoxin Yan
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Yudi Pan
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Hongyan Shi
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Da Shi
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Jianfei Chen
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Longjun Guo
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Li Feng
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
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15
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Poydenot F, Lebreton A, Haiech J, Andreotti B. At the crossroads of epidemiology and biology: Bridging the gap between SARS-CoV-2 viral strain properties and epidemic wave characteristics. Biochimie 2023; 213:54-65. [PMID: 36931337 PMCID: PMC10017177 DOI: 10.1016/j.biochi.2023.03.006] [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: 09/29/2022] [Revised: 02/08/2023] [Accepted: 03/14/2023] [Indexed: 03/17/2023]
Abstract
The COVID-19 pandemic has given rise to numerous articles from different scientific fields (epidemiology, virology, immunology, airflow physics …) without any effort to link these different insights. In this review, we aim to establish relationships between epidemiological data and the characteristics of the virus strain responsible for the epidemic wave concerned. We have carried out this study on the Wuhan, Alpha, Delta and Omicron strains allowing us to illustrate the evolution of the relationships we have highlighted according to these different viral strains. We addressed the following questions. 1) How can the mean infectious dose (one quantum, by definition in epidemiology) be measured and expressed as an amount of viral RNA molecules (in genome units, GU) or as a number of replicative viral particles (in plaque-forming units, PFU)? 2) How many infectious quanta are exhaled by an infected person per unit of time? 3) How many infectious quanta are exhaled, on average, integrated over the whole contagious period? 4) How do these quantities relate to the epidemic reproduction rate R as measured in epidemiology, and to the viral load, as measured by molecular biological methods? 5) How has the infectious dose evolved with the different strains of SARS-CoV-2? We make use of state-of-the-art modelling, reviewed and explained in the appendix of the article (Supplemental Information, SI), to answer these questions using data from the literature in both epidemiology and virology. We have considered the modification of these relationships according to the vaccination status of the population.
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Affiliation(s)
- Florian Poydenot
- Laboratoire de Physique de l'Ecole Normale Supérieure (LPENS), CNRS UMR 8023, Ecole Normale Supérieure, Université PSL, Sorbonne Université, and Université de Paris, 75005, Paris, France
| | - Alice Lebreton
- Institut de Biologie de l'ENS (IBENS), École Normale Supérieure, CNRS, INSERM, Université PSL, 75005, Paris, France; INRAE, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Jacques Haiech
- CNRS UMR7242 BSC ESBS, 300 Bd Sébastien Brant, CS 10413, 67412, Illkirch cedex, France.
| | - Bruno Andreotti
- Laboratoire de Physique de l'Ecole Normale Supérieure (LPENS), CNRS UMR 8023, Ecole Normale Supérieure, Université PSL, Sorbonne Université, and Université de Paris, 75005, Paris, France
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16
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Wang S, Zhang K, Song X, Huang Q, Lin S, Deng S, Qi M, Yang Y, Lu Q, Zhao D, Meng F, Li J, Lian Z, Luo C, Yao Y. TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models. Cells 2023; 12:1769. [PMID: 37443803 PMCID: PMC10340758 DOI: 10.3390/cells12131769] [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: 05/29/2023] [Revised: 06/25/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023] Open
Abstract
Gram-negative bacterial infections pose a significant threat to public health. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and induces innate immune responses, autophagy, and cell death, which have major impacts on the body's physiological homeostasis. However, the role of TLR4 in bacterial LPS-induced autophagy and apoptosis in large mammals, which are closer to humans than rodents in many physiological characteristics, remains unknown. So far, few reports focus on the relationship between TLR, autophagy, and apoptosis in large mammal levels, and we urgently need more tools to further explore their crosstalk. Here, we generated a TLR4-enriched mammal model (sheep) and found that a high-dose LPS treatment blocked autophagic degradation and caused strong innate immune responses and severe apoptosis in monocytes/macrophages of transgenic offspring. Excessive accumulation of autophagosomes/autolysosomes might contribute to LPS-induced apoptosis in monocytes/macrophages of transgenic animals. Further study demonstrated that inhibiting TLR4 downstream NF-κB or p38 MAPK signaling pathways reversed the LPS-induced autophagy activity and apoptosis. These results indicate that the elevated TLR4 aggravates LPS-induced monocytes/macrophages apoptosis by leading to lysosomal dysfunction and impaired autophagic flux, which is associated with TLR4 downstream NF-κB and MAPK signaling pathways. This study provides a novel TLR4-enriched mammal model to study its potential effects on autophagy activity, inflammation, oxidative stress, and cell death. These findings also enrich the biological functions of TLR4 and provide powerful evidence for bacterial infection.
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Affiliation(s)
- Sutian Wang
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China (C.L.)
| | - Kunli Zhang
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou 510640, China
| | - Xuting Song
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Qiuyan Huang
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China (C.L.)
| | - Sen Lin
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
| | - Shoulong Deng
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
| | - Meiyu Qi
- Institute of Animal Husbandry, Heilongjiang Academy of Agricultural Sciences, Harbin 150028, China
| | - Yecheng Yang
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China (C.L.)
| | - Qi Lu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Duowei Zhao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Fanming Meng
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China (C.L.)
| | - Jianhao Li
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China (C.L.)
| | - Zhengxing Lian
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100083, China
| | - Chenglong Luo
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China (C.L.)
| | - Yuchang Yao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
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17
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Mertowska P, Smolak K, Mertowski S, Grywalska E. Immunomodulatory Role of Interferons in Viral and Bacterial Infections. Int J Mol Sci 2023; 24:10115. [PMID: 37373262 DOI: 10.3390/ijms241210115] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/02/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Interferons are a group of immunomodulatory substances produced by the human immune system in response to the presence of pathogens, especially during viral and bacterial infections. Their remarkably diverse mechanisms of action help the immune system fight infections by activating hundreds of genes involved in signal transduction pathways. In this review, we focus on discussing the interplay between the IFN system and seven medically important and challenging viruses (herpes simplex virus (HSV), influenza, hepatitis C virus (HCV), lymphocytic choriomeningitis virus (LCMV), human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), and SARS-CoV coronavirus) to highlight the diversity of viral strategies. In addition, the available data also suggest that IFNs play an important role in the course of bacterial infections. Research is currently underway to identify and elucidate the exact role of specific genes and effector pathways in generating the antimicrobial response mediated by IFNs. Despite the numerous studies on the role of interferons in antimicrobial responses, many interdisciplinary studies are still needed to understand and optimize their use in personalized therapeutics.
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Affiliation(s)
- Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Konrad Smolak
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
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18
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Rao R, Musante CJ, Allen R. A quantitative systems pharmacology model of the pathophysiology and treatment of COVID-19 predicts optimal timing of pharmacological interventions. NPJ Syst Biol Appl 2023; 9:13. [PMID: 37059734 PMCID: PMC10102696 DOI: 10.1038/s41540-023-00269-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 02/09/2023] [Indexed: 04/16/2023] Open
Abstract
A quantitative systems pharmacology (QSP) model of the pathogenesis and treatment of SARS-CoV-2 infection can streamline and accelerate the development of novel medicines to treat COVID-19. Simulation of clinical trials allows in silico exploration of the uncertainties of clinical trial design and can rapidly inform their protocols. We previously published a preliminary model of the immune response to SARS-CoV-2 infection. To further our understanding of COVID-19 and treatment, we significantly updated the model by matching a curated dataset spanning viral load and immune responses in plasma and lung. We identified a population of parameter sets to generate heterogeneity in pathophysiology and treatment and tested this model against published reports from interventional SARS-CoV-2 targeting mAb and antiviral trials. Upon generation and selection of a virtual population, we match both the placebo and treated responses in viral load in these trials. We extended the model to predict the rate of hospitalization or death within a population. Via comparison of the in silico predictions with clinical data, we hypothesize that the immune response to virus is log-linear over a wide range of viral load. To validate this approach, we show the model matches a published subgroup analysis, sorted by baseline viral load, of patients treated with neutralizing Abs. By simulating intervention at different time points post infection, the model predicts efficacy is not sensitive to interventions within five days of symptom onset, but efficacy is dramatically reduced if more than five days pass post symptom onset prior to treatment.
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Affiliation(s)
- Rohit Rao
- Early Clinical Development, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA.
| | - Cynthia J Musante
- Early Clinical Development, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA
| | - Richard Allen
- Early Clinical Development, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA
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19
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Huang Z, Guo H, Lin L, Li S, Yang Y, Han Y, Huang W, Yang J. Application of oncolytic virus in tumor therapy. J Med Virol 2023; 95:e28729. [PMID: 37185868 DOI: 10.1002/jmv.28729] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 05/17/2023]
Abstract
Oncolytic viruses (OVs) can selectively kill tumor cells without affecting normal cells, as well as activate the innate and adaptive immune systems in patients. Thus, they have been considered as a promising measure for safe and effective cancer treatment. Recently, a few genetically engineered OVs have been developed to further improve the effect of tumor elimination by expressing specific immune regulatory factors and thus enhance the body's antitumor immunity. In addition, the combined therapies of OVs and other immunotherapies have been applied in clinical. Although there are many studies on this hot topic, a comprehensive review is missing on illustrating the mechanisms of tumor clearance by OVs and how to modify engineered OVs to further enhance their antitumor effects. In this study, we provided a review on the mechanisms of immune regulatory factors in OVs. In addition, we reviewed the combined therapies of OVs with other therapies including radiotherapy and CAR-T or TCR-T cell therapy. The review is useful in further generalize the usage of OV in cancer treatment.
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Affiliation(s)
- Zhijian Huang
- Department of Breast Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Hongen Guo
- Department of Dermatology, Dermatology Hospital of Fuzhou, Fujian, Fuzhou, China
| | - Lin Lin
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Shixiong Li
- Department of Breast Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Yong Yang
- Department of Liver Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Yuanyuan Han
- Center of Tree Shrew Germplasm Resources, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
| | - Weiwei Huang
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Jialiang Yang
- Geneis Beijing Co., Ltd, Beijing, China
- Academician Workstation, Changsha Medical University, Changsha, China
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20
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Wahyuningtyas R, Wu ML, Chung WB, Chaung HC, Chang KT. Toll-like Receptor-Mediated Immunomodulation of Th1-Type Response Stimulated by Recombinant Antigen of Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2). Viruses 2023; 15:v15030775. [PMID: 36992483 PMCID: PMC10057405 DOI: 10.3390/v15030775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/05/2023] [Accepted: 03/14/2023] [Indexed: 03/22/2023] Open
Abstract
PRRSV infects CD163-positive macrophages and skews their polarization toward an M2 phenotype, followed by T-cell inactivation. In our previous study, we found that recombinant protein A1 antigen derived from PRRSV-2 was a potential vaccine or adjuvant for immunization against PRRSV-2 infection due to its ability to repolarize macrophages into M1 subtype, thereby reducing CD163 expression for viral entry and promoting immunomodulation for Th1-type responses, except for stimulating Toll-like receptor (TLR) activation. The aim of our current study was to evaluate the effects of another two recombinant antigens, A3 (ORF6L5) and A4 (NLNsp10L11), for their ability to trigger innate immune responses including TLR activation. We isolated pulmonary alveolar macrophages (PAMs) from 8- to 12-week-old specific pathogen free (SPF) piglets and stimulated them with PRRSV (0.01 MOI and 0.05 MOI) or antigens. We also investigated the T-cell differentiation by immunological synapse activation of PAMs and CD4+ T-cells in the cocultured system. To confirm the infection of PRRSV in PAMs, we checked the expression of TLR3, 7, 8, and 9. Our results showed that the expression of TLR3, 7, and 9 were significantly upregulated in PAMs by A3 antigen induction, similar to the extent of PRRSV infection. Gene profile results showed that A3 repolarizes macrophages into the M1 subtype potently, in parallel with A1, as indicated by significant upregulation of proinflammatory genes (TNF-α, IL-6, IL-1β and IL-12). Upon immunological synapse activation, A3 potentially differentiated CD4 T cells into Th1 cells, determined by the expression of IL-12 and IFN-γ secretion. On the contrary, antigen A4 promoted regulatory T cell (T-reg) differentiation by significant upregulation of IL-10 expression. Finally, we concluded that the PRRSV-2 recombinant protein A3 provided better protection against PRRSV infection, suggested by its capability to reeducate immunosuppressive M2 macrophages into proinflammatory M1 cells. As M1 macrophages are prone to be functional antigen-presenting cells (APCs), they can call for TLR activation and Th1-type immune response within the immunological synapse.
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Affiliation(s)
- Rika Wahyuningtyas
- Research Centre for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
| | - Mei-Li Wu
- Research Centre for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Department of Food Science, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
| | - Wen-Bin Chung
- Research Centre for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
| | - Hso-Chi Chaung
- Research Centre for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Flow Cytometry Center, Precision Instruments Center, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Correspondence: (H.-C.C.); (K.-T.C.)
| | - Ko-Tung Chang
- Research Centre for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Flow Cytometry Center, Precision Instruments Center, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Correspondence: (H.-C.C.); (K.-T.C.)
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21
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Zhou H, Yan Y, Gao J, Ma M, Liu Y, Shi X, Zhang Q, Xu X. Heterogeneous Nuclear Protein U Degraded the m 6A Methylated TRAF3 Transcript by YTHDF2 To Promote Porcine Epidemic Diarrhea Virus Replication. J Virol 2023; 97:e0175122. [PMID: 36752613 PMCID: PMC9973030 DOI: 10.1128/jvi.01751-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 01/06/2023] [Indexed: 02/09/2023] Open
Abstract
Porcine epidemic diarrhea virus (PEDV) belongs to the genus Alphacoronavirus of the Coronaviridae family and can cause fatal watery diarrhea in piglets, causing significant economic losses. Heterogeneous nuclear protein U (HNRNPU) is a novel RNA sensor involved in sensing viral RNA in the nucleus and mediating antiviral immunity. However, it remains elusive whether and how cytoplasmic PEDV can be sensed by the RNA sensor HNRNPU. In this study we determined that HNRNPU was the binding partner of Nsp13 by immunoprecipitation-liquid chromatography-tandem mass spectrometry (IP/LC-MS/MS) analysis. The interaction between Nsp13 and HNRNPU was demonstrated by using coimmunoprecipitation and confocal immunofluorescence. Next, we identified that HNRNPU expression is significantly increased during PEDV infection, whereas the transcription factor hepatocyte nuclear factor 1α (HNF1A) could negatively regulate HNRNPU expression. HNRNPU was retained in the cytoplasm by interaction with PEDV Nsp13. We found that HNRNPU overexpression effectively facilitated PEDV replication, while knockdown of HNRNPU impaired viral replication, suggesting a promoting function of HNRNPU to PEDV infection. Additionally, HNRNPU was found to promote PEDV replication by affecting TRAF3 degradation at the transcriptional level to inhibit PEDV-induced beta interferon (IFN-β) production. Mechanistically, HNRNPU downregulates TRAF3 mRNA levels via the METTL3-METTL14/YTHDF2 axis and regulates immune responses through YTHDF2-dependent mRNA decay. Together, our findings reveal that HNRNPU serves as a negative regulator of innate immunity by degrading TRAF3 mRNA in a YTHDF2-dependent manner and consequently facilitating PEDV propagation. Our findings provide new insights into the immune escape of PEDV. IMPORTANCE PEDV, a highly infectious enteric coronavirus, has spread rapidly worldwide and caused severe economic losses. During virus infection, the host regulates innate immunity to inhibit virus infection. However, PEDV has evolved a variety of different strategies to suppress host IFN-mediated antiviral responses. Here, we identified that HNRNPU interacted with viral protein Nsp13. HNRNPU protein expression was upregulated, and the transcription factor HNF1A could negatively regulate HNRNPU expression during PEDV infection. HNRNPU also downregulated TRAF3 mRNA through the METTL3-METTL14/YTHDF2 axis to inhibit the production of IFN-β and downstream antiviral genes in PEDV-infected cells, thereby promoting viral replication. Our findings reveal a new mechanism with which PEDV suppresses the host antiviral response.
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Affiliation(s)
- Hongchao Zhou
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Yuchao Yan
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Jie Gao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Mingrui Ma
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Yi Liu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Xiaojie Shi
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Qi Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Xingang Xu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
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22
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Lai JY, Ho JX, Kow ASF, Liang G, Tham CL, Ho YC, Lee MT. Interferon therapy and its association with depressive disorders - A review. Front Immunol 2023; 14:1048592. [PMID: 36911685 PMCID: PMC9992192 DOI: 10.3389/fimmu.2023.1048592] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 01/13/2023] [Indexed: 02/24/2023] Open
Abstract
Interferons (IFNs) are important in controlling the innate immune response to viral infections. Besides that, studies have found that IFNs also have antimicrobial, antiproliferative/antitumor and immunomodulatory effects. IFNs are divided into Type I, II and III. Type I IFNs, in particular IFN-α, is an approved treatment for hepatitis C. However, patients developed neuropsychological disorders during treatment. IFN-α induces proinflammatory cytokines, indoleamine 2,3-dioxygenase (IDO), oxidative and nitrative stress that intensifies the body's inflammatory response in the treatment of chronic inflammatory disease. The severity of the immune response is related to behavioral changes in both animal models and humans. Reactive oxygen species (ROS) is important for synaptic plasticity and long-term potentiation (LTP) in the hippocampus. However, excess ROS will generate highly reactive free radicals which may lead to neuronal damage and neurodegeneration. The limbic system regulates memory and emotional response, damage of neurons in this region is correlated with mood disorders. Due to the drawbacks of the treatment, often patients will not complete the treatment sessions, and this affects their recovery process. However, with proper management, this could be avoided. This review briefly describes the different types of IFNs and its pharmacological and clinical usages and a focus on IFN-α and its implications on depression.
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Affiliation(s)
- Jing Yung Lai
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Jian Xiang Ho
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
| | | | - Gengfan Liang
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Chau Ling Tham
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Yu-Cheng Ho
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan
| | - Ming Tatt Lee
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
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23
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Padoan E, Ferraresso S, Pegolo S, Barnini C, Castagnaro M, Bargelloni L. Gene Expression Profiles of the Immuno-Transcriptome in Equine Asthma. Animals (Basel) 2022; 13:ani13010004. [PMID: 36611613 PMCID: PMC9817691 DOI: 10.3390/ani13010004] [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: 09/30/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Mild equine asthma (MEA) and severe equine asthma (SEA) are two of the most frequent equine airway inflammatory diseases, but knowledge about their pathogenesis is limited. The goal of this study was to investigate gene expression differences in the respiratory tract of MEA- and SEA-affected horses and their relationship with clinical signs. METHODS Clinical examination and endoscopy were performed in 8 SEA- and 10 MEA-affected horses and 7 healthy controls. Cytological and microbiological analyses of bronchoalveolar lavage (BAL) fluid were performed. Gene expression profiling of BAL fluid was performed by means of a custom oligo-DNA microarray. RESULTS In both MEA and SEA, genes involved in the genesis, length, and motility of respiratory epithelium cilia were downregulated. In MEA, a significant overexpression for genes encoding inflammatory mediators was observed. In SEA, transcripts involved in bronchoconstriction, apoptosis, and hypoxia pathways were significantly upregulated, while genes involved in the formation of the protective muco-protein film were underexpressed. The SEA group also showed enrichment of gene networks activated during human asthma. CONCLUSIONS The present study provides new insight into equine asthma pathogenesis, representing the first step in transcriptomic analysis to improve diagnostic and therapeutic approaches for this respiratory disease.
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Affiliation(s)
- Elisa Padoan
- Department of Comparative Biomedicine and Food Science, University of Padova, 35020 Legnaro, Italy
| | - Serena Ferraresso
- Department of Comparative Biomedicine and Food Science, University of Padova, 35020 Legnaro, Italy
- Correspondence: ; Tel.: +39-049-8272506
| | - Sara Pegolo
- Department of Agronomy, Food, Natural Resources, Animals and Environment, University of Padova, 35020 Legnaro, Italy
| | | | - Massimo Castagnaro
- Department of Comparative Biomedicine and Food Science, University of Padova, 35020 Legnaro, Italy
| | - Luca Bargelloni
- Department of Comparative Biomedicine and Food Science, University of Padova, 35020 Legnaro, Italy
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24
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Fu C, Cao N, Liu W, Zhang Z, Yang Z, Zhu W, Fan S. Crosstalk between mitophagy and innate immunity in viral infection. Front Microbiol 2022; 13:1064045. [PMID: 36590405 PMCID: PMC9800879 DOI: 10.3389/fmicb.2022.1064045] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/29/2022] [Indexed: 12/23/2022] Open
Abstract
Mitochondria are important organelles involved in cell metabolism and programmed cell death in eukaryotic cells and are closely related to the innate immunity of host cells against viruses. Mitophagy is a process in which phagosomes selectively phagocytize damaged or dysfunctional mitochondria to form autophagosomes and is degraded by lysosomes, which control mitochondrial mass and maintain mitochondrial dynamics and cellular homeostasis. Innate immunity is an important part of the immune system and plays a vital role in eliminating viruses. Viral infection causes many physiological and pathological alterations in host cells, including mitophagy and innate immune pathways. Accumulating evidence suggests that some virus promote self-replication through regulating mitophagy-mediated innate immunity. Clarifying the regulatory relationships among mitochondria, mitophagy, innate immunity, and viral infection will shed new insight for pathogenic mechanisms and antiviral strategies. This review systemically summarizes the activation pathways of mitophagy and the relationship between mitochondria and innate immune signaling pathways, and then discusses the mechanisms of viruses on mitophagy and innate immunity and how viruses promote self-replication by regulating mitophagy-mediated innate immunity.
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Affiliation(s)
- Cheng Fu
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China
| | - Nan Cao
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China
| | - Wenjun Liu
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China
| | - Zilin Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Zihui Yang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Wenhui Zhu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China,*Correspondence: Wenhui Zhu,
| | - Shuangqi Fan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China,Shuangqi Fan,
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25
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Rhinovirus Infection and Virus-Induced Asthma. Viruses 2022; 14:v14122616. [PMID: 36560620 PMCID: PMC9781665 DOI: 10.3390/v14122616] [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: 10/18/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
While the aetiology of asthma is unclear, the onset and/or exacerbation of asthma may be associated with respiratory infections. Virus-induced asthma is also known as virus-associated/triggered asthma, and the reported main causative agent is rhinovirus (RV). Understanding the relationship between viral infections and asthma may overcome the gaps in deferential immunity between viral infections and allergies. Moreover, understanding the complicated cytokine networks involved in RV infection may be necessary. Therefore, the complexity of RV-induced asthma is not only owing to the response of airway and immune cells against viral infection, but also to allergic immune responses caused by the wide variety of cytokines produced by these cells. To better understand RV-induced asthma, it is necessary to elucidate the nature RV infections and the corresponding host defence mechanisms. In this review, we attempt to organise the complexity of RV-induced asthma to make it easily understandable for readers.
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26
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Wu Y, Shi Z, Chen J, Zhang H, Li M, Zhao Y, Shi H, Shi D, Guo L, Feng L. Porcine deltacoronavirus E protein induces interleukin-8 production via NF-κB and AP-1 activation. Vet Microbiol 2022; 274:109553. [PMID: 36181744 PMCID: PMC9428115 DOI: 10.1016/j.vetmic.2022.109553] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/22/2022] [Accepted: 08/27/2022] [Indexed: 11/23/2022]
Abstract
Infection induces the production of proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) and interleukin-6 (IL-6). Although they facilitate local antiviral immunity, their excessive release leads to life-threatening cytokine release syndrome, exemplified by the severe cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present study, we found that interleukin-8 (IL-8) was upregulated by PDCoV infection. We then demonstrated that PDCoV E protein induced IL-8 production and that the TM domain and the C-terminal domain of the E protein were important for IL-8 production. Subsequently, we showed here that deleting the AP-1 and NF-κB binding motif in porcine IL-8 promoter abrogated its activation, suggesting that IL-8 expression was dependent on AP-1 and NF-κB. Furthermore, PDCoV E induced IL-8 production, which was also dependent on the NF-κB pathway through activating nuclear factor p65 phosphorylation and NF-κB inhibitor alpha (IκBα) protein phosphorylation, as well as inducing the nuclear translocation of p65, eventually resulting in the promotion of IL-8 production. PDCoV E also activated c-fos and c-jun, both of which are members of the AP-1 family. These findings provide new insights into the molecular mechanisms of PDCoV-induced IL-8 production and help us further understand the pathogenesis of PDCoV infection.
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Affiliation(s)
- Yang Wu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
| | - Zhaorong Shi
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
| | - Jianfei Chen
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
| | - Hongling Zhang
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
| | - Mingwei Li
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
| | - Ying Zhao
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
| | - Hongyan Shi
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
| | - Da Shi
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
| | - Longjun Guo
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
| | - Li Feng
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
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27
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Juibari AD, Rezadoost MH, Soleimani M. The key role of Calpain in COVID-19 as a therapeutic strategy. Inflammopharmacology 2022; 30:1479-1491. [PMID: 35635676 PMCID: PMC9149670 DOI: 10.1007/s10787-022-01002-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/24/2022] [Indexed: 12/02/2022]
Abstract
COVID-19 is one of the viral diseases that has caused many deaths and financial losses to humans. Using the available information, this virus appears to activate the host cell-death mechanism through Calpain activation. Calpain inhibition can stop its downstream cascade reactions that cause cell death. Given the main roles of Calpain in the entry and pathogenicity of the SARS-CoV-2, its inhibition can be effective in controlling the COVID-19. This review describes how the virus activates Calpain by altering calcium flow. When Calpain was activated, the virus can enter the target cell. Subsequently, many complications of the disease, such as inflammation, cytokine storm and pulmonary fibrosis, are caused by virus-activated Calpain function. Calpain inhibitors appear to be a potential drug to control the disease and prevent death from COVID-19.
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Affiliation(s)
- Aref Doozandeh Juibari
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modarres University, Tehran, Iran
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28
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Zheng Q, Wang D, Lin R, Lv Q, Wang W. IFI44 is an immune evasion biomarker for SARS-CoV-2 and Staphylococcus aureus infection in patients with RA. Front Immunol 2022; 13:1013322. [PMID: 36189314 PMCID: PMC9520788 DOI: 10.3389/fimmu.2022.1013322] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 08/29/2022] [Indexed: 12/04/2022] Open
Abstract
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of severe coronavirus disease 2019 (COVID-19). Staphylococcus aureus is one of the most common pathogenic bacteria in humans, rheumatoid arthritis (RA) is among the most prevalent autoimmune conditions. RA is a significant risk factor for SARS-CoV-2 and S. aureus infections, although the mechanism of RA and SARS-CoV-2 infection in conjunction with S. aureus infection has not been elucidated. The purpose of this study is to investigate the biomarkers and disease targets between RA and SARS-CoV-2 and S. aureus infections using bioinformatics analysis, to search for the molecular mechanisms of SARS-CoV-2 and S. aureus immune escape and potential drug targets in the RA population, and to provide new directions for further analysis and targeted development of clinical treatments. Methods The RA dataset (GSE93272) and the S. aureus bacteremia (SAB) dataset (GSE33341) were used to obtain differentially expressed gene sets, respectively, and the common differentially expressed genes (DEGs) were determined through the intersection. Functional enrichment analysis utilizing GO, KEGG, and ClueGO methods. The PPI network was created utilizing the STRING database, and the top 10 hub genes were identified and further examined for functional enrichment using Metascape and GeneMANIA. The top 10 hub genes were intersected with the SARS-CoV-2 gene pool to identify five hub genes shared by RA, COVID-19, and SAB, and functional enrichment analysis was conducted using Metascape and GeneMANIA. Using the NetworkAnalyst platform, TF-hub gene and miRNA-hub gene networks were built for these five hub genes. The hub gene was verified utilizing GSE17755, GSE55235, and GSE13670, and its effectiveness was assessed utilizing ROC curves. CIBERSORT was applied to examine immune cell infiltration and the link between the hub gene and immune cells. Results A total of 199 DEGs were extracted from the GSE93272 and GSE33341 datasets. KEGG analysis of enrichment pathways were NLR signaling pathway, cell membrane DNA sensing pathway, oxidative phosphorylation, and viral infection. Positive/negative regulation of the immune system, regulation of the interferon-I (IFN-I; IFN-α/β) pathway, and associated pathways of the immunological response to viruses were enriched in GO and ClueGO analyses. PPI network and Cytoscape platform identified the top 10 hub genes: RSAD2, IFIT3, GBP1, RTP4, IFI44, OAS1, IFI44L, ISG15, HERC5, and IFIT5. The pathways are mainly enriched in response to viral and bacterial infection, IFN signaling, and 1,25-dihydroxy vitamin D3. IFI44, OAS1, IFI44L, ISG15, and HERC5 are the five hub genes shared by RA, COVID-19, and SAB. The pathways are primarily enriched for response to viral and bacterial infections. The TF-hub gene network and miRNA-hub gene network identified YY1 as a key TF and hsa-mir-1-3p and hsa-mir-146a-5p as two important miRNAs related to IFI44. IFI44 was identified as a hub gene by validating GSE17755, GSE55235, and GSE13670. Immune cell infiltration analysis showed a strong positive correlation between activated dendritic cells and IFI44 expression. Conclusions IFI144 was discovered as a shared biomarker and disease target for RA, COVID-19, and SAB by this study. IFI44 negatively regulates the IFN signaling pathway to promote viral replication and bacterial proliferation and is an important molecular target for SARS-CoV-2 and S. aureus immune escape in RA. Dendritic cells play an important role in this process. 1,25-Dihydroxy vitamin D3 may be an important therapeutic agent in treating RA with SARS-CoV-2 and S. aureus infections.
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Affiliation(s)
- Qingcong Zheng
- Department of Orthopedics, 900th Hospital of Joint Logistics Support Force, Fuzhou, China
| | - Du Wang
- Arthritis Clinical and Research Center, Peking University People’s Hospital, Beijing, China
| | - Rongjie Lin
- Department of Orthopedics, 900th Hospital of Joint Logistics Support Force, Fuzhou, China
| | - Qi Lv
- Department of Orthopedics, 900th Hospital of Joint Logistics Support Force, Fuzhou, China
| | - Wanming Wang
- Department of Orthopedics, 900th Hospital of Joint Logistics Support Force, Fuzhou, China
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Xiong F, Wang Q, Wu GH, Liu WZ, Wang B, Chen YJ. Direct and indirect effects of IFN-α2b in malignancy treatment: not only an archer but also an arrow. Biomark Res 2022; 10:69. [PMID: 36104718 PMCID: PMC9472737 DOI: 10.1186/s40364-022-00415-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/22/2022] [Indexed: 12/02/2022] Open
Abstract
Interferon-α2b (IFN-α2b) is a highly active cytokine that belongs to the interferon-α (IFN-α) family. IFN-α2b has beneficial antiviral, antitumour, antiparasitic and immunomodulatory activities. Direct and indirect antiproliferative effects of IFN-α2b have been found to occur via multiple pathways, mainly the JAK-STAT pathway, in certain cancers. This article reviews mechanistic studies and clinical trials on IFN-α2b. Potential regulators of the function of IFN-α2b were also reviewed, which could be utilized to relieve the poor response to IFN-α2b. IFN-α2b can function not only by enhancing the systematic immune response but also by directly killing tumour cells. Different parts of JAK-STAT pathway activated by IFN-α2b, such as interferon alpha and beta receptors (IFNARs), Janus kinases (JAKs) and IFN‐stimulated gene factor 3 (ISGF3), might serve as potential target for enhancing the pharmacological action of IFN-α2b. Despite some issues that remain to be solved, based on current evidence, IFN-α2b can inhibit disease progression and improve the survival of patients with certain types of malignant tumours. More efforts should be made to address potential adverse effects and complications.
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Wang Y, Abe JI, Chau KM, Wang Y, Vu HT, Reddy Velatooru L, Gulraiz F, Imanishi M, Samanthapudi VSK, Nguyen MTH, Ko KA, Lee LL, Thomas TN, Olmsted-Davis EA, Kotla S, Fujiwara K, Cooke JP, Zhao D, Evans SE, Le NT. MAGI1 inhibits interferon signaling to promote influenza A infection. Front Cardiovasc Med 2022; 9:791143. [PMID: 36082118 PMCID: PMC9445416 DOI: 10.3389/fcvm.2022.791143] [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: 10/08/2021] [Accepted: 07/21/2022] [Indexed: 11/21/2022] Open
Abstract
We have shown that membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1), a scaffold protein with six PSD95/DiscLarge/ZO-1 (PDZ) domains, is involved in the regulation of endothelial cell (EC) activation and atherogenesis in mice. In addition to causing acute respiratory disease, influenza A virus (IAV) infection plays an important role in atherogenesis and triggers acute coronary syndromes and fatal myocardial infarction. Therefore, the aim of this study is to investigate the function and regulation of MAGI1 in IAV-induced EC activation. Whereas, EC infection by IAV increases MAGI1 expression, MAGI1 depletion suppresses IAV infection, suggesting that the induction of MAGI1 may promote IAV infection. Treatment of ECs with oxidized low-density lipoprotein (OxLDL) increases MAGI1 expression and IAV infection, suggesting that MAGI1 is part of the mechanistic link between serum lipid levels and patient prognosis following IAV infection. Our microarray studies suggest that MAGI1-depleted ECs increase protein expression and signaling networks involve in interferon (IFN) production. Specifically, infection of MAGI1-null ECs with IAV upregulates expression of signal transducer and activator of transcription 1 (STAT1), interferon b1 (IFNb1), myxovirus resistance protein 1 (MX1) and 2'-5'-oligoadenylate synthetase 2 (OAS2), and activate STAT5. By contrast, MAGI1 overexpression inhibits Ifnb1 mRNA and MX1 expression, again supporting the pro-viral response mediated by MAGI1. MAGI1 depletion induces the expression of MX1 and virus suppression. The data suggests that IAV suppression by MAGI1 depletion may, in part, be due to MX1 induction. Lastly, interferon regulatory factor 3 (IRF3) translocates to the nucleus in the absence of IRF3 phosphorylation, and IRF3 SUMOylation is abolished in MAGI1-depleted ECs. The data suggests that MAGI1 inhibits IRF3 activation by maintaining IRF3 SUMOylation. In summary, IAV infection occurs in ECs in a MAGI1 expression-dependent manner by inhibiting anti-viral responses including STATs and IRF3 activation and subsequent MX1 induction, and MAGI1 plays a role in EC activation, and in upregulating a pro-viral response. Therefore, the inhibition of MAGI1 is a potential therapeutic target for IAV-induced cardiovascular disease.
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Affiliation(s)
- Yin Wang
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jun-ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States,*Correspondence: Jun-ichi Abe
| | - Khanh M. Chau
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States
| | - Yongxing Wang
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Hang Thi Vu
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Loka Reddy Velatooru
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States
| | - Fahad Gulraiz
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Masaki Imanishi
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | | | - Minh T. H. Nguyen
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States
| | - Kyung Ae Ko
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ling-Ling Lee
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Tamlyn N. Thomas
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elizabeth A. Olmsted-Davis
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States
| | - Sivareddy Kotla
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Keigi Fujiwara
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - John P. Cooke
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States
| | - Di Zhao
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Scott E. Evans
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States,Scott E. Evans
| | - Nhat-Tu Le
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States,Nhat-Tu Le
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Wu Y, Zhang H, Chen J, Shi Z, Li M, Zhao Y, Shi H, Shi D, Guo L, Feng L. Stromal Antigen 2 Deficiency Induces Interferon Responses and Restricts Porcine Deltacoronavirus Infection. Viruses 2022; 14:1783. [PMID: 36016405 PMCID: PMC9414771 DOI: 10.3390/v14081783] [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: 07/18/2022] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 11/20/2022] Open
Abstract
Porcine deltacoronavirus (PDCoV) is a recently discovered enteropathogenic coronavirus and has caused significant economic impacts on the pork industry. Although studies have partly uncovered the molecular mechanism of PDCoV-host interaction, it requires further research. In this study, we explored the roles of Stromal Antigen 2 (STAG2) in PDCoV infection. We found that STAG2-deficient cells inhibited infection with vesicular stomatitis virus (VSV) and PDCoV, whereas restoration of STAG2 expression in STAG2-depleted (STAG2-/-) IPEC-J2 cells line restored PDCoV infection, suggesting that STAG2 is involved in the PDCoV replication. Furthermore, we found that STAG2 deficiency results in robust interferon (IFN) expression. Subsequently, we found that STAG2 deficiency results in the activation of JAK-STAT signaling and the expression of IFN stimulated gene (ISG), which establish an antiviral state. Taken together, the depletion of STAG2 activates the JAK-STAT signaling and induces the expression of ISG, thereby inhibiting PDCoV replication. Our study provides new insights and potential therapeutic targets for unraveling the mechanism of PDCoV replication.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Longjun Guo
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China
| | - Li Feng
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China
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You J, Wu W, Lu M, Xie Y, Miao R, Gu M, Xi D, Yan W, Wu D, Wang X, Chen T, Ning Q, Han M. Hepatic exosomes with declined MiR-27b-3p trigger RIG-I/TBK1 signal pathway in macrophages. Liver Int 2022; 42:1676-1691. [PMID: 35460174 DOI: 10.1111/liv.15281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 04/18/2022] [Accepted: 04/19/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Evidence suggests that interferon alpha (IFNα) plays an essential role in decreasing the HBsAg quantification and elevating the rate of clinical cure in chronic hepatitis B (CHB). However, the mechanisms underlying the effects of the exosomes on the expression of host genes in IFNα treatment remain unclear. METHODS CHB patients with IFNα treatment were divided into responders and non-responders according to the degree of HBsAg decline. Through microRNA sequencing and a series of molecular biology methods, the key microRNAs in serum exosomes associated with clinical antiviral response of Peg-IFNα treatment in nucleotide analogue-treated CHB patients were investigated. The roles of exosomal miRNAs on the IFNα signal pathway were explored in macrophages. RESULTS MicroRNA sequencing and RT-qPCR assays confirmed six distinctly declined miRNAs in serum exosomes of responders at week 12 compared with levels at baseline. Exosomes with declined miR27b-3p in the serum of Peg-IFNα-treated responders activated phosphorylation of interferon regulatory factor 3/7 (IRF3/7) in IFNα synthesis pathway in macrophages. However, miR27b-3p overexpression in HepAD38 cells suppressed IFNα synthesis in macrophages, resulting in insufficient ability to eliminate HBV, whereas the inhibitory effect could be blocked by inhibitors of exosomes release. Luciferase assay showed miR-27b-3p directly suppressed retinoic acid-inducible gene I (RIG-I) and TANK-binding kinase 1 (TBK1) expressions, and these effects could be abrogated in mutation experiments. CONCLUSIONS In IFNα treatment, exosomes with declined miR-27b-3p triggered activation of RIG-I/TBK1 signalling in macrophages against HBV. Serum exosomal miR-27-3p might represent a potential biomarker for patients with CHB.
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Affiliation(s)
- Jie You
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Wenyu Wu
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Mengxin Lu
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Yanghao Xie
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Rui Miao
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Misi Gu
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Dong Xi
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Weiming Yan
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Di Wu
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Xiaojing Wang
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Tao Chen
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
| | - Meifang Han
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Medical Center for Major Public Health Events, Wuhan, China
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Wei M, Zheng Y, Xu J, Sun Q. AZI2 positively regulates the induction of type I interferon in influenza-trigger pediatric pneumonia. Pathog Dis 2022; 80:6590038. [PMID: 35595469 DOI: 10.1093/femspd/ftac016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/20/2022] [Accepted: 05/18/2022] [Indexed: 11/13/2022] Open
Abstract
5-azacytidine-induced protein 2 (AZI2) is known to have a crucial role in antiviral innate immunity. This study aims to explore the roles of AZI2 in influenza-trigger pediatric pneumonia and its molecular mechanism. qPCR and immunoblotting assays were used to determine the levels of target genes and proteins. The lung infection mouse model was established by using PR8 H1N1 virus in AZI2 germline knockout (AZI2-/-) and wide-type (WT) mice. In addition, HEK293T cell-based luciferase reporter assays were used to investigate the regulatory effects of AZI2 on type I interferon. Immune precipitation and immunofluorescence staining were used to evaluate the interactions between AZI2 and TANK binding kinase 1 (TBK1). We observed an elevation in the expressions of IFN-I and AZI2 in peripheral blood mononuclear cells from the pneumonia patients with mild symptoms. Interestingly, AZI2 deficiency deteriorated the influenza-induced pathological symptoms in the lung as well as reduced the survival rate. It was further showed that AZI2 positively regulated the expressions of type I interferon, inflammatory cytokines, and IFN production-related genes. The molecular mechanism data revealed that AZI2 regulated the interactions between TBK1 and TANK. In summary, AZI2 positively regulates type I interferon production in influenza-induced pediatric pneumonia by promoting the interactions between TBK1 and TANK.
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Affiliation(s)
- Meili Wei
- Department of Pediatrics, Zibo Central Hospital, NO.54 Gongqingtuan West Road, Zibo 255036, Shandong, China
| | - Yanfei Zheng
- Department of Pediatrics, Zibo Central Hospital, NO.54 Gongqingtuan West Road, Zibo 255036, Shandong, China
| | - Jing Xu
- Department of Pediatrics, Zibo Central Hospital, NO.54 Gongqingtuan West Road, Zibo 255036, Shandong, China
| | - Qiwei Sun
- Department of Pediatrics, Zibo Central Hospital, NO.54 Gongqingtuan West Road, Zibo 255036, Shandong, China
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Xu X, Wang L, Liu Y, Shi X, Yan Y, Zhang S, Zhang Q. TRIM56 overexpression restricts porcine epidemic diarrhoea virus replication in Marc-145 cells by enhancing TLR3-TRAF3-mediated IFN-β antiviral response. J Gen Virol 2022; 103. [PMID: 35503719 DOI: 10.1099/jgv.0.001748] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Infection with the porcine epidemic diarrhoea virus (PEDV) causes severe enteric disease in suckling piglets, causing massive economic losses in the swine industry worldwide. Tripartite motif-containing 56 (TRIM56) has been shown to augment type I IFN response, but whether it affects PEDV replication remains uncharacterized. Here we investigated the role of TRIM56 in Marc-145 cells during PEDV infection. We found that TRIM56 expression was upregulated in cells infected with PEDV. Overexpression of TRIM56 effectively reduced PEDV replication, while knockdown of TRIM56 resulted in increased viral replication. TRIM56 overexpression significantly increased the phosphorylation of IRF3 and NF-κB P65, and enhanced the IFN-β antiviral response, while silencing TRIM56 did not affect IRF3 activation. TRIM56 overexpression increased the protein level of TRAF3, the component of the TLR3 pathway, thereby significantly activating downstream IRF3 and NF-κB signalling. We demonstrated that TRIM56 overexpression inhibited PEDV replication and upregulated expression of IFN-β, IFN-stimulated genes (ISGs) and chemokines in a dose-dependent manner. Moreover, truncations of the RING domain, N-terminal domain or C-terminal portion on TRIM56 were unable to induce IFN-β expression and failed to restrict PEDV replication. Together, our results suggested that TRIM56 was upregulated in Marc-145 cells in response to PEDV infection. Overexpression of TRIM56 inhibited PEDV replication by positively regulating the TLR3-mediated antiviral signalling pathway. These findings provide evidence that TRIM56 plays a positive role in the innate immune response during PEDV infection.
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Affiliation(s)
- Xingang Xu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Lixiang Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Yi Liu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Xiaojie Shi
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Yuchao Yan
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Shuxia Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Qi Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, PR China
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Label-free proteomics-based analysis of peripheral nerve injury induced by Japanese encephalitis virus. J Proteomics 2022; 264:104619. [DOI: 10.1016/j.jprot.2022.104619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/08/2022] [Accepted: 05/14/2022] [Indexed: 11/20/2022]
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Shinchi H, Komaki F, Yuki M, Ohara H, Hayakawa N, Wakao M, Cottam HB, Hayashi T, Carson DA, Moroishi T, Suda Y. Glyco-Nanoadjuvants: Impact of Linker Length for Conjugating a Synthetic Small-Molecule TLR7 Ligand to Glyco-Nanoparticles on Immunostimulatory Effects. ACS Chem Biol 2022; 17:957-968. [PMID: 35353497 DOI: 10.1021/acschembio.2c00108] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Immunotherapy has become a powerful clinical strategy for treating infectious diseases and cancer. Synthetic small-molecule toll-like receptor 7 (TLR7) ligands are attractive candidates as immunostimulatory agents for immunotherapy. TLR7 is mainly localized in intracellular endosomal compartments so that the formulation of their small-molecule ligands with macromolecules enhances endocytic uptake of TLR7 ligands and improves the pharmaceutical properties. Previously, we demonstrated that gold nanoparticles co-immobilized with a TLR7 ligand derivative, that is, a conjugate of synthetic small-molecule TLR7 ligand (1V209) and thioctic acid (TA) via 4,7,10-trioxa-1,13-tridecanediamine, and α-mannose (1V209-αMan-GNPs: glyco-nanoadjuvants) significantly enhances immunostimulatory effects. In the present study, we designed a second-generation glyco-nanoadjuvant that possesses a poly(ethylene glycol) (PEG) chain as a spacer between 1V209 and GNPs and investigated the impact of linker length in 1V209 derivatives on the immunostimulatory activities. We used different chain lengths of PEG (n = 3, 5, 11, or 23) as spacers between 1V209 and thioctic acid to prepare four 1V209-αMan-GNPs. In the in vitro study using primary mouse bone-marrow-derived dendritic cells, 1V209-αMan-GNPs that immobilized with longer 1V209 derivatives, especially the 1V209 derivative possessing PEG23 (1V209-PEG23-TA), showed the highest potency toward induction both for interleukin-6 and type I interferon production than those derivatives with shorter PEG chains. Furthermore, 1V209-αMan-GNPs that immobilized with 1V209-PEG23-TA showed significantly higher adjuvant effects for inducing both humoral and cell-mediated immune responses against ovalbumin in the in vivo immunization study. These results indicate that the linker length for immobilizing small-molecule TLR7 ligand on the GNPs significantly affects the adjuvant activity of 1V209-αMan-GNPs and that 1V209-αMan-GNPs immobilized with 1V209-PEG-23-TA could be superior adjuvants for immunotherapies.
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Affiliation(s)
- Hiroyuki Shinchi
- Department of Chemistry, Biotechnology and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan
| | - Fumikazu Komaki
- Department of Chemistry, Biotechnology and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan
| | - Masaharu Yuki
- Department of Chemistry, Biotechnology and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan
| | - Haruka Ohara
- Department of Chemistry, Biotechnology and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan
| | - Naohiro Hayakawa
- Department of Chemistry, Biotechnology and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan
| | - Masahiro Wakao
- Department of Chemistry, Biotechnology and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan
| | - Howard B. Cottam
- Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0809, United States
| | - Tomoko Hayashi
- Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0809, United States
| | - Dennis A. Carson
- Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0809, United States
| | - Toshiro Moroishi
- Department of Cell Signaling and Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Yasuo Suda
- Department of Chemistry, Biotechnology and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan
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Abstract
The global coronavirus disease-19 (COVID-19) has affected more than 140 million and killed more than 3 million people worldwide as of April 20, 2021. The novel human severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been identified as an etiological agent for COVID-19. Several kinases have been proposed as possible mediators of multiple viral infections, including life-threatening coronaviruses like SARS-CoV-1, Middle East syndrome coronavirus (MERS-CoV), and SARS-CoV-2. Viral infections hijack abundant cell signaling pathways, resulting in drastic phosphorylation rewiring in the host and viral proteins. Some kinases play a significant role throughout the viral infection cycle (entry, replication, assembly, and egress), and several of them are involved in the virus-induced hyperinflammatory response that leads to cytokine storm, acute respiratory distress syndrome (ARDS), organ injury, and death. Here, we highlight kinases that are associated with coronavirus infections and their inhibitors with antiviral and potentially anti-inflammatory, cytokine-suppressive, or antifibrotic activity.
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Affiliation(s)
- Thanigaimalai Pillaiyar
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry
and Tuebingen Center for Academic Drug Discovery, Eberhard Karls University
Tübingen, Auf der Morgenstelle 8, 72076 Tübingen,
Germany
| | - Stefan Laufer
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry
and Tuebingen Center for Academic Drug Discovery, Eberhard Karls University
Tübingen, Auf der Morgenstelle 8, 72076 Tübingen,
Germany
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Astrocyte Control of Zika Infection Is Independent of Interferon Type I and Type III Expression. BIOLOGY 2022; 11:biology11010143. [PMID: 35053142 PMCID: PMC8772967 DOI: 10.3390/biology11010143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 12/23/2022]
Abstract
Simple Summary Zika virus (ZIKV) is a mosquito-borne virus first isolated from the Zika forest, Uganda, in 1947, which has been spreading across continents since then. We now know ZIKV causes both microencephaly in newborns and neurological complications in adults; however, no effective treatment options have yet been found. A more complete understanding of Zika-infection-mediated pathogenesis and host responses is required to enable the development of novel treatment strategies. In this study, efforts were made to elucidate the host responses following Zika virus infection using several astrocyte cell models, as astrocytes are a major cell type within the central nervous system (CNS) with significant antiviral ability. Our data suggest that astrocytes can resist ZIKV both in an interferon type I- and III-independent manner and suggest that an early and more diverse antiviral response may be more effective in controlling Zika infection. This study also identifies astrocyte cellular models that appear to display differential abilities in the control of viral infection, which may assist in the study of alternate neurotropic virus infections. Overall, this work adds to the growing body of knowledge surrounding ZIKV-mediated cellular host interactions and will contribute to a better understanding of ZIKV-mediated pathogenesis. Abstract Zika virus (ZIKV) is a pathogenic neurotropic virus that infects the central nervous system (CNS) and results in various neurological complications. Astrocytes are the dominant CNS cell producer of the antiviral cytokine IFN-β, however little is known about the factors involved in their ability to mediate viral infection control. Recent studies have displayed differential responses in astrocytes to ZIKV infection, and this study sought to elucidate astrocyte cell-specific responses to ZIKV using a variety of cell models infected with either the African (MR766) or Asian (PRVABC59) ZIKV strains. Expression levels of pro-inflammatory (TNF-α and IL-1β) and inflammatory (IL-8) cytokines following viral infection were low and mostly comparable within the ZIKV-resistant and ZIKV-susceptible astrocyte models, with better control of proinflammatory cytokines displayed in resistant astrocyte cells, synchronising with the viral infection level at specific timepoints. Astrocyte cell lines displaying ZIKV-resistance also demonstrated early upregulation of multiple antiviral genes compared with susceptible astrocytes. Interestingly, pre-stimulation of ZIKV-susceptible astrocytes with either poly(I:C) or poly(dA:dT) showed efficient protection against ZIKV compared with pre-stimulation with either recombinant IFN-β or IFN-λ, perhaps indicating that a more diverse antiviral gene expression is necessary for astrocyte control of ZIKV, and this is driven in part through interferon-independent mechanisms.
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Lenoir JJ, Parisien JP, Horvath CM. Immune regulator LGP2 targets Ubc13/UBE2N to mediate widespread interference with K63 polyubiquitination and NF-κB activation. Cell Rep 2021; 37:110175. [PMID: 34965427 DOI: 10.1016/j.celrep.2021.110175] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 09/27/2021] [Accepted: 12/02/2021] [Indexed: 11/17/2022] Open
Abstract
Lysine 63-linked polyubiquitin (K63-Ub) chains activate a range of cellular immune and inflammatory signaling pathways, including the mammalian antiviral response. Interferon and antiviral genes are triggered by TRAF family ubiquitin ligases that form K63-Ub chains. LGP2 is a feedback inhibitor of TRAF-mediated K63-Ub that can interfere with diverse immune signaling pathways. Our results demonstrate that LGP2 inhibits K63-Ub by association with and sequestration of the K63-Ub-conjugating enzyme, Ubc13/UBE2N. The LGP2 helicase subdomain, Hel2i, mediates protein interaction that engages and inhibits Ubc13/UBE2N, affecting control over a range of K63-Ub ligase proteins, including TRAF6, TRIM25, and RNF125, all of which are inactivated by LGP2. These findings establish a unifying mechanism for LGP2-mediated negative regulation that can modulate a variety of K63-Ub signaling pathways.
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Affiliation(s)
- Jessica J Lenoir
- Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA
| | | | - Curt M Horvath
- Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
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Abstract
Cytokines belong to the most widely studied group of intracellular molecules involved in the function of the immune system. Their secretion is induced by various infectious stimuli. Cytokine release by host cells has been extensively used as a powerful tool for studying immune reactions in the early stages of viral and bacterial infections. Recently, research attention has shifted to the investigation of cytokine responses using mRNA expression, an essential mechanism related to pathogenic and nonpathogenic-immune stimulants in fish. This review represents the current knowledge of cytokine responses to infectious diseases in the common carp (Cyprinus carpio L.). Given the paucity of literature on cytokine responses to many infections in carp, only select viral diseases, such as koi herpesvirus disease (KHVD), spring viremia of carp (SVC), and carp edema virus disease (CEVD), are discussed. Aeromonas hydrophila is one of the most studied bacterial pathogens associated with cytokine responses in common carp. Therefore, the cytokine-based immunoreactivity raised by this specific bacterial pathogen is also highlighted in this review.
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Locke M, Lythe G, López-García M, Muñoz-Fontela C, Carroll M, Molina-París C. Quantification of Type I Interferon Inhibition by Viral Proteins: Ebola Virus as a Case Study. Viruses 2021; 13:v13122441. [PMID: 34960709 PMCID: PMC8705787 DOI: 10.3390/v13122441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/22/2021] [Accepted: 11/27/2021] [Indexed: 11/16/2022] Open
Abstract
Type I interferons (IFNs) are cytokines with both antiviral properties and protective roles in innate immune responses to viral infection. They induce an antiviral cellular state and link innate and adaptive immune responses. Yet, viruses have evolved different strategies to inhibit such host responses. One of them is the existence of viral proteins which subvert type I IFN responses to allow quick and successful viral replication, thus, sustaining the infection within a host. We propose mathematical models to characterise the intra-cellular mechanisms involved in viral protein antagonism of type I IFN responses, and compare three different molecular inhibition strategies. We study the Ebola viral protein, VP35, with this mathematical approach. Approximate Bayesian computation sequential Monte Carlo, together with experimental data and the mathematical models proposed, are used to perform model calibration, as well as model selection of the different hypotheses considered. Finally, we assess if model parameters are identifiable and discuss how such identifiability can be improved with new experimental data.
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Affiliation(s)
- Macauley Locke
- Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds LS2 9JT, UK; (M.L.); (G.L.); (M.L.-G.)
| | - Grant Lythe
- Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds LS2 9JT, UK; (M.L.); (G.L.); (M.L.-G.)
| | - Martín López-García
- Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds LS2 9JT, UK; (M.L.); (G.L.); (M.L.-G.)
| | - César Muñoz-Fontela
- Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Straße 74, 20359 Hamburg, Germany;
- German Center for Infection Research (DZIF), Partner Site Hamburg, Bernhard Nocht Straße 74, 20359 Hamburg, Germany
| | - Miles Carroll
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK;
| | - Carmen Molina-París
- Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds LS2 9JT, UK; (M.L.); (G.L.); (M.L.-G.)
- T-6, Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
- Correspondence:
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Feige L, Zaeck LM, Sehl-Ewert J, Finke S, Bourhy H. Innate Immune Signaling and Role of Glial Cells in Herpes Simplex Virus- and Rabies Virus-Induced Encephalitis. Viruses 2021; 13:2364. [PMID: 34960633 PMCID: PMC8708193 DOI: 10.3390/v13122364] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 11/12/2021] [Accepted: 11/18/2021] [Indexed: 12/19/2022] Open
Abstract
The environment of the central nervous system (CNS) represents a double-edged sword in the context of viral infections. On the one hand, the infectious route for viral pathogens is restricted via neuroprotective barriers; on the other hand, viruses benefit from the immunologically quiescent neural environment after CNS entry. Both the herpes simplex virus (HSV) and the rabies virus (RABV) bypass the neuroprotective blood-brain barrier (BBB) and successfully enter the CNS parenchyma via nerve endings. Despite the differences in the molecular nature of both viruses, each virus uses retrograde transport along peripheral nerves to reach the human CNS. Once inside the CNS parenchyma, HSV infection results in severe acute inflammation, necrosis, and hemorrhaging, while RABV preserves the intact neuronal network by inhibiting apoptosis and limiting inflammation. During RABV neuroinvasion, surveilling glial cells fail to generate a sufficient type I interferon (IFN) response, enabling RABV to replicate undetected, ultimately leading to its fatal outcome. To date, we do not fully understand the molecular mechanisms underlying the activation or suppression of the host inflammatory responses of surveilling glial cells, which present important pathways shaping viral pathogenesis and clinical outcome in viral encephalitis. Here, we compare the innate immune responses of glial cells in RABV- and HSV-infected CNS, highlighting different viral strategies of neuroprotection or Neuroinflamm. in the context of viral encephalitis.
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Affiliation(s)
- Lena Feige
- Institut Pasteur, Université de Paris, Lyssavirus Epidemiology and Neuropathology, 28 Rue Du Docteur Roux, 75015 Paris, France;
| | - Luca M. Zaeck
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut (FLI), Federal Institute of Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany; (L.M.Z.); (S.F.)
| | - Julia Sehl-Ewert
- Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut (FLI), Federal Institute of Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany;
| | - Stefan Finke
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut (FLI), Federal Institute of Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany; (L.M.Z.); (S.F.)
| | - Hervé Bourhy
- Institut Pasteur, Université de Paris, Lyssavirus Epidemiology and Neuropathology, 28 Rue Du Docteur Roux, 75015 Paris, France;
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Ekanayaka P, Shin SH, Weeratunga P, Lee H, Kim TH, Chathuranga K, Subasinghe A, Park JH, Lee JS. Foot-and-Mouth Disease Virus 3C Protease Antagonizes Interferon Signaling and C142T Substitution Attenuates the FMD Virus. Front Microbiol 2021; 12:737031. [PMID: 34867853 PMCID: PMC8639872 DOI: 10.3389/fmicb.2021.737031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 10/28/2021] [Indexed: 12/24/2022] Open
Abstract
3C protease (3Cpro), a chymotrypsin-like cysteine protease encoded by the foot-and-mouth disease virus (FMDV), plays an essential role in processing the FMDV P1 polyprotein into individual viral capsid proteins in FMDV replication. Previously, it has been shown that 3Cpro is involved in the blockage of the host type-I interferon (IFN) responses by FMDV. However, the underlying mechanisms are poorly understood. Here, we demonstrated that the protease activity of 3Cpro contributed to the degradation of RIG-I and MDA5, key cytosolic sensors of the type-I IFN signaling cascade in proteasome, lysosome and caspase-independent manner. And also, we examined the degradation ability on RIG-I and MDA5 of wild-type FMDV 3Cpro and FMDV 3Cpro C142T mutant which is known to significantly alter the enzymatic activity of 3Cpro. The results showed that the FMDV 3Cpro C142T mutant dramatically reduce the degradation of RIG-I and MDA5 due to weakened protease activity. Thus, the protease activity of FMDV 3Cpro governs its RIG-I and MDA5 degradation ability and subsequent negative regulation of the type-I IFN signaling. Importantly, FMD viruses harboring 3Cpro C142T mutant showed the moderate attenuation of FMDV in a pig model. In conclusion, our results indicate that a novel mechanism evolved by FMDV 3Cpro to counteract host type-I IFN responses and a rational approach to virus attenuation that could be utilized for future vaccine development.
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Affiliation(s)
- Pathum Ekanayaka
- College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea
| | - Sung Ho Shin
- Animal and Plant Quarantine Agency, Gyeongsangbuk-do, South Korea
| | - Prasanna Weeratunga
- College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea
| | - Hyuncheol Lee
- College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea
- California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, United States
| | - Tae-Hwan Kim
- College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea
- Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Kiramage Chathuranga
- College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea
| | - Ashan Subasinghe
- College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea
| | - Jong-Hyeon Park
- Animal and Plant Quarantine Agency, Gyeongsangbuk-do, South Korea
| | - Jong-Soo Lee
- College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea
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Shi LZ, Bonner JA. Bridging Radiotherapy to Immunotherapy: The IFN-JAK-STAT Axis. Int J Mol Sci 2021; 22:12295. [PMID: 34830176 PMCID: PMC8619591 DOI: 10.3390/ijms222212295] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/10/2021] [Accepted: 11/12/2021] [Indexed: 12/12/2022] Open
Abstract
The unprecedented successes of immunotherapies (IOs) including immune checkpoint blockers (ICBs) and adoptive T-cell therapy (ACT) in patients with late-stage cancer provide proof-of-principle evidence that harnessing the immune system, in particular T cells, can be an effective approach to eradicate cancer. This instills strong interests in understanding the immunomodulatory effects of radiotherapy (RT), an area that was actually investigated more than a century ago but had been largely ignored for many decades. With the "newly" discovered immunogenic responses from RT, numerous endeavors have been undertaken to combine RT with IOs, in order to bolster anti-tumor immunity. However, the underlying mechanisms are not well defined, which is a subject of much investigation. We therefore conducted a systematic literature search on the molecular underpinnings of RT-induced immunomodulation and IOs, which identified the IFN-JAK-STAT pathway as a major regulator. Our further analysis of relevant studies revealed that the signaling strength and duration of this pathway in response to RT and IOs may determine eventual immunological outcomes. We propose that strategic targeting of this axis can boost the immunostimulatory effects of RT and radiosensitizing effects of IOs, thereby promoting the efficacy of combination therapy of RT and IOs.
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Affiliation(s)
- Lewis Zhichang Shi
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
- Programs in Immunology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - James A. Bonner
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA
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Getz M, Wang Y, An G, Asthana M, Becker A, Cockrell C, Collier N, Craig M, Davis CL, Faeder JR, Ford Versypt AN, Mapder T, Gianlupi JF, Glazier JA, Hamis S, Heiland R, Hillen T, Hou D, Islam MA, Jenner AL, Kurtoglu F, Larkin CI, Liu B, Macfarlane F, Maygrundter P, Morel PA, Narayanan A, Ozik J, Pienaar E, Rangamani P, Saglam AS, Shoemaker JE, Smith AM, Weaver JJA, Macklin P. Iterative community-driven development of a SARS-CoV-2 tissue simulator. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021:2020.04.02.019075. [PMID: 32511322 PMCID: PMC7239052 DOI: 10.1101/2020.04.02.019075] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The 2019 novel coronavirus, SARS-CoV-2, is a pathogen of critical significance to international public health. Knowledge of the interplay between molecular-scale virus-receptor interactions, single-cell viral replication, intracellular-scale viral transport, and emergent tissue-scale viral propagation is limited. Moreover, little is known about immune system-virus-tissue interactions and how these can result in low-level (asymptomatic) infections in some cases and acute respiratory distress syndrome (ARDS) in others, particularly with respect to presentation in different age groups or pre-existing inflammatory risk factors. Given the nonlinear interactions within and among each of these processes, multiscale simulation models can shed light on the emergent dynamics that lead to divergent outcomes, identify actionable "choke points" for pharmacologic interventions, screen potential therapies, and identify potential biomarkers that differentiate patient outcomes. Given the complexity of the problem and the acute need for an actionable model to guide therapy discovery and optimization, we introduce and iteratively refine a prototype of a multiscale model of SARS-CoV-2 dynamics in lung tissue. The first prototype model was built and shared internationally as open source code and an online interactive model in under 12 hours, and community domain expertise is driving regular refinements. In a sustained community effort, this consortium is integrating data and expertise across virology, immunology, mathematical biology, quantitative systems physiology, cloud and high performance computing, and other domains to accelerate our response to this critical threat to international health. More broadly, this effort is creating a reusable, modular framework for studying viral replication and immune response in tissues, which can also potentially be adapted to related problems in immunology and immunotherapy.
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Kim H, Subbannayya Y, Humphries F, Skejsol A, Pinto SM, Giambelluca M, Espevik T, Fitzgerald KA, Kandasamy RK. UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis. PLoS One 2021; 16:e0258989. [PMID: 34705862 PMCID: PMC8550426 DOI: 10.1371/journal.pone.0258989] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 10/09/2021] [Indexed: 12/30/2022] Open
Abstract
Toll-like receptors (TLRs) are highly-conserved pattern recognition receptors that mediate innate immune responses to invading pathogens and endogenous danger signals released from damaged and dying cells. Activation of TLRs trigger downstream signaling cascades, that culminate in the activation of interferon regulatory factors (IRFs), which subsequently leads to type I interferon (IFN) response. In the current study, we sought to expand the scope of gene expression changes in THP1-derived macrophages upon TLR4 activation and to identify interferon-stimulated genes. RNA-seq analysis led to the identification of several known and novel differentially expressed genes, including CMPK2, particularly in association with type I IFN signaling. We performed an in-depth characterization of CMPK2 expression, a nucleoside monophosphate kinase that supplies intracellular UTP/CTP for nucleic acid synthesis in response to type I IFN signaling in macrophages. CMPK2 was significantly induced at both RNA and protein levels upon stimulation with TLR4 ligand-LPS and TLR3 ligand-Poly (I:C). Confocal microscopy and subcellular fractionation indicated CMPK2 localization in both cytoplasm and mitochondria of THP-1 macrophages. Furthermore, neutralizing antibody-based inhibition of IFNAR receptor in THP-1 cells and BMDMs derived from IFNAR KO and IRF3 KO knockout mice further revealed that CMPK2 expression is dependent on LPS/Poly (I:C) mediated IRF3- type I interferon signaling. In summary, our findings suggest that CMPK2 is a potential interferon-stimulated gene in THP-1 macrophages and that CMPK2 may facilitate IRF3- type I IFN-dependent anti-bacterial and anti-viral roles.
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Affiliation(s)
- Hera Kim
- Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, Norway
| | - Yashwanth Subbannayya
- Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, Norway
| | - Fiachra Humphries
- Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA, United States of America
| | - Astrid Skejsol
- Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, Norway
| | - Sneha M. Pinto
- Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, Norway
| | - Miriam Giambelluca
- Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, Norway
| | - Terje Espevik
- Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, Norway
| | - Katherine A. Fitzgerald
- Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA, United States of America
| | - Richard K. Kandasamy
- Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, Trondheim, Norway
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE
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Zhou J, Huang S, Fan B, Niu B, Guo R, Gu J, Gao S, Li B. iTRAQ-based proteome analysis of porcine group A rotavirus-infected porcine IPEC-J2 intestinal epithelial cells. J Proteomics 2021; 248:104354. [PMID: 34418579 DOI: 10.1016/j.jprot.2021.104354] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 07/20/2021] [Accepted: 08/10/2021] [Indexed: 11/25/2022]
Abstract
Porcine rotavirus (PoRV), particularly group A, is one of the most important swine pathogens, causing substantial economic losses in the animal husbandry industry. To improve understanding of host responses to PoRV infection, we applied isobaric tags for relative and absolute quantification (iTRAQ) labeling coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantitatively identify the differentially expressed proteins in PoRV-infected IPEC-J2 cells and confirmed the differentially accumulated proteins (DAPs) expression differences by performing RT-qPCR and Western blot analysis. Herein, in PoRV- and mock-infected IPEC-J2 cells, relative quantitative data were identified for 4724 proteins, 223 of which were DAPs (125 up-accumulated and 98 down-accumulated). Bioinformatics analyses further revealed that a majority of the DAPs are involved in numerous crucial biological processes and signaling pathways, such as metabolic process, immune system process, amino acid metabolism, energy metabolism, immune system, MHC class I peptide loading complex, Hippo signaling pathway, Th1 and Th2 cell differentiation, antigen processing and presentation, and tubule bicarbonate reclamation. The cellular localization prediction analysis indicated that these DAPs may be located in the Golgi apparatus, nucleus, peroxisomal, cytoplasm, mitochondria, extracellular, plasma membrane, and endoplasmic reticulum (ER). Expression levels of three up-accumulated (VAMP4, IKBKE, and TJP3) or two down-accumulated (SOD3 and DHX9) DAPs upon PoRV infection, were further validated by RT-qPCR and Western blot analysis. Collectively, this work is the first time to investigate the protein profile of PoRV-infected IPEC-J2 cells using quantitative proteomics; these findings provide valuable information to better understand the mechanisms underlying the host responses to PoRV infection in piglets. SIGNIFICANCE: The proteomics analysis of this study uncovered the target associated with PoRV-induced innate immune response or cellular damage, and provided relevant insights into the molecular functions, biological processes, and signaling pathway in these targets. Out of these 223 DAPs, the expression levels of three up-accumulated (VAMP4, IKBKE, and TJP3) and two down-accumulated (SOD3 and DHX9) DAPs upon PoRV infection, have been further validated using RT-qPCR and Western blot analysis. These outcomes could uncover how PoRV manipulated the cellular machinery, which could further our understanding of PoRV pathogenesis in piglets.
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Affiliation(s)
- Jinzhu Zhou
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing 210014, Jiangsu, China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonose, Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou 225009, PR China
| | - Shimeng Huang
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing 210014, Jiangsu, China
| | - Baochao Fan
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing 210014, Jiangsu, China; School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Beibei Niu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing 210014, Jiangsu, China; College of Veterinary Medicine, Nanjing Agricultural University, No.1 Wei-gang, Nanjing 210095, China
| | - Rongli Guo
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing 210014, Jiangsu, China
| | - Jun Gu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing 210014, Jiangsu, China; School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
| | - Song Gao
- Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonose, Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou 225009, PR China
| | - Bin Li
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing 210014, Jiangsu, China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonose, Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou 225009, PR China; School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; School of Life Sciences, Jiangsu University, Zhenjiang 212013, China.
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48
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Wang H, Zheng Y, Huang J, Li J. Mitophagy in Antiviral Immunity. Front Cell Dev Biol 2021; 9:723108. [PMID: 34540840 PMCID: PMC8446632 DOI: 10.3389/fcell.2021.723108] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/06/2021] [Indexed: 12/22/2022] Open
Abstract
Mitochondria are important organelles whose primary function is energy production; in addition, they serve as signaling platforms for apoptosis and antiviral immunity. The central role of mitochondria in oxidative phosphorylation and apoptosis requires their quality to be tightly regulated. Mitophagy is the main cellular process responsible for mitochondrial quality control. It selectively sends damaged or excess mitochondria to the lysosomes for degradation and plays a critical role in maintaining cellular homeostasis. However, increasing evidence shows that viruses utilize mitophagy to promote their survival. Viruses use various strategies to manipulate mitophagy to eliminate critical, mitochondria-localized immune molecules in order to escape host immune attacks. In this article, we will review the scientific advances in mitophagy in viral infections and summarize how the host immune system responds to viral infection and how viruses manipulate host mitophagy to evade the host immune system.
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Affiliation(s)
- Hongna Wang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou, China.,GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yongfeng Zheng
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou, China
| | - Jieru Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou, China
| | - Jin Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou, China
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49
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Jangra S, Landers JJ, Rathnasinghe R, O’Konek JJ, Janczak KW, Cascalho M, Kennedy AA, Tai AW, Baker JR, Schotsaert M, Wong PT. A Combination Adjuvant for the Induction of Potent Antiviral Immune Responses for a Recombinant SARS-CoV-2 Protein Vaccine. Front Immunol 2021; 12:729189. [PMID: 34603303 PMCID: PMC8481386 DOI: 10.3389/fimmu.2021.729189] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 01/03/2023] Open
Abstract
Several SARS-CoV-2 vaccines have received EUAs, but many issues remain unresolved, including duration of conferred immunity and breadth of cross-protection. Adjuvants that enhance and shape adaptive immune responses that confer broad protection against SARS-CoV-2 variants will be pivotal for long-term protection as drift variants continue to emerge. We developed an intranasal, rationally designed adjuvant integrating a nanoemulsion (NE) that activates TLRs and NLRP3 with an RNA agonist of RIG-I (IVT DI). The combination adjuvant with spike protein antigen elicited robust responses to SARS-CoV-2 in mice, with markedly enhanced TH1-biased cellular responses and high virus-neutralizing antibody titers towards both homologous SARS-CoV-2 and a variant harboring the N501Y mutation shared by B1.1.7, B.1.351 and P.1 variants. Furthermore, passive transfer of vaccination-induced antibodies protected naive mice against heterologous viral challenge. NE/IVT DI enables mucosal vaccination, and has the potential to improve the immune profile of a variety of SARS-CoV-2 vaccine candidates to provide effective cross-protection against future drift variants.
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MESH Headings
- Adaptive Immunity/immunology
- Adjuvants, Immunologic/pharmacology
- Animals
- Antibodies, Neutralizing/blood
- Antibodies, Neutralizing/immunology
- Antibodies, Viral/blood
- Antibodies, Viral/immunology
- COVID-19/prevention & control
- COVID-19 Vaccines/immunology
- Chlorocebus aethiops
- Cross Protection/immunology
- DEAD Box Protein 58
- HEK293 Cells
- Humans
- Immunity, Humoral/immunology
- Immunization, Passive
- Mice
- Mice, Inbred C57BL
- Receptors, Immunologic/agonists
- Recombinant Proteins/immunology
- SARS-CoV-2/immunology
- Spike Glycoprotein, Coronavirus/immunology
- Vaccination
- Vaccines, Synthetic/immunology
- Vero Cells
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Affiliation(s)
- Sonia Jangra
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, NY, United States
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jeffrey J. Landers
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
- Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, United States
- Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Raveen Rathnasinghe
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, NY, United States
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jessica J. O’Konek
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
- Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, United States
- Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Katarzyna W. Janczak
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
- Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, United States
- Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Marilia Cascalho
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Andrew A. Kennedy
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Andrew W. Tai
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
- Medicine Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, United States
| | - James R. Baker
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
- Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, United States
- Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Michael Schotsaert
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, NY, United States
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Pamela T. Wong
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
- Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, United States
- Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, United States
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50
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Ekanayaka P, Lee BH, Weerawardhana A, Chathuranga K, Park JH, Lee JS. Inhibition of MAVS Aggregation-Mediated Type-I Interferon Signaling by Foot-and-Mouth Disease Virus VP3. Viruses 2021; 13:v13091776. [PMID: 34578357 PMCID: PMC8473216 DOI: 10.3390/v13091776] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/30/2021] [Accepted: 08/30/2021] [Indexed: 01/19/2023] Open
Abstract
As a structural protein of the Foot-and-mouth disease virus (FMDV), VP3 plays a vital role in virus assembly and inhibiting the interferon (IFN) signal transduction to promote FMDV replication. Previous studies demonstrated that FMDV VP3 blocks the type-I IFN response by inhibiting the mRNA expression of the mitochondrial antiviral-signaling protein (MAVS); however, the underlying mechanism is poorly understood. Here, we describe the specificity of FMDV VP3 interaction with the transmembrane (TM) domain of MAVS as FMDV driven type-I IFN inhibitory mechanism for its effective replication. The TM domain of MAVS governs the mitochondria localization of MAVS, and it is a key factor in type-I IFN signaling transduction via MAVS aggregation. Thereby, the interaction of FMDV VP3 with the TM domain of MAVS leads to the inhibition of MAVS mitochondria localization, self-association, and aggregation, resulting in the suppression of type-I IFN response. Collectively, these results provide a clear understanding of a key molecular mechanism used by the FMDV VP3 for the suppression of IFN responses via targeting MAVS.
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Affiliation(s)
- Pathum Ekanayaka
- College of Veterinary Medicine, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon 34134, Korea; (P.E.); (B.-H.L.); (A.W.); (K.C.)
| | - Byeong-Hoon Lee
- College of Veterinary Medicine, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon 34134, Korea; (P.E.); (B.-H.L.); (A.W.); (K.C.)
| | - Asela Weerawardhana
- College of Veterinary Medicine, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon 34134, Korea; (P.E.); (B.-H.L.); (A.W.); (K.C.)
| | - Kiramage Chathuranga
- College of Veterinary Medicine, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon 34134, Korea; (P.E.); (B.-H.L.); (A.W.); (K.C.)
| | - Jong-Hyeon Park
- Animal and Plant Quarantine Agency, 177 Hyeoksin 8-ro, Gyeongsangbuk-do, Gimcheon-si 39660, Korea;
| | - Jong-Soo Lee
- College of Veterinary Medicine, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon 34134, Korea; (P.E.); (B.-H.L.); (A.W.); (K.C.)
- Correspondence: ; Tel.: +82-(42)-821-6753; Fax: +82-(42)-825-7910
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