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Lozhkov A, Dobrovolskaya O, Romanovskaya-Romanko E, Shishlyannikov S, Elpaeva E, Garshinina A, Zabrodskaya Y, Shaldzhyan A, Egorov V, Vasin A. Exploring the protective role of recombinant type III interferons in respiratory infections: Insights from an Mx1-deficient mouse model. Int J Antimicrob Agents 2025; 66:107491. [PMID: 40081775 DOI: 10.1016/j.ijantimicag.2025.107491] [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: 01/13/2025] [Revised: 02/28/2025] [Accepted: 03/07/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND Type III interferons (IFNs) are regarded as safe and effective preventive agents for viral infections of the respiratory tract. The effectiveness of the preventive use of type III IFNs in patients with polymorphisms in critical antiviral ISGs is particularly relevant. We utilized Balb/c mice deficient in the Mx1 gene as model organisms. METHODS Recombinant IFNs were administered intranasally one day before infection with the mouse-adapted pandemic strain of influenza A virus (IAV), A/California/07/09 (H1N1pdm09). In the model of mixed infection (sequential infection with IAV at a sublethal dose and Staphylococcus aureus), a bacterial suspension was administered intranasally a day after IAV infection. Influenza nucleoprotein level and bacterial load were assessed in the lungs on the third day post-infection. RESULTS Type III IFNs demonstrated a protective effect against infection with IAV. A single intranasal administration of IFN-λ protected mice from weight loss, reduced the level of viral nucleoprotein in lung homogenates, and significant differences in survival curves were also observed. In the case of mixed infection, a single intranasal administration of IFN-λ was associated with a decrease in bacterial load in the lungs, and minimal weight loss was observed in the mice. CONCLUSION The study demonstrated that IFN-λ can have a protective effect in Mx1-deficient Balb/c mice. These data support the universality of type III IFN use, suggesting that these preventive agents can be effective even in patients with a suboptimal genetic background.
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Affiliation(s)
- A Lozhkov
- Russian Ministry of Health, Smorodintsev Research Institute of Influenza, St. Petersburg, Russia; Institute of Biomedical Systems and Biotechnology, Peter the Great Saint-Petersburg Polytechnic University, St. Petersburg, Russia.
| | - O Dobrovolskaya
- Russian Ministry of Health, Smorodintsev Research Institute of Influenza, St. Petersburg, Russia
| | - E Romanovskaya-Romanko
- Russian Ministry of Health, Smorodintsev Research Institute of Influenza, St. Petersburg, Russia
| | - S Shishlyannikov
- Russian Ministry of Health, Smorodintsev Research Institute of Influenza, St. Petersburg, Russia; Institute of Biomedical Systems and Biotechnology, Peter the Great Saint-Petersburg Polytechnic University, St. Petersburg, Russia
| | - E Elpaeva
- Russian Ministry of Health, Smorodintsev Research Institute of Influenza, St. Petersburg, Russia
| | - A Garshinina
- Russian Ministry of Health, Smorodintsev Research Institute of Influenza, St. Petersburg, Russia
| | - Y Zabrodskaya
- Russian Ministry of Health, Smorodintsev Research Institute of Influenza, St. Petersburg, Russia; Institute of Biomedical Systems and Biotechnology, Peter the Great Saint-Petersburg Polytechnic University, St. Petersburg, Russia
| | - A Shaldzhyan
- Russian Ministry of Health, Smorodintsev Research Institute of Influenza, St. Petersburg, Russia
| | - V Egorov
- Russian Ministry of Health, Smorodintsev Research Institute of Influenza, St. Petersburg, Russia; Department of Molecular Genetics, Federal State Budgetary Scientific Institution "Institute of Experimental Medicine", St. Petersburg, Russia; Biological Faculty, Saint-Petersburg State University, St. Petersburg, Russia
| | - A Vasin
- Russian Ministry of Health, Smorodintsev Research Institute of Influenza, St. Petersburg, Russia; Institute of Biomedical Systems and Biotechnology, Peter the Great Saint-Petersburg Polytechnic University, St. Petersburg, Russia
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Passos-Silva AM, Araújo A, Roca TP, Queiroz JADS, Sgorlon G, Rampazzo RDCP, Salcedo JMV, Zuliani JP, Vieira D. Screening Biomarkers and Risk Factors for COVID-19 Progression in a Border Population Between Brazil-Bolivia. Biomed Eng Comput Biol 2025; 16:11795972241298786. [PMID: 40314039 PMCID: PMC12044272 DOI: 10.1177/11795972241298786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 10/24/2024] [Indexed: 05/03/2025] Open
Abstract
Background The performance and genetic role in host response delineate investigative points of polymorphisms as potential biomarkers in viral infections. Methods Thus, this research aimed to map biomarkers and risk factors in the severity of COVID-19 in individuals in Western Amazon (n = 243). Results Patients aged 40 to 59 years showed an association with clinical progression (P = .003), also evidencing the relationship for individuals >60 years (P < .001), besides the non-vaccination influenced the pathology (P = .023). qPCR for human genotyping of the targets rs2070788, rs4702, rs76635825, rs540856718, rs35803318, rs12979860, and rs16899066, as well as for gene expression of ACE2, HLA-A, HLA-B, IFNL-3/2, IL-6, and TMPRSS2 was used. The rs12979860 (C > T) and rs2070788 (A > G) showed association among the analyzed groups (P < .05) with the allelic and genotypic frequency of rs12979860 (x 2 < 3.84) and evolutionary pointing of rs2070788G allele among infected people, including deaths. Conclusion Gene expression showed high levels between the moderate and severe groups, with emphasis on TMPRSS2 and IL-6 genes that performed better. Thus, there is possibly an association regarding the role of the TMPRSS2 gene and rs2070788G, as well as age and IL-6 levels for COVID-19, pointing in parallel to the considerable influence of the vaccine on the SARS-CoV-2 pathway.
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Affiliation(s)
- Ana Maísa Passos-Silva
- Laboratório de Virologia Molecular, Fundação Oswaldo Cruz Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Programa de Pós-Graduação em Biologia Experimental, Universidade Federal de Rondônia – UNIR/FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Centro de Pesquisa em Medicina Tropical – CEPEM, Porto Velho, Rondônia, Brazil
- Instituto Nacional de Epidemiologia da Amazônia Ocidental - INCT EpiAmO, Porto Velho, Rondônia, Brazil
| | - Adrhyan Araújo
- Laboratório de Virologia Molecular, Fundação Oswaldo Cruz Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Programa de Pós-Graduação em Biologia Experimental, Universidade Federal de Rondônia – UNIR/FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Centro de Pesquisa em Medicina Tropical – CEPEM, Porto Velho, Rondônia, Brazil
- Instituto Nacional de Epidemiologia da Amazônia Ocidental - INCT EpiAmO, Porto Velho, Rondônia, Brazil
| | - Tárcio Peixoto Roca
- Laboratório de Virologia Molecular, Fundação Oswaldo Cruz Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Instituto Nacional de Epidemiologia da Amazônia Ocidental - INCT EpiAmO, Porto Velho, Rondônia, Brazil
- Programa de Pós-Graduação em Medicina Tropical, Instituto Oswaldo Cruz/IOC, FIOCRUZ, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jackson Alves da Silva Queiroz
- Laboratório de Virologia Molecular, Fundação Oswaldo Cruz Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Programa de Pós-Graduação em Biologia Experimental, Universidade Federal de Rondônia – UNIR/FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Instituto Nacional de Epidemiologia da Amazônia Ocidental - INCT EpiAmO, Porto Velho, Rondônia, Brazil
| | - Gabriella Sgorlon
- Centro Universitário São Lucas – UNISL, Porto Velho, Rondônia, Brazil
| | | | - Juan Miguel Villalobos Salcedo
- Centro de Pesquisa em Medicina Tropical – CEPEM, Porto Velho, Rondônia, Brazil
- Instituto Nacional de Epidemiologia da Amazônia Ocidental - INCT EpiAmO, Porto Velho, Rondônia, Brazil
- Department Medicina, Universidade Federal de Rondônia (UNIR), Porto Velho, Rondônia, Brazil
| | - Juliana Pavan Zuliani
- Instituto Nacional de Epidemiologia da Amazônia Ocidental - INCT EpiAmO, Porto Velho, Rondônia, Brazil
- Department Medicina, Universidade Federal de Rondônia (UNIR), Porto Velho, Rondônia, Brazil
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz Rondônia (FIOCRUZ-RO), Porto Velho, Rondônia, Brazil
| | - Deusilene Vieira
- Laboratório de Virologia Molecular, Fundação Oswaldo Cruz Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Programa de Pós-Graduação em Biologia Experimental, Universidade Federal de Rondônia – UNIR/FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Instituto Nacional de Epidemiologia da Amazônia Ocidental - INCT EpiAmO, Porto Velho, Rondônia, Brazil
- Programa de Pós-Graduação em Medicina Tropical, Instituto Oswaldo Cruz/IOC, FIOCRUZ, Rio de Janeiro, Rio de Janeiro, Brazil
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Novotny LA, Meissner EG. Expression and function of interferon lambda receptor 1 variants. FEBS Lett 2025; 599:466-475. [PMID: 39435588 PMCID: PMC11850208 DOI: 10.1002/1873-3468.15041] [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: 07/02/2024] [Revised: 09/05/2024] [Accepted: 09/26/2024] [Indexed: 10/23/2024]
Abstract
Lambda interferons (IFNLs) provide critical host defense against pathogens encountered at mucosal surfaces. In humans, IFNL signaling is regulated in part by low and cell-type restricted expression of the lambda interferon receptor 1 protein with expression restricted primarily to epithelial cells located at mucosal surfaces. This review will examine the evidence suggesting a role for IFNLR1 transcriptional variants in mediating cell responsiveness to IFNL ligand exposure and regulation of pathway activity.
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Affiliation(s)
- Laura A. Novotny
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Eric G. Meissner
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
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Woods E, Mena A, Sierpinska S, Carr E, STTAR Bioresource, Hagan R, Crowley J, Bergin C, Clark D, Brophy C, Macallan D, Gardiner CM. Reduced IFNL1 and/or IFNL2, but not IFNL3 is associated with worse outcome in patients with COVID-19. Clin Exp Immunol 2024; 218:300-307. [PMID: 38953458 PMCID: PMC11557148 DOI: 10.1093/cei/uxae047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 04/05/2024] [Accepted: 06/28/2024] [Indexed: 07/04/2024] Open
Abstract
The recent pandemic was caused by the emergence of a new human pathogen, SARS-CoV-2. While the rapid development of many vaccines provided an end to the immediate crisis, there remains an urgent need to understand more about this new virus and what constitutes a beneficial immune response in terms of successful resolution of infection. Indeed, this is key for development of vaccines that provide long lasting protective immunity. The interferon lambda (IFNL) family of cytokines are produced early in response to infection and are generally considered anti-viral and beneficial. However, data regarding production of IFNL cytokines in coronavirus disease 2019 (COVID-19) patients is highly variable, and generally from underpowered studies. In this study, we measured all three IFNL1, IFNL2, and IFNL3 cytokines in plasma from a well characterized, large COVID-19 cohort (n = 399) that included good representation from patients with a more indolent disease progression, and hence a beneficial immune response. While all three cytokines were produced, they differed in both the frequency of expression in patients, and the levels produced. IFNL3 was produced in almost all patients but neither protein level nor IFNL3/IFNL4 single nucleotide polymorphisms were associated with clinical outcome. In contrast, both IFNL1 and IFNL2 levels were significantly lower, or absent, in plasma of patients that had a more severe disease outcome. These data are consistent with the concept that early IFNL1 and IFNL2 cytokine production is protective against SARS-CoV-2 infection.
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Affiliation(s)
- Elena Woods
- School of Biochemistry and Immunology, Trinity Biomedical Research Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Adriana Mena
- School of Biochemistry and Immunology, Trinity Biomedical Research Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Sophie Sierpinska
- Institute for Infection and Immunity, St George’s, University of London, Cranmer Terrace, London, UK
| | - Emily Carr
- Institute for Infection and Immunity, St George’s, University of London, Cranmer Terrace, London, UK
| | | | - Richard Hagan
- National Histocompatibility and Immunogenetics Reference Laboratory, National Blood Centre, Dublin, Ireland
| | - John Crowley
- National Histocompatibility and Immunogenetics Reference Laboratory, National Blood Centre, Dublin, Ireland
| | - Colm Bergin
- Department of Infectious Diseases, St. James’s Hospital, Dublin, Ireland
| | - David Clark
- Institute for Infection and Immunity, St George’s, University of London, Cranmer Terrace, London, UK
| | - Caroline Brophy
- School of Computer Science and Statistics, Trinity College Dublin, Dublin 2, Ireland
| | - Derek Macallan
- Institute for Infection and Immunity, St George’s, University of London, Cranmer Terrace, London, UK
- Infection and Immunity Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust, London, UK
| | - Clair M Gardiner
- School of Biochemistry and Immunology, Trinity Biomedical Research Institute, Trinity College Dublin, Dublin 2, Ireland
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Huang H, Li X, Deng Y, San S, Qiu D, Xu A, Luo J, Xu L, Li Y, Zhang H, Li Y. Associations between prenatal exposure to per- and polyfluoroalkyl substances and plasma immune molecules in three-year-old children in China. Toxicol Appl Pharmacol 2024; 490:117044. [PMID: 39074624 DOI: 10.1016/j.taap.2024.117044] [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: 04/30/2024] [Revised: 07/12/2024] [Accepted: 07/24/2024] [Indexed: 07/31/2024]
Abstract
BACKGROUND Many studies have reported that prenatal exposure to Per- and Polyfluoroalkyl Substances (PFASs) can disrupt immune function. However, little is known about the effects of PFASs on immune molecules. The study analyzed the association between prenatal exposure to mixed and single PFASs and plasma immune molecules in three-year-old children. METHODS Ten PFASs were measured in umbilical cord serum, while peripheral blood samples were collected at age three to measure immune molecules. Associations between exposure to individual and combined PFASs and immune molecules were analyzed using Generalized Linear Models and Weighted Quantile Sum (WQS) regression. RESULTS (1) Interleukin-4 (IL-4) increased by 23.85% (95% CI:2.99,48.94) with each doubling of Perfluorooctanoic Acid (PFOA), and Interleukin-6 (IL-6) increased by 39.07% (95%CI:4.06,85.86) with Perfluorotridecanoic Acid (PFTrDA). Elevated PFOA and Perfluorononanoic Acid (PFNA) were correlated with increases of 34.06% (95% CI: 6.41, 70.28) and 24.41% (95% CI: 0.99, 53.27) in Eotaxin-3, respectively. Additionally, the doubling of Perfluorohexane Sulfonic Acid (PFHxS) was associated with a 9.51% decrease in Periostin (95% CI: -17.84, -0.33). (2) The WQS analysis revealed that mixed PFASs were associated with increased IL-6 (β = 0.37, 95%CI:0.04,0.69), mainly driven by PFTrDA, PFNA, and 8:2 Chlorinated Perfluoroethyl Sulfonamide (8:2 Cl-PFESA). Moreover, mixed PFASs were linked to an increase in Eotaxin-3 (β = 0.32, 95% CI: 0.09,0.55), primarily influenced by PFOA, PFTrDA, and Perfluorododecanoic Acid (PFDoDA). CONCLUSIONS Prenatal PFASs exposure significantly alters the levels of immune molecules in three-year-old children, highlighting the importance of understanding environmental impacts on early immune development.
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Affiliation(s)
- Haiyun Huang
- School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, Hubei, China
| | - Xiaojun Li
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Yican Deng
- School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, Hubei, China
| | - Siyi San
- School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, Hubei, China
| | - Dongmei Qiu
- School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, Hubei, China
| | - Ao Xu
- School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, Hubei, China
| | - Jiyu Luo
- School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, Hubei, China
| | - Lingyun Xu
- School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, Hubei, China
| | - Yang Li
- School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, Hubei, China
| | - Hongling Zhang
- School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, Hubei, China.
| | - Yuanyuan Li
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
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Gautam D, Sindhu A, Vats A, Rajput S, Roshan M, Pal H, De S. Characterization and expression profiling of buffalo IFN-lambda family. Vet Immunol Immunopathol 2024; 272:110770. [PMID: 38735115 DOI: 10.1016/j.vetimm.2024.110770] [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: 01/29/2024] [Revised: 04/12/2024] [Accepted: 04/26/2024] [Indexed: 05/14/2024]
Abstract
Interferon lambda (IFN-λ) is an important type III interferon triggered mainly by viral infection. IFN-λ binds to their heterodimeric receptors and signals through JAK-STAT pathways similar to type I IFN. In this study, we deduced the buffalo IFN-λ sequences through the polymerase chain reaction, and then studied IFN-λ's expression patterns in different tissues, and post induction with poly I:C and live MRSA using RT-qPCR. The full-length sequences of buffalo IFN-λ3, IFN-λ receptors, and a transcript variant of IFN-λ4 were determined. IFN-λ1 is identified as a pseudogene. Virus response elements and a recombination hotspot factor was observed in the regulatory region of IFN-λ. The IFN-λ3 expressed highest in lungs and monocytes but IFN-λ4 did not. The expression of Interferon Lambda Receptor 1 was tissue specific, while Interleukin 10 Receptor subunit beta was ubiquitous. Following poly I:C induction, IFN-λ3 expression was primarily observed in epithelial cells as opposed to fibroblasts, displaying cell type-dependent expression. The cytosolic RNA sensors were expressed highest in endometrial epithelial cells, whereas the endosomal receptor was higher in fibroblasts. 2',5'-oligoadenylate synthetase expressed higher in fibroblasts, myxoma resistance protein 1 and IFN-stimulated gene 56 in epithelial cells, displaying cell-specific antiviral response of the interferon stimulated genes (ISGs). The endometrial epithelial cells expressed IFN-λ3 after live S. aureus infection indicating its importance in bacterial infection. The induction of IFN-λ3 was S. aureus isolate specific at the same multiplicity of infection (MOI). This study elucidates the IFN-λ sequences, diverse expression patterns revealing tissue specificity, and specificity in response to poly I:C and bacterial stimuli, emphasising its crucial role in innate immune response modulation.
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Affiliation(s)
- Devika Gautam
- Animal Genomics Lab, Animal Biotechnology Centre, ICAR-National Dairy Research Institute (NDRI), Karnal, HR 132001, India; Deenbandhu Chhotu Ram University of Science and Technology, Murthal, Sonepat, HR 139031, India
| | - Anil Sindhu
- Deenbandhu Chhotu Ram University of Science and Technology, Murthal, Sonepat, HR 139031, India
| | - Ashutosh Vats
- Animal Genomics Lab, Animal Biotechnology Centre, ICAR-National Dairy Research Institute (NDRI), Karnal, HR 132001, India
| | - Shiveeli Rajput
- Animal Genomics Lab, Animal Biotechnology Centre, ICAR-National Dairy Research Institute (NDRI), Karnal, HR 132001, India
| | - Mayank Roshan
- Animal Genomics Lab, Animal Biotechnology Centre, ICAR-National Dairy Research Institute (NDRI), Karnal, HR 132001, India
| | - Hanshika Pal
- Animal Genomics Lab, Animal Biotechnology Centre, ICAR-National Dairy Research Institute (NDRI), Karnal, HR 132001, India
| | - Sachinandan De
- Animal Genomics Lab, Animal Biotechnology Centre, ICAR-National Dairy Research Institute (NDRI), Karnal, HR 132001, India.
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Kalugotla G, Marmerstein V, Baldridge MT. Regulation of host/pathogen interactions in the gastrointestinal tract by type I and III interferons. Curr Opin Immunol 2024; 87:102425. [PMID: 38763032 PMCID: PMC11162908 DOI: 10.1016/j.coi.2024.102425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 02/01/2024] [Accepted: 05/06/2024] [Indexed: 05/21/2024]
Abstract
Interferons (IFNs) are an integral component of the host innate immune response during viral infection. Recent advances in the study of type I and III IFNs suggest that though both types counteract viral infection, type III IFNs act predominantly at epithelial barrier sites, while type I IFNs drive systemic responses. The dynamics and specific roles of type I versus III IFNs have been studied in the context of infection by a variety of enteric pathogens, including reovirus, rotavirus, norovirus, astrovirus, and intestinal severe acute respiratory syndrome coronavirus 2, revealing shared patterns of regulatory influence. An important role for the gut microbiota, including the virome, in regulating homeostasis and priming of intestinal IFN responses has also recently emerged.
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Affiliation(s)
- Gowri Kalugotla
- Division of Infectious Diseases, Department of Medicine, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Vivien Marmerstein
- Division of Infectious Diseases, Department of Medicine, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Megan T Baldridge
- Division of Infectious Diseases, Department of Medicine, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
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Liu YG, Jin SW, Zhang SS, Xia TJ, Liao YH, Pan RL, Yan MZ, Chang Q. Interferon lambda in respiratory viral infection: immunomodulatory functions and antiviral effects in epithelium. Front Immunol 2024; 15:1338096. [PMID: 38495892 PMCID: PMC10940417 DOI: 10.3389/fimmu.2024.1338096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 02/19/2024] [Indexed: 03/19/2024] Open
Abstract
Type III interferon (IFN-λ), a new member of the IFN family, was initially considered to possess antiviral functions similar to those of type I interferon, both of which are induced via the JAK/STAT pathway. Nevertheless, recent findings demonstrated that IFN-λ exerts a nonredundant antiviral function at the mucosal surface, preferentially produced in epithelial cells in contrast to type I interferon, and its function cannot be replaced by type I interferon. This review summarizes recent studies showing that IFN-λ inhibits the spread of viruses from the cell surface to the body. Further studies have found that the role of IFN-λ is not only limited to the abovementioned functions, but it can also can exert direct and/or indirect effects on immune cells in virus-induced inflammation. This review focuses on the antiviral activity of IFN-λ in the mucosal epithelial cells and its action on immune cells and summarizes the pathways by which IFN-λ exerts its action and differentiates it from other interferons in terms of mechanism. Finally, we conclude that IFN-λ is a potent epidermal antiviral factor that enhances the respiratory mucosal immune response and has excellent therapeutic potential in combating respiratory viral infections.
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Affiliation(s)
| | | | | | | | | | | | - Ming-Zhu Yan
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi Chang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Pereira LA, Lapinscki BA, Santos JS, Debur MC, Petterle RR, Nogueira MB, Vidal LRR, De Almeida SM, Raboni SM. Influenza A infections: predictors of disease severity. Braz J Microbiol 2024; 55:75-86. [PMID: 38049661 PMCID: PMC10920610 DOI: 10.1007/s42770-023-01186-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 11/14/2023] [Indexed: 12/06/2023] Open
Abstract
Influenza affects approximately 10% of the world's population annually. It is associated with high morbidity and mortality rates due to its propensity to progress to severe acute respiratory infection, leading to 10-40% of hospitalized patients needing intensive care. Characterizing the multifactorial predictors of poor prognosis is essential for developing strategies against this disease. This study aimed to identify predictors of disease severity in influenza A-infected (IFA-infected) patients and to propose a prognostic score. A retrospective cross-sectional study was conducted with 142 IFA-infected out- and inpatients treated at a tertiary hospital between 2010 and 2018. The viral subtypes, hemagglutinin mutations, viral load, IL-28B SNPs, and clinical risk factors were evaluated according to the patient's ICU admission. Multivariate analysis identified the following risk factors for disease severity: neuromuscular diseases (OR = 7.02; 95% CI = 1.18-41.75; p = 0.032), cardiovascular diseases (OR = 5.47; 95% CI = 1.96-15.27; p = 0.001), subtype (H1N1) pdm09 infection (OR = 2.29; 95% CI = 1.02-5.15; p = 0.046), and viral load (OR = 1.43; 95% CI = 1.09-1.88; p = 0.009). The prognosis score for ICU admission is based on these predictors of severity presented and ROC curve AUC = 0.812 (p < 0.0001). Our results identified viral and host predictors of disease severity in IFA-infected patients, yielding a prognostic score that had a high performance in predicting the IFA patients' ICU admission and better results than a viral load value alone. However, its implementation in health services needs to be validated in a broader population.
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Affiliation(s)
- L A Pereira
- Graduate Program in Internal Medicine and Health Science, Federal University of Paraná, Curitiba, 82060-240, Brazil
| | - B A Lapinscki
- Graduate Program in Internal Medicine and Health Science, Federal University of Paraná, Curitiba, 82060-240, Brazil
| | - J S Santos
- Public Health Laboratory (LACEN-PR), Curitiba, Brazil
| | - M C Debur
- Public Health Laboratory (LACEN-PR), Curitiba, Brazil
| | - R R Petterle
- Medical School, Sector of Health Sciences, Federal University of Paraná, Curitiba, 82060-240, Brazil
| | - M B Nogueira
- Clinical Analysis Department, Federal University of Parana, Curitiba, 82060-240, Brazil
| | - L R R Vidal
- Virology Laboratory, Federal University of Paraná, Curitiba, 82060-240, Brazil
- Virology Laboratory, Complexo Hospital de Clínicas, Federal University of Paraná, Curitiba, 82060-240, Brazil
| | - S M De Almeida
- Department of Medical Pathology, Federal University of Paraná, Curitiba, 82060-240, Brazil
| | - S M Raboni
- Virology Laboratory, Complexo Hospital de Clínicas, Federal University of Paraná, Curitiba, 82060-240, Brazil.
- Division of Infectious Diseases, Federal University of Paraná, Curitiba, 82060-240, Brazil.
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10
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Uhl K, Paithankar S, Leshchiner D, Jager TE, Abdelgied M, Dixit B, Marashdeh R, Luo-Li D, Tripp K, Peraino AM, Tamae Kakazu M, Lawson C, Chesla DW, Luo-Li N, Murphy ET, Prokop J, Chen B, Girgis RE, Li X. Differential Transcriptomic Signatures of Small Airway Cell Cultures Derived from IPF and COVID-19-Induced Exacerbation of Interstitial Lung Disease. Cells 2023; 12:2501. [PMID: 37887346 PMCID: PMC10605205 DOI: 10.3390/cells12202501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/18/2023] [Accepted: 10/19/2023] [Indexed: 10/28/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a pathological condition wherein lung injury precipitates the deposition of scar tissue, ultimately leading to a decline in pulmonary function. Existing research indicates a notable exacerbation in the clinical prognosis of IPF patients following infection with COVID-19. This investigation employed bulk RNA-sequencing methodologies to describe the transcriptomic profiles of small airway cell cultures derived from IPF and post-COVID fibrosis patients. Differential gene expression analysis unveiled heightened activation of pathways associated with microtubule assembly and interferon signaling in IPF cell cultures. Conversely, post-COVID fibrosis cell cultures exhibited distinctive characteristics, including the upregulation of pathways linked to extracellular matrix remodeling, immune system response, and TGF-β1 signaling. Notably, BMP signaling levels were elevated in cell cultures derived from IPF patients compared to non-IPF control and post-COVID fibrosis samples. These findings underscore the molecular distinctions between IPF and post-COVID fibrosis, particularly in the context of signaling pathways associated with each condition. A better understanding of the underlying molecular mechanisms holds the promise of identifying potential therapeutic targets for future interventions in these diseases.
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Affiliation(s)
- Katie Uhl
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
| | - Shreya Paithankar
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
| | - Dmitry Leshchiner
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
| | - Tara E. Jager
- Corewell Health Medical Group, Grand Rapids, MI 49503, USA (A.M.P.); (M.T.K.)
| | - Mohamed Abdelgied
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
| | - Bhavna Dixit
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
| | - Raya Marashdeh
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
| | - Dewen Luo-Li
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
| | - Kaylie Tripp
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
| | - Angela M. Peraino
- Corewell Health Medical Group, Grand Rapids, MI 49503, USA (A.M.P.); (M.T.K.)
| | | | - Cameron Lawson
- Corewell Health Medical Group, Grand Rapids, MI 49503, USA (A.M.P.); (M.T.K.)
| | - Dave W. Chesla
- Corewell Health Medical Group, Grand Rapids, MI 49503, USA (A.M.P.); (M.T.K.)
| | - Ningzhi Luo-Li
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
| | - Edward T. Murphy
- Corewell Health Medical Group, Grand Rapids, MI 49503, USA (A.M.P.); (M.T.K.)
- Richard DeVos Lung Transplant Program, Corewell Health, Grand Rapids, MI 49503, USA
| | - Jeremy Prokop
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | - Bin Chen
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | - Reda E. Girgis
- Corewell Health Medical Group, Grand Rapids, MI 49503, USA (A.M.P.); (M.T.K.)
| | - Xiaopeng Li
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA (D.L.); (M.A.); (B.D.); (R.M.); (J.P.)
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11
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Cao L, Qian W, Li W, Ma Z, Xie S. Type III interferon exerts thymic stromal lymphopoietin in mediating adaptive antiviral immune response. Front Immunol 2023; 14:1250541. [PMID: 37809098 PMCID: PMC10556530 DOI: 10.3389/fimmu.2023.1250541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023] Open
Abstract
Previously, it was believed that type III interferon (IFN-III) has functions similar to those of type I interferon (IFN-I). However, recently, emerging findings have increasingly indicated the non-redundant role of IFN-III in innate antiviral immune responses. Still, the regulatory activity of IFN-III in adaptive immune response has not been clearly reported yet due to the low expression of IFN-III receptors on most immune cells. In the present study, we reviewed the adjuvant, antiviral, antitumor, and disease-moderating activities of IFN-III in adaptive immunity; moreover, we further elucidated the mechanisms of IFN-III in mediating the adaptive antiviral immune response in a thymic stromal lymphopoietin (TSLP)-dependent manner, a pleiotropic cytokine involved in mucosal adaptive immunity. Research has shown that IFN-III can enhance the antiviral immunogenic response in mouse species by activating germinal center B (GC B) cell responses after stimulating TSLP production by microfold (M) cells, while in human species, TSLP exerts OX40L for regulating GC B cell immune responses, which may also depend on IFN-III. In conclusion, our review highlights the unique role of the IFN-III/TSLP axis in mediating host adaptive immunity, which is mechanically different from IFN-I. Therefore, the IFN-III/TSLP axis may provide novel insights for clinical immunotherapy.
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Affiliation(s)
- Luhong Cao
- Department of Otolaryngology Head and Neck Surgery Surgery, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Weiwei Qian
- Department of Emergency Medicine, Laboratory of Emergency Medicine, West China Hospital, and Disaster Medical Center, Sichuan University, Chengdu, Sichuan, China
| | - Wanlin Li
- National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, Shenzhen, China
| | - Zhiyue Ma
- Department of Otolaryngology Head and Neck Surgery Surgery, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shenglong Xie
- Department of Thoracic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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12
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de Weerd NA, Ogungbola O, Liu X, Matthews AY, Ismail A, Vivian JP, Lim SS, Tyrrell DL, Putcha N, Skawinski M, Dickensheets H, Lavoie TB, Donnelly RP, Hertzog PJ, Santer DM. Characterization of Monoclonal Antibodies to Measure Cell Surface Protein Levels of Human Interferon-Lambda Receptor 1. J Interferon Cytokine Res 2023; 43:403-413. [PMID: 37499093 DOI: 10.1089/jir.2023.0040] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023] Open
Abstract
Type III interferons (IFN-lambdas, IFN-λs) are important antiviral cytokines that can also modulate immune responses by acting through a heterodimeric receptor composed of the specific and limited expressed IFN-λR1 chain and the ubiquitous IL-10R2 chain, which is shared with IL-10 family cytokines. Conflicting data have been reported regarding which cells express the IFN-λR1 subunit and directly respond to IFN-λs. This is, in part, owing to transcript levels of the IFN-λR1 gene, IFNLR1, not always correlating with cell surface protein levels. In this study, we tested a panel of novel monoclonal antibodies (mAbs) that specifically recognize human IFN-λR1. Initially, antigen specificity was confirmed by enzyme-linked immunosorbent assay (ELISA), from which a subset of antibodies was selected for additional flow cytometry and neutralization assays. We further characterized two antibodies based on their strong ELISA binding activity (HLR1 and HLR14) and found only HLR14 could reliably detect cell surface IFN-λR1 protein on a variety of cell lines by flow cytometry. HLR14 could also detect IFN-λR1 protein on certain primary human blood cells, including plasmacytoid dendritic cells and B cells from peripheral blood. Availability of the HLR14 mAb will enable the quantification of IFN-λR1 protein levels on cells and better characterization of the cell specificity of the IFN-λ response.
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Affiliation(s)
- Nicole A de Weerd
- Department of Molecular and Translational Science, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | | | - Xinyun Liu
- Department of Immunology, University of Manitoba, Winnipeg, Canada
| | - Antony Y Matthews
- Department of Molecular and Translational Science, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | - Amina Ismail
- Department of Molecular and Translational Science, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | - Julian P Vivian
- St. Vincent's Institute of Medical Research, Fitzroy, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Australia
| | - San S Lim
- Department of Molecular and Translational Science, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | - D Lorne Tyrrell
- Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Canada
| | - Niru Putcha
- PBL Assay Science, Piscataway, New Jersey, USA
| | | | - Harold Dickensheets
- Division of Biotechnology Research and Review II, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Thomas B Lavoie
- PBL Assay Science, Piscataway, New Jersey, USA
- Strategic Biomarker Deployment, Califon, New Jersey, USA
| | - Raymond P Donnelly
- Division of Biotechnology Research and Review II, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Paul J Hertzog
- Department of Molecular and Translational Science, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | - Deanna M Santer
- Department of Immunology, University of Manitoba, Winnipeg, Canada
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13
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Pan YY, Wang LC, Yang F, Yu M. Interferon-lambda: New role in intestinal symptoms of COVID-19. World J Gastroenterol 2023; 29:1942-1954. [PMID: 37155525 PMCID: PMC10122791 DOI: 10.3748/wjg.v29.i13.1942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/25/2022] [Accepted: 03/20/2023] [Indexed: 04/06/2023] Open
Abstract
The tremendous public health and economic impact of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a huge challenge globally. There is increasing evidence that SARS-CoV-2 induces intestinal infections. Type III interferon (IFN-λ) has an antiviral role in intestinal infection, with focused, long-lasting, and non-inflammatory characteristics. This review presents a summary of the structure of SARS-CoV-2, including its invasion and immune escape mechanisms. Emphasis was placed on the gastrointestinal impact of SARS-CoV-2, including changes to the intestinal microbiome, activation of immune cells, and inflammatory responses. We also describe the comprehensive functions of IFN-λ in anti-enteric SARS-CoV-2 infection, and discuss the potential application of IFN-λ as a therapeutic agent for COVID-19 with intestinal symptoms.
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Affiliation(s)
- Yi-Yang Pan
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Liu-Can Wang
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Feng Yang
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Min Yu
- Department of General Surgery, Chongqing General Hospital, Chongqing 400013, China
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14
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Chen J, Li P, Zou W, Jiang Y, Li L, Hao P, Gao Z, Qu Q, Pang Z, Zhuang X, Nan F, Jin N, Du S, Li C. Identification of a Novel Interferon Lambda Splice Variant in Chickens. J Virol 2023; 97:e0174322. [PMID: 36877044 PMCID: PMC10062172 DOI: 10.1128/jvi.01743-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/08/2023] [Indexed: 03/07/2023] Open
Abstract
Type III interferons (IFNLs) have critical roles in the host's innate immune system, also serving as the first line against pathogenic infections of mucosal surfaces. In mammals, several IFNLs have been reported; however, only limited data on the repertoire of IFNLs in avian species is available. Previous studies showed only one member in chicken (chIFNL3). Herein, we identified a novel chicken IFNL for the first time, termed chIFNL3a, which contains 354 bp, and encodes 118 amino acids. The predicted protein is 57.1% amino acid identity with chIFNL. Genetic, evolutionary, and sequence analyses indicated that the new open reading frame (ORF) groups with type III chicken IFNs represent a novel splice variant. Compared to IFNs from different species, the new ORF is clustered within the type III IFNs group. Further study showed that chIFNL3a could activate a panel of IFN-regulated genes and function mediated by the IFNL receptor, and chIFNL3a markedly inhibited the replication of Newcastle disease virus (NDV) and influenza virus in vitro. These data collectively shed light on the repertoire of IFNs in avian species and provide useful information that further elucidate the interaction of the chIFNLs and viral infection of poultry. IMPORTANCE Interferons (IFNs) are critical soluble factors in the immune system, and are composed of 3 types (I, II, and III) that utilize different receptor complexes (IFN-αR1/IFN-αR2, IFN-γR1/IFN-γR2, and IFN-λR1/IL-10R2, respectively). Herein, we identified IFNL from the genomic sequences of chicken and termed it chIFNL3a, located on chromosome 7 of chicken. Phylogenetically clustered with all known types of chicken IFNs, the finding of this IFN is considered a type III IFN. To further evaluate the biological properties of chIFNL3a, the target protein was prepared by the baculovirus expression system (BES), which could markedly inhibit the replication of NDV and influenza viruses. In this study, we uncovered a new interferon lambda splice variant of chicken, termed chIFNL3a, which could inhibit viral replication in cells. Importantly, these novel findings may extend to other viruses, offering a new direction for therapeutic interventions.
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Affiliation(s)
- Jing Chen
- College of Veterinary Medicine, Key Lab for Zoonoses Research, Ministry of Education, Jilin University, Changchun, China
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Peiheng Li
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Wancheng Zou
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Yuhang Jiang
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Letian Li
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Pengfei Hao
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Zihan Gao
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Qiaoqiao Qu
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Zhaoxia Pang
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Xinyu Zhuang
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Fulong Nan
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Ningyi Jin
- College of Veterinary Medicine, Key Lab for Zoonoses Research, Ministry of Education, Jilin University, Changchun, China
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Shouwen Du
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Chang Li
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
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15
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Numata M, Sajuthi S, Bochkov YA, Loeffler J, Everman J, Vladar EK, Cooney RA, Reinhardt RL, Liu AH, Seibold MA, Voelker DR. Anionic Pulmonary Surfactant Lipid Treatment Inhibits Rhinovirus A Infection of the Human Airway Epithelium. Viruses 2023; 15:747. [PMID: 36992456 PMCID: PMC10055697 DOI: 10.3390/v15030747] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/03/2023] [Accepted: 03/08/2023] [Indexed: 03/16/2023] Open
Abstract
Rhinoviruses (RVs) are major instigators of acute exacerbations of asthma, COPD, and other respiratory diseases. RVs are categorized into three species (RV-A, RV-B, and RV-C), which comprise more than 160 serotypes, making it difficult to develop an effective vaccine. Currently, no effective treatment for RV infection is available. Pulmonary surfactant is an extracellular complex of lipids and proteins that plays a central role in regulating innate immunity in the lung. The minor pulmonary surfactant lipids, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI), are potent regulators of inflammatory processes and exert antiviral activity against respiratory syncytial virus (RSV) and influenza A viruses (IAV). In the current study, we examined the potencies of POPG and PI against rhinovirus A16 (RV-A16) in primary human airway epithelial cells (AECs) differentiated at an air-liquid interface (ALI). After AECs were infected with RV-A16, PI reduced the viral RNA copy number by 70% and downregulated (55-75%) the expression of antiviral (MDA5, IRF7, and IFN-lambda) and CXCL11 chemokine genes. In contrast, POPG only slightly decreased MDA5 (24%) and IRF7 (11%) gene expression but did not inhibit IFN-lambda gene expression or RV-A16 replication in AECs. However, both POPG and PI inhibited (50-80%) IL6 gene expression and protein secretion and CXCL11 protein secretion. PI treatment dramatically attenuated global gene expression changes induced by RV-A16 infection alone in AECs. The observed inhibitory effects were indirect and resulted mainly from the inhibition of virus replication. Cell-type enrichment analysis of viral-regulated genes opposed by PI treatment revealed the PI-inhibited viral induction of goblet cell metaplasia and the virus-induced downregulation of ciliated, club, and ionocyte cell types. Notably, the PI treatment also altered the ability of RV-A16 to regulate the expression of some phosphatidylinositol 4-kinase (PI4K); acyl-CoA-binding, domain-containing (ACBD); and low-density lipoprotein receptor (LDLR) genes that play critical roles in the formation and functioning of replication organelles (ROs) required for RV replication in host cells. These data suggest PI can be used as a potent, non-toxic, antiviral agent for RV infection prophylaxis and treatment.
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Affiliation(s)
- Mari Numata
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Satria Sajuthi
- Center for Genes, Environment and Health, National Jewish Health, Denver, CO 80206, USA
| | - Yury A. Bochkov
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
| | - Jessica Loeffler
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Jamie Everman
- Center for Genes, Environment and Health, National Jewish Health, Denver, CO 80206, USA
| | - Eszter K. Vladar
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Riley A. Cooney
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Richard Lee Reinhardt
- Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Andrew H. Liu
- Section of Pediatric Pulmonary & Sleep Medicine, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Max A. Seibold
- Center for Genes, Environment and Health, National Jewish Health, Denver, CO 80206, USA
- Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA
| | - Dennis R. Voelker
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
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16
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The main protease of SARS-CoV-2 cleaves histone deacetylases and DCP1A, attenuating the immune defense of the interferon-stimulated genes. J Biol Chem 2023; 299:102990. [PMID: 36758802 PMCID: PMC9907797 DOI: 10.1016/j.jbc.2023.102990] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/11/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019, constitutes an emerging human pathogen of zoonotic origin. A critical role in protecting the host against invading pathogens is carried out by interferon-stimulated genes (ISGs), the primary effectors of the type I interferon (IFN) response. All coronaviruses studied thus far have to first overcome the inhibitory effects of the IFN/ISG system before establishing efficient viral replication. However, whether SARS-CoV-2 evades IFN antiviral immunity by manipulating ISG activation remains to be elucidated. Here, we show that the SARS-CoV-2 main protease (Mpro) significantly suppresses the expression and transcription of downstream ISGs driven by IFN-stimulated response elements in a dose-dependent manner, and similar negative regulations were observed in two mammalian epithelial cell lines (simian Vero E6 and human A549). Our analysis shows that to inhibit the ISG production, Mpro cleaves histone deacetylases (HDACs) rather than directly targeting IFN signal transducers. Interestingly, Mpro also abolishes the activity of ISG effector mRNA-decapping enzyme 1a (DCP1A) by cleaving it at residue Q343. In addition, Mpro from different genera of coronaviruses has the protease activity to cleave both HDAC2 and DCP1A, even though the alphacoronaviruse Mpro exhibits weaker catalytic activity in cleaving HDAC2. In conclusion, our findings clearly demonstrate that SARS-CoV-2 Mpro constitutes a critical anti-immune effector that modulates the IFN/ISG system at multiple levels, thus providing a novel molecular explanation for viral immune evasion and allowing for new therapeutic approaches against coronavirus disease 2019 infection.
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17
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Matic S, Milovanovic D, Mijailovic Z, Djurdjevic P, Sazdanovic P, Stefanovic S, Todorovic D, Popovic S, Vitosevic K, Vukicevic V, Vukic M, Vukovic N, Milivojevic N, Zivanovic M, Jakovljevic V, Filipovic N, Baskic D, Djordjevic N. IFNL3/4 polymorphisms as a two-edged sword: An association with COVID-19 outcome. J Med Virol 2023; 95:e28506. [PMID: 36655749 DOI: 10.1002/jmv.28506] [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: 10/08/2022] [Revised: 12/14/2022] [Accepted: 01/14/2023] [Indexed: 01/20/2023]
Abstract
Coronavirus Disease 2019 (COVID-19) has been ranked among the most fatal infectious diseases worldwide, with host's immune response significantly affecting the prognosis. With an aim to timely predict the most likely outcome of SARS-CoV-2 infection, we investigated the association of IFNL3 and IFNL4 polymorphisms, as well as other potentially relevant factors, with the COVID-19 mortality. This prospective observational case-control study involved 178 COVID-19 patients, hospitalized at Corona Center or Clinic for Infectious Diseases of University Clinical Centre Kragujevac, Serbia, followed up until hospital discharge or in-hospital death. Demographic and clinical data on all participants were retrieved from the electronic medical records, and TaqMan assays were employed in genotyping for IFNL3 and IFNL4 single nucleotide polymorphisms (SNPs), namely rs12980275, rs8099917, rs12979860, and rs368234815. 21.9% and 65.0% of hospitalized and critically ill COVID-19 patients, respectively, died in-hospital. Multivariable logistic regression analysis revealed increased Charlson Comorbidity Index (CCI), N/L, and lactate dehydrogenase (LDH) level to be associated with an increased likelihood of a lethal outcome. Similarly, females and the carriers of at least one variant allele of IFNL3 rs8099917 were almost 36-fold more likely not to survive SARS-CoV-2 infection. On the other hand, the presence of at least one ancestral allele of IFNL4 rs368234815 decreased more than 15-fold the likelihood of mortality from COVID-19. Our results suggest that, in addition to LDH level, N/L ratio, and CCI, IFNL4 rs368234815 and IFNL3 rs8099917 polymorphisms, but also patients' gender, significantly affect the outcome of COVID-19.
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Affiliation(s)
- Sanja Matic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Dragan Milovanovic
- Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Department of Clinical Pharmacology, University Clinical Centre Kragujevac, Kragujevac, Serbia
| | - Zeljko Mijailovic
- Department of Infectious Diseases, Serbia, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Infectious Diseases Clinic, University Clinical Centre Kragujevac, Kragujevac, Serbia
| | - Predrag Djurdjevic
- Department of Internal medicine, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Clinic for Haematology, University Clinical Centre Kragujevac, Kragujevac, Serbia
| | - Predrag Sazdanovic
- Department of Anatomy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Gynecology and Obstetrics Clinic, University Clinical Centre Kragujevac, Kragujevac, Serbia
| | - Srdjan Stefanovic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Danijela Todorovic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Suzana Popovic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Katarina Vitosevic
- Department of Forensic Medicine, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Vladimir Vukicevic
- Corona Centre, University Clinical Centre Kragujevac, Kragujevac, Serbia
| | - Milena Vukic
- Department of Chemistry, Faculty of Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nenad Vukovic
- Department of Chemistry, Faculty of Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nevena Milivojevic
- Bioengineering Research and Development Center (BioIRC), Kragujevac, Serbia.,Department of Sciences, Institute for Information Technologies Kragujevac, University of Kragujevac, Kragujevac, Serbia
| | - Marko Zivanovic
- Bioengineering Research and Development Center (BioIRC), Kragujevac, Serbia.,Department of Sciences, Institute for Information Technologies Kragujevac, University of Kragujevac, Kragujevac, Serbia
| | - Vladimir Jakovljevic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Deprtment of Human Pathology, 1st Moscow Medical Unuversity "I. M. Sechenov", Moscow, Russia
| | - Nenad Filipovic
- Bioengineering Research and Development Center (BioIRC), Kragujevac, Serbia.,Faculty of Engineering, University of Kragujevac, Kragujevac, Serbia
| | - Dejan Baskic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Institute of Public Health Kragujevac, Kragujevac, Serbia
| | - Natasa Djordjevic
- Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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18
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Damane BP, Mulaudzi TV, Kader SS, Naidoo P, Savkovic SD, Dlamini Z, Mkhize-Kwitshana ZL. Unraveling the Complex Interconnection between Specific Inflammatory Signaling Pathways and Mechanisms Involved in HIV-Associated Colorectal Oncogenesis. Cancers (Basel) 2023; 15:748. [PMID: 36765706 PMCID: PMC9913377 DOI: 10.3390/cancers15030748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/16/2023] [Accepted: 01/22/2023] [Indexed: 01/27/2023] Open
Abstract
The advancement of HIV treatment has led to increased life expectancy. However, people living with HIV (PLWH) are at a higher risk of developing colorectal cancers. Chronic inflammation has a key role in oncogenesis, affecting the initiation, promotion, transformation, and advancement of the disease. PLWH are prone to opportunistic infections that trigger inflammation. It has been documented that 15-20% of cancers are triggered by infections, and this percentage is expected to be increased in HIV co-infections. The incidence of parasitic infections such as helminths, with Ascariasis being the most common, is higher in HIV-infected individuals. Cancer cells and opportunistic infections drive a cascade of inflammatory responses which assist in evading immune surveillance, making them survive longer in the affected individuals. Their survival leads to a chronic inflammatory state which further increases the probability of oncogenesis. This review discusses the key inflammatory signaling pathways involved in disease pathogenesis in HIV-positive patients with colorectal cancers. The possibility of the involvement of co-infections in the advancement of the disease, along with highlights on signaling mechanisms that can potentially be utilized as therapeutic strategies to prevent oncogenesis or halt cancer progression, are addressed.
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Affiliation(s)
- Botle Precious Damane
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
- Department of Medical Microbiology, School of Laboratory Medicine & Medical Sciences, Medical School Campus, College of Health Sciences, University of KwaZulu-Natal-Natal, Durban 4041, South Africa
| | - Thanyani Victor Mulaudzi
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
| | - Sayed Shakeel Kader
- Department of Surgery, University of KwaZulu Natal, Congella, Durban 4013, South Africa
| | - Pragalathan Naidoo
- Department of Medical Microbiology, School of Laboratory Medicine & Medical Sciences, Medical School Campus, College of Health Sciences, University of KwaZulu-Natal-Natal, Durban 4041, South Africa
- SAMRC Research Capacity Development Division, South African Medical Research Council, Tygerberg, Cape Town 4091, South Africa
| | - Suzana D. Savkovic
- School of Medicine, Department of Pathology & Laboratory Medicine, 1430 Tulane Ave., SL-79, New Orleans, LA 70112, USA
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa
| | - Zilungile Lynette Mkhize-Kwitshana
- Department of Medical Microbiology, School of Laboratory Medicine & Medical Sciences, Medical School Campus, College of Health Sciences, University of KwaZulu-Natal-Natal, Durban 4041, South Africa
- SAMRC Research Capacity Development Division, South African Medical Research Council, Tygerberg, Cape Town 4091, South Africa
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19
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Manivasagam S, Williams JL, Vollmer LL, Bollman B, Bartleson JM, Ai S, Wu GF, Klein RS. Targeting IFN-λ Signaling Promotes Recovery from Central Nervous System Autoimmunity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1341-1351. [PMID: 35181638 PMCID: PMC9012116 DOI: 10.4049/jimmunol.2101041] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/07/2022] [Indexed: 06/14/2023]
Abstract
Type III IFNs (IFNLs) are newly discovered cytokines, acting at epithelial and other barriers, that exert immunomodulatory functions in addition to their primary roles in antiviral defense. In this study, we define a role for IFNLs in maintaining autoreactive T cell effector function and limiting recovery in a murine model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis. Genetic or Ab-based neutralization of the IFNL receptor (IFNLR) resulted in lack of disease maintenance during experimental autoimmune encephalomyelitis, with loss of CNS Th1 effector responses and limited axonal injury. Phenotypic effects of IFNLR signaling were traced to increased APC function, with associated increase in T cell production of IFN-γ and GM-CSF. Consistent with this, IFNL levels within lesions of CNS tissues derived from patients with MS were elevated compared with MS normal-appearing white matter. Furthermore, expression of IFNLR was selectively elevated in MS active lesions compared with inactive lesions or normal-appearing white matter. These findings suggest IFNL signaling as a potential therapeutic target to prevent chronic autoimmune neuroinflammation.
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Affiliation(s)
- Sindhu Manivasagam
- Department of Medicine, Washington University in St. Louis, St. Louis, MO
| | | | - Lauren L Vollmer
- Department of Medicine, Washington University in St. Louis, St. Louis, MO
| | - Bryan Bollman
- Department of Neurology, Washington University in St. Louis, St. Louis, MO; and
| | - Juliet M Bartleson
- Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO
| | - Shenjian Ai
- Department of Medicine, Washington University in St. Louis, St. Louis, MO
| | - Gregory F Wu
- Department of Neurology, Washington University in St. Louis, St. Louis, MO; and
- Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO
| | - Robyn S Klein
- Department of Medicine, Washington University in St. Louis, St. Louis, MO;
- Department of Neurology, Washington University in St. Louis, St. Louis, MO; and
- Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO
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20
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Wyatt KD, Sarr D, Sakamoto K, Watford WT. Influenza-induced Tpl2 expression within alveolar epithelial cells is dispensable for host viral control and anti-viral immunity. PLoS One 2022; 17:e0262832. [PMID: 35051238 PMCID: PMC8775564 DOI: 10.1371/journal.pone.0262832] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 01/05/2022] [Indexed: 01/22/2023] Open
Abstract
Tumor progression locus 2 (Tpl2) is a serine/threonine kinase that regulates the expression of inflammatory mediators in response to Toll-like receptors (TLR) and cytokine receptors. Global ablation of Tpl2 leads to severe disease in response to influenza A virus (IAV) infection, characterized by respiratory distress, and studies in bone marrow chimeric mice implicated Tpl2 in non-hematopoietic cells. Lung epithelial cells are primary targets and replicative niches of influenza viruses; however, the specific regulation of antiviral responses by Tpl2 within lung epithelial cells has not been investigated. Herein, we show that Tpl2 is basally expressed in primary airway epithelial cells and that its expression increases in both type I and type II airway epithelial cells (AECI and AECII) in response to influenza infection. We used Nkx2.1-cre to drive Tpl2 deletion within pulmonary epithelial cells to delineate epithelial cell-specific functions of Tpl2 during influenza infection in mice. Although modest increases in morbidity and mortality were attributed to cre-dependent deletion in lung epithelial cells, no alterations in host cytokine production or lung pathology were observed. In vitro, Tpl2 inhibition within the type I airway epithelial cell line, LET1, as well as genetic ablation in primary airway epithelial cells did not alter cytokine production. Overall, these findings establish that Tpl2-dependent defects in cells other than AECs are primarily responsible for the morbidity and mortality seen in influenza-infected mice with global Tpl2 ablation.
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Affiliation(s)
- Kara D. Wyatt
- Department of Infectious Diseases, University of Georgia, Athens, Georgia, United States of America
| | - Demba Sarr
- Department of Infectious Diseases, University of Georgia, Athens, Georgia, United States of America
| | - Kaori Sakamoto
- Department of Pathology, University of Georgia, Athens, Georgia, United States of America
| | - Wendy T. Watford
- Department of Infectious Diseases, University of Georgia, Athens, Georgia, United States of America
- * E-mail:
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21
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Devan AR, Nair B, Kumar AR, Gorantla JN, T S A, Nath LR. Unravelling the Immune Modulatory Effect of Indian Spices to Impede the Transmission of COVID-19: A Promising Approach. Curr Pharm Biotechnol 2022; 23:201-220. [PMID: 33593256 DOI: 10.2174/1389201022666210216144917] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 12/24/2020] [Accepted: 12/28/2020] [Indexed: 02/08/2023]
Abstract
Months after WHO declared COVID-19 as a Global Public Health Emergency of International Concern, it does not seem to be flattening the curve as we are still devoid of an effective treatment modality and vaccination is in the first phase in many countries. Amid such uncertainty, being immune is the best strategy to defend against corona attacks. As the whole world is referring back to immune-boosting traditional remedies, interest is rekindled in the Indian system of Medicine, which is gifted with an abundance of herbal medicines as well as remedies. Among them, spices (root, rhizome, seed, fruit, leaf, bud, and flower of various plants used to add taste and flavors to food) are bestowed with immense medicinal potential. A plethora of clinical as well as preclinical studies reported the effectiveness of various spices for various ailments. The potential immune-boosting properties together with their excellent safety profiles are making spices the current choice of phytoresearch as well as the immune-boosting home remedies during these sceptical times. The present review critically evaluates the immune impact of various Indian spices and their potential to tackle the novel coronavirus, with comments on the safety and toxicity aspects of spices.
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Affiliation(s)
- Aswathy R Devan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - Ayana R Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - Jaggaiah N Gorantla
- Department of Chemistry, Wayne State University, Detroit, 48201, Michigan, USA
| | - Aishwarya T S
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
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22
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Huebner ST, Henny S, Giezendanner S, Brack T, Brutsche M, Chhajed P, Clarenbach C, Dieterle T, Egli A, Frey M, Heijnen I, Irani S, Sievi NA, Thurnheer R, Trendelenburg M, Kohler M, Leuppi-Taegtmeyer AB, Leuppi JD. Prediction of Acute COPD Exacerbation in the Swiss Multicenter COPD Cohort Study (TOPDOCS) by Clinical Parameters, Medication Use, and Immunological Biomarkers. Respiration 2021; 101:441-454. [PMID: 34942619 PMCID: PMC9153354 DOI: 10.1159/000520196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 09/17/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Whether immunological biomarkers combined with clinical characteristics measured during an exacerbation-free period are predictive of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) frequency and severity is unknown. METHOD We measured immunological biomarkers and clinical characteristics in 271 stable chronic obstructive pulmonary disease (COPD) patients (67% male, mean age 63 years) from "The Obstructive Pulmonary Disease Outcomes Cohort of Switzerland" cohort on a single occasion. One-year follow-up data were available for 178 patients. Variables independently associated with AECOPD frequency and severity were identified by multivariable regression analyses. Receiver operating characteristic analysis was used to obtain optimal cutoff levels and measure the area under the curve (AUC) in order to assess if baseline data can be used to predict future AECOPD. RESULTS Higher number of COPD medications (adjusted incident rate ratio [aIRR] 1.17) and platelet count (aIRR 1.03), and lower FEV1% predicted (aIRR 0.84) and IgG2 (aIRR 0.84) were independently associated with AECOPD frequency in the year before baseline. Optimal cutoff levels for experiencing frequent (>1) AECOPD were ≥3 COPD medications (AUC = 0.72), FEV1 ≤40% predicted (AUC = 0.72), and IgG2 ≤2.6 g/L (AUC = 0.64). The performance of a model using clinical and biomarker parameters to predict future, frequent AECOPD events in the same patients was fair (AUC = 0.78) but not superior to a model using only clinical parameters (AUC = 0.79). The IFN-lambda rs8099917GG-genotype was more prevalent in patients who had severe AECOPD. CONCLUSIONS Clinical and biomarker parameters assessed at a single point in time correlated with the frequency of AECOPD events during the year before and the year after assessment. However, only clinical parameters had fair discriminatory power in identifying patients likely to experience frequent AECOPD.
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Affiliation(s)
- Simona Tabea Huebner
- University Clinic of Medicine, Cantonal Hospital Baselland, Liestal, Switzerland,
- Faculty of Medicine, University of Basel, Basel, Switzerland,
| | - Simona Henny
- University Clinic of Medicine, Cantonal Hospital Baselland, Liestal, Switzerland
| | | | - Thomas Brack
- Department of Internal Medicine, Cantonal Hospital Glarus, Glarus, Switzerland
| | - Martin Brutsche
- Division of Respiratory Medicine, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Prashant Chhajed
- University Clinic of Medicine, Cantonal Hospital Baselland, Liestal, Switzerland
| | - Christian Clarenbach
- Division of Respiratory Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Thomas Dieterle
- Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Adrian Egli
- Division of Clinical Microbiology, University Hospital Basel, University of Basel, Basel, Switzerland
- Applied Microbiology Research, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Martin Frey
- Division of Respiratory Medicine, Hospital Barmelweid, Barmelweid, Switzerland
| | - Ingmar Heijnen
- Division of Medical Immunology, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Sarosh Irani
- Division of Respiratory Medicine, Cantonal Hospital Aarau, Aarau, Switzerland
| | | | - Robert Thurnheer
- Division of Respiratory Medicine, Cantonal Hospital Münsterlingen, Münsterlingen, Switzerland
| | - Marten Trendelenburg
- Faculty of Medicine, University of Basel, Basel, Switzerland
- Division of Internal Medicine, University Hospital Basel, and Clinical Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Malcolm Kohler
- Division of Respiratory Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Anne Barbara Leuppi-Taegtmeyer
- Faculty of Medicine, University of Basel, Basel, Switzerland
- Department of Clinical Pharmacology, University Hospital Basel, Basel, Switzerland
| | - Joerg Daniel Leuppi
- University Clinic of Medicine, Cantonal Hospital Baselland, Liestal, Switzerland
- Faculty of Medicine, University of Basel, Basel, Switzerland
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23
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Das A, Chauhan KS, Kumar H, Tailor P. Mutation in Irf8 Gene ( Irf8R294C ) Impairs Type I IFN-Mediated Antiviral Immune Response by Murine pDCs. Front Immunol 2021; 12:758190. [PMID: 34867997 PMCID: PMC8635750 DOI: 10.3389/fimmu.2021.758190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/25/2021] [Indexed: 12/01/2022] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are the key producers of type I interferons (IFNs), thus playing a central role in initiating antiviral immune response. Besides robust type I IFN production, pDCs also act as antigen presenting cells post immunogenic stimulation. Transcription factor Irf8 is indispensable for the development of both pDC and cDC1 subset. However, the mechanism underlying the differential regulation by IRF8 in cDC1- and pDC-specific genomic architecture of developmental pathways still remains to be fully elucidated. Previous studies indicated that the Irf8R294C mutation specifically abrogates development of cDC1 without affecting that of pDC. In the present study using RNA-seq based approach, we have found that though the point mutation Irf8R294C did not affect pDC development, it led to defective type I IFN production, thus resulting in inefficient antiviral response. This observation unraveled the distinctive roles of IRF8 in these two subpopulations—regulating the development of cDC1 whereas modulating the functionality of pDCs without affecting development. We have reported here that Irf8R294C mutation also caused defect in production of ISGs as well as defective upregulation of costimulatory molecules in pDCs in response to NDV infection (or CpG stimulation). Through in vivo studies, we demonstrated that abrogation of type I IFN production was concomitant with reduced upregulation of costimulatory molecules in pDCs and increased NDV burden in IRF8R294C mice in comparison with wild type, indicating inefficient viral clearance. Further, we have also shown that Irf8R294C mutation abolished the activation of type I IFN promoter by IRF8, justifying the low level of type I IFN production. Taken together, our study signifies that the single point mutation in Irf8, Irf8R294C severely compromised type I IFN-mediated immune response by murine pDCs, thereby causing impairment in antiviral immunity.
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Affiliation(s)
- Annesa Das
- Laboratory of Innate Immunity, National Institute of Immunology, New Delhi, India
| | | | - Himanshu Kumar
- Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, India
| | - Prafullakumar Tailor
- Laboratory of Innate Immunity, National Institute of Immunology, New Delhi, India.,Special Centre for Systems Medicine (SCSM), Jawaharlal Nehru University, New Delhi, India
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24
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Le Roux M, Ollivier A, Kervoaze G, Beke T, Gillet L, Pichavant M, Gosset P. IL-20 Cytokines Are Involved in Epithelial Lesions Associated with Virus-Induced COPD Exacerbation in Mice. Biomedicines 2021; 9:biomedicines9121838. [PMID: 34944654 PMCID: PMC8699027 DOI: 10.3390/biomedicines9121838] [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: 11/01/2021] [Revised: 11/26/2021] [Accepted: 12/02/2021] [Indexed: 12/24/2022] Open
Abstract
(1) Background: viral infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are responsible for disease progression and mortality. Previous reports showed that IL-20 cytokines facilitate bacterial lung infection, but their production and their role in COPD and viral infection has not yet been investigated. (2) Methods: C57BL/6 WT and IL-20 Rb KO mice were chronically exposed to air or cigarette smoke (CS) to mimic COPD. Cytokine production, antiviral response, inflammation and tissue damages were analyzed after PVM infection. (3) Results: CS exposure was associated with an increase in viral burden and antiviral response. PVM infection in CS mice enhanced IFN-γ, inflammation and tissue damage compared to Air mice. PVM infection and CS exposure induced, in an additive manner, IL-20 cytokines expression and the deletion of IL-20 Rb subunit decreased the expression of interferon-stimulated genes and the production of IFN-λ2/3, without an impact on PVM replication. Epithelial cell damages and inflammation were also reduced in IL-20 Rb-/- mice, and this was associated with reduced lung permeability and the maintenance of intercellular junctions. (4) Conclusions: PVM infection and CS exposure additively upregulates the IL-20 pathway, leading to the promotion of epithelial damages. Our data in our model of viral exacerbation of COPD identify IL-20 cytokine as a potential therapeutic target.
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Affiliation(s)
- Mélina Le Roux
- CIIL-Center for Infection and Immunity of Lille, CHRU Lille, Institute Pasteur de Lille, University Lille, CNRS UMR9017, Inserm U1019, 59000 Lille, France; (M.L.R.); (A.O.); (G.K.); (T.B.); (M.P.)
| | - Anaïs Ollivier
- CIIL-Center for Infection and Immunity of Lille, CHRU Lille, Institute Pasteur de Lille, University Lille, CNRS UMR9017, Inserm U1019, 59000 Lille, France; (M.L.R.); (A.O.); (G.K.); (T.B.); (M.P.)
| | - Gwenola Kervoaze
- CIIL-Center for Infection and Immunity of Lille, CHRU Lille, Institute Pasteur de Lille, University Lille, CNRS UMR9017, Inserm U1019, 59000 Lille, France; (M.L.R.); (A.O.); (G.K.); (T.B.); (M.P.)
| | - Timothé Beke
- CIIL-Center for Infection and Immunity of Lille, CHRU Lille, Institute Pasteur de Lille, University Lille, CNRS UMR9017, Inserm U1019, 59000 Lille, France; (M.L.R.); (A.O.); (G.K.); (T.B.); (M.P.)
| | - Laurent Gillet
- Immunology-Vaccinology Laboratory, Department of Infection and Parasitic Diseases, FARAH, University of Liege, 4000 Liege, Belgium;
| | - Muriel Pichavant
- CIIL-Center for Infection and Immunity of Lille, CHRU Lille, Institute Pasteur de Lille, University Lille, CNRS UMR9017, Inserm U1019, 59000 Lille, France; (M.L.R.); (A.O.); (G.K.); (T.B.); (M.P.)
| | - Philippe Gosset
- CIIL-Center for Infection and Immunity of Lille, CHRU Lille, Institute Pasteur de Lille, University Lille, CNRS UMR9017, Inserm U1019, 59000 Lille, France; (M.L.R.); (A.O.); (G.K.); (T.B.); (M.P.)
- Correspondence: ; Tel.: +33-320-877-965
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25
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Manivasagam S, Klein RS. Type III Interferons: Emerging Roles in Autoimmunity. Front Immunol 2021; 12:764062. [PMID: 34899712 PMCID: PMC8660671 DOI: 10.3389/fimmu.2021.764062] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Type III interferons (IFNs) or the lambda IFNs (IFNLs or IFN-λs) are antimicrobial cytokines that play key roles in immune host defense at endothelial and epithelial barriers. IFNLs signal via their heterodimeric receptor, comprised of two subunits, IFNLR1 and interleukin (IL)10Rβ, which defines the cellular specificity of the responses to the cytokines. Recent studies show that IFNL signaling regulates CD4+ T cell differentiation, favoring Th1 cells, which has led to the identification of IFNL as a putative therapeutic target for autoimmune diseases. Here, we summarize the IFNL signaling pathways during antimicrobial immunity, IFNL-mediated immunomodulation of both innate and adaptive immune cells, and induction of autoimmunity.
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Affiliation(s)
- Sindhu Manivasagam
- Center for Neuroimmunology & Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| | - Robyn S. Klein
- Center for Neuroimmunology & Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
- Department of Neurosciences, Washington University School of Medicine, St. Louis, MO, United States
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26
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Roberts JA, Varma VR, An Y, Varma S, Candia J, Fantoni G, Tiwari V, Anerillas C, Williamson A, Saito A, Loeffler T, Schilcher I, Moaddel R, Khadeer M, Lovett J, Tanaka T, Pletnikova O, Troncoso JC, Bennett DA, Albert MS, Yu K, Niu M, Haroutunian V, Zhang B, Peng J, Croteau DL, Resnick SM, Gorospe M, Bohr VA, Ferrucci L, Thambisetty M. A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets. SCIENCE ADVANCES 2021; 7:eabi8178. [PMID: 34757788 PMCID: PMC8580310 DOI: 10.1126/sciadv.abi8178] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 09/14/2021] [Indexed: 05/13/2023]
Abstract
Aptamer-based proteomics revealed differentially abundant proteins in Alzheimer’s disease (AD) brains in the Baltimore Longitudinal Study of Aging and Religious Orders Study (mean age, 89 ± 9 years). A subset of these proteins was also differentially abundant in the brains of young APOE ε4 carriers relative to noncarriers (mean age, 39 ± 6 years). Several of these proteins represent targets of approved and experimental drugs for other indications and were validated using orthogonal methods in independent human brain tissue samples as well as in transgenic AD models. Using cell culture–based phenotypic assays, we showed that drugs targeting the cytokine transducer STAT3 and the Src family tyrosine kinases, YES1 and FYN, rescued molecular phenotypes relevant to AD pathogenesis. Our findings may accelerate the development of effective interventions targeting the earliest molecular triggers of AD.
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Affiliation(s)
- Jackson A. Roberts
- Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
- Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032
| | - Vijay R. Varma
- Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Yang An
- Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | | | - Julián Candia
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Giovanna Fantoni
- Clinical Research Core, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Vinod Tiwari
- Section on DNA Repair, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Carlos Anerillas
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Andrew Williamson
- Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Atsushi Saito
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Tina Loeffler
- QPS Austria GmbH, Parkring 12, 8074 Grambach, Austria
| | | | - Ruin Moaddel
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Mohammed Khadeer
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Jacqueline Lovett
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Toshiko Tanaka
- Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Olga Pletnikova
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA
| | - Juan C. Troncoso
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - David A. Bennett
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
| | - Marilyn S. Albert
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Kaiwen Yu
- Departments of Structural Biology and Developmental Neurobiology, Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Mingming Niu
- Departments of Structural Biology and Developmental Neurobiology, Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Vahram Haroutunian
- Departments of Psychiatry and Neuroscience, The Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Mental Illness Research, Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY 10468, USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences and Department of Pharmacological Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Junmin Peng
- Departments of Structural Biology and Developmental Neurobiology, Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Deborah L. Croteau
- Section on DNA Repair, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Susan M. Resnick
- Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Vilhelm A. Bohr
- Section on DNA Repair, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Luigi Ferrucci
- Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Madhav Thambisetty
- Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
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Shaldzhyan A, Zabrodskaya Y, Yolshin N, Kudling T, Lozhkov A, Plotnikova M, Ramsay E, Taraskin A, Nekrasov P, Grudinin M, Vasin A. Clean and folded: Production of active, high quality recombinant human interferon-λ1. Process Biochem 2021; 111:32-39. [PMID: 34493923 PMCID: PMC8411590 DOI: 10.1016/j.procbio.2021.08.029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 12/09/2022]
Abstract
Type III interferons exhibit antiviral activity against influenza viruses, coronaviruses, rotaviruses, and others. In addition, this type of interferon theoretically has therapeutic advantages, in comparison with type I interferons, due to its ability to activate a narrower group of genes in a relatively small group of target cells. Hence, it can elicit more targeted antiviral or immunomodulatory responses. Obtaining biologically-active interferon lambda (hIFN-λ1) is fraught with difficulties at the stage of expression in soluble form or, in the case of expression in the form of inclusion bodies, at the stage of refolding. In this work, hIFN-λ1 was expressed in the form of inclusion bodies, and a simple, effective refolding method was developed. Efficient and scalable methods for chromatographic purification of recombinant hIFN-λ1 were also developed. High-yield, high-purity product was obtained through optimization of several processes including: recombinant protein expression; metal affinity chromatography; cation exchange chromatography; and an intermediate protein refolding stage. The obtained protein was shown to feature expected specific biological activity in line with published effects: induction of MxA gene expression in A549 cells and antiviral activity against influenza A virus.
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Affiliation(s)
- Aram Shaldzhyan
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Prof. Popov St., St. Petersburg, 197376, Russia
| | - Yana Zabrodskaya
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Prof. Popov St., St. Petersburg, 197376, Russia.,Peter the Great Saint Petersburg Polytechnic University, 29 Polytechnicheskaya, St. Petersburg, 194064, Russia.,Petersburg Nuclear Physics Institute named by B. P. Konstantinov of National Research Center "Kurchatov Institute", mkr. Orlova roshcha 1, Gatchina, 188300, Russia
| | - Nikita Yolshin
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Prof. Popov St., St. Petersburg, 197376, Russia
| | - Tatiana Kudling
- Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Alexey Lozhkov
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Prof. Popov St., St. Petersburg, 197376, Russia.,Peter the Great Saint Petersburg Polytechnic University, 29 Polytechnicheskaya, St. Petersburg, 194064, Russia
| | - Marina Plotnikova
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Prof. Popov St., St. Petersburg, 197376, Russia
| | - Edward Ramsay
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Prof. Popov St., St. Petersburg, 197376, Russia
| | - Aleksandr Taraskin
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Prof. Popov St., St. Petersburg, 197376, Russia.,Peter the Great Saint Petersburg Polytechnic University, 29 Polytechnicheskaya, St. Petersburg, 194064, Russia
| | - Peter Nekrasov
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Prof. Popov St., St. Petersburg, 197376, Russia
| | - Mikhail Grudinin
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Prof. Popov St., St. Petersburg, 197376, Russia
| | - Andrey Vasin
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Prof. Popov St., St. Petersburg, 197376, Russia.,Peter the Great Saint Petersburg Polytechnic University, 29 Polytechnicheskaya, St. Petersburg, 194064, Russia
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28
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Yang F, Li H, Li Y, Hao Y, Wang C, Jia P, Chen X, Ma S, Xiao Z. Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis. Int Immunopharmacol 2021; 99:108051. [PMID: 34426110 DOI: 10.1016/j.intimp.2021.108051] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/28/2021] [Accepted: 08/04/2021] [Indexed: 02/08/2023]
Abstract
Hepatic fibrosis represents as a dynamic pathological process characterized by the net accumulation of extracellular matrix in the progression of various chronic liver diseases, including viral hepatitis, alcoholic liver disease, and metabolic associated fatty liver disease (MAFLD). Activation of hepatic stellate cells (HSCs) is well-defined to play a central role in the initiation and progression of hepatic fibrosis. However, the activation of HSCs is affected by the complicated microenvironments in liver, which largely attributes to the communication between hepatocytes and multiple tissue-resident cells, including sinusoidal endothelial cells, bile duct epithelial cells, platelets, T cells, B cells, macrophages, natural killer cells, neutrophils, dendritic cells, in the direct or indirect mechanisms. Cellular crosstalk between HSCs and surrounding cells contributes to the activation of HSCs and the progression of hepatic fibrosis. Currently, accumulating evidence have proven the complexity and plasticity of HSCs activation, and further clarification of cellular communication between HSCs and surrounding cells will provide sufficient clue to the development of novel diagnostic methods and therapeutic strategies for hepatic fibrosis.
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Affiliation(s)
- Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Heng Li
- Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yanmin Li
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Yaokun Hao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Chenxiao Wang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Pan Jia
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Xinju Chen
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
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29
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Antony F, Pundkar C, Sandey M, Jaiswal AK, Mishra A, Kumar A, Channappanavar R, Suryawanshi A. IFN-λ Regulates Neutrophil Biology to Suppress Inflammation in Herpes Simplex Virus-1-Induced Corneal Immunopathology. THE JOURNAL OF IMMUNOLOGY 2021; 206:1866-1877. [PMID: 33811102 DOI: 10.4049/jimmunol.2000979] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 02/08/2021] [Indexed: 12/13/2022]
Abstract
HSV-1 infection of the cornea causes a severe immunoinflammatory and vision-impairing condition called herpetic stromal keratitis (SK). The virus replication in corneal epithelium followed by neutrophil- and CD4+ T cell-mediated inflammation plays a dominant role in SK. Although previous studies demonstrate critical functions of type I IFNs (IFN-α/β) in HSV-1 infection, the role of recently discovered IFN-λ (type III IFN), specifically at the corneal mucosa, is poorly defined. Our study using a mouse model of SK pathogenesis shows that HSV-1 infection induces a robust IFN-λ response compared with type I IFN production at the corneal mucosal surface. However, the normal progression of SK indicates that the endogenous IFN responses are insufficient to suppress HSV-1-induced corneal pathology. Therefore, we examined the therapeutic efficacy of exogenous rIFN-λ during SK progression. Our results show that rIFN-λ therapy suppressed inflammatory cell infiltration in the cornea and significantly reduced the SK pathologic condition. Early rIFN-λ treatment significantly reduced neutrophil and macrophage infiltration, and IL-6, IL-1β, and CXCL-1 production in the cornea. Notably, the virucidal capacity of neutrophils and macrophages measured by reactive oxygen species generation was not affected. Similarly, ex vivo rIFN-λ treatment of HSV-1-stimulated bone marrow-derived neutrophils significantly promoted IFN-stimulated genes without affecting reactive oxygen species production. Collectively, our data demonstrate that exogenous topical rIFN-λ treatment during the development and progression of SK could represent a novel therapeutic approach to control HSV-1-induced inflammation and associated vision impairment.
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Affiliation(s)
- Ferrin Antony
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849
| | - Chetan Pundkar
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849
| | - Maninder Sandey
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849
| | - Anil K Jaiswal
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849
| | - Amarjit Mishra
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849
| | - Ashok Kumar
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, MI 48201; and
| | | | - Amol Suryawanshi
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849;
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30
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Saeed H, Thoendel M, Razonable RR. Individualized management of cytomegalovirus in solid organ transplant recipients. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2021. [DOI: 10.1080/23808993.2021.1964951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Huma Saeed
- Division of Infectious Diseases, Department of Medicine and the William J Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, United States
| | - Matthew Thoendel
- Division of Infectious Diseases, Department of Medicine and the William J Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, United States
| | - Raymund R Razonable
- Division of Infectious Diseases, Department of Medicine and the William J Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, United States
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31
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Plotnikova M, Lozhkov A, Romanovskaya-Romanko E, Baranovskaya I, Sergeeva M, Kаа K, Klotchenko S, Vasin A. IFN-λ1 Displays Various Levels of Antiviral Activity In Vitro in a Select Panel of RNA Viruses. Viruses 2021; 13:1602. [PMID: 34452467 PMCID: PMC8402797 DOI: 10.3390/v13081602] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 12/25/2022] Open
Abstract
Type III interferons (lambda IFNs) are a quite new, small family of three closely related cytokines with interferon-like activity. Attention to IFN-λ is mainly focused on direct antiviral activity in which, as with IFN-α, viral genome replication is inhibited without the participation of immune system cells. The heterodimeric receptor for lambda interferons is exposed mainly on epithelial cells, which limits its possible action on other cells, thus reducing the likelihood of developing undesirable side effects compared to type I IFN. In this study, we examined the antiviral potential of exogenous human IFN-λ1 in cellular models of viral infection. To study the protective effects of IFN-λ1, three administration schemes were used: 'preventive' (pretreatment); 'preventive/therapeutic' (pre/post); and 'therapeutic' (post). Three IFN-λ1 concentrations (from 10 to 500 ng/mL) were used. We have shown that human IFN-λ1 restricts SARS-CoV-2 replication in Vero cells with all three treatment schemes. In addition, we have shown a decrease in the viral loads of CHIKV and IVA with the 'preventive' and 'preventive/therapeutic' regimes. No significant antiviral effect of IFN-λ1 against AdV was detected. Our study highlights the potential for using IFN-λ as a broad-spectrum therapeutic agent against respiratory RNA viruses.
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Affiliation(s)
- Marina Plotnikova
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
| | - Alexey Lozhkov
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
- Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia
| | - Ekaterina Romanovskaya-Romanko
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
| | - Irina Baranovskaya
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
- Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia
| | - Mariia Sergeeva
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
- Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia
| | - Konstantin Kаа
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS, 108819 Moscow, Russia;
| | - Sergey Klotchenko
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
| | - Andrey Vasin
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
- Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia
- Scientific and Educational Center for Biophysical Research in The Field of Pharmaceuticals, Saint Petersburg State Chemical Pharmaceutical University, 197022 St. Petersburg, Russia
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Zhang X, Wang S, Zhu Y, Zhang M, Zhao Y, Yan Z, Wang Q, Li X. Double-edged effects of interferons on the regulation of cancer-immunity cycle. Oncoimmunology 2021; 10:1929005. [PMID: 34262796 PMCID: PMC8253121 DOI: 10.1080/2162402x.2021.1929005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Interferons (IFNs) are a large family of pleiotropic cytokines that regulate both innate and adaptive immunity and show anti-cancer effects in various cancer types. Moreover, it was revealed that IFN signaling plays critical roles in the success of cancer therapy strategies, thereby enhancing their therapeutic effects. However, IFNs have minimal or even adverse effects on cancer eradication, and mediate cancer immune escape in some instances. Thus, IFNs have a double-edged effect on the cancer immune response. Recent studies suggest that IFNs regulate each step of the cancer immunity-cycle, consisting of cancer antigen release, presentation of antigens and activation of T cells, trafficking and infiltration of effector T cells into the tumor microenvironment, and recognition and killing of cancer cells, which contributes to our understanding of the mechanisms of IFNs in regulating cancer immunity. In this review, we focus on IFNs and cancer immunity and elaborate on the roles of IFNs in regulating the cancer-immunity cycle.
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Affiliation(s)
- Xiao Zhang
- Department of Stomatology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.,Department of Pathology, Harbin Medical University, Harbin, China
| | - Song Wang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Yuanyuan Zhu
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Minghui Zhang
- Department of Oncology, Chifeng City Hospital, Chifeng, China
| | - Yan Zhao
- Department of Oncology, Chifeng City Hospital, Chifeng, China
| | - Zhengbin Yan
- Department of Stomatology, the PeopIe's Hospital of Longhua, Shenzhen, China
| | - Qiuxu Wang
- Department of Stomatology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.,Department of Stomatology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Xiaobo Li
- Department of Stomatology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.,Department of Pathology, Harbin Medical University, Harbin, China
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33
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Novotny LA, Evans JG, Su L, Guo H, Meissner EG. Review of Lambda Interferons in Hepatitis B Virus Infection: Outcomes and Therapeutic Strategies. Viruses 2021; 13:1090. [PMID: 34207487 PMCID: PMC8230240 DOI: 10.3390/v13061090] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/27/2022] Open
Abstract
Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer. Approved treatments for chronic infection include injectable type-I interferons and nucleos(t)ide reverse transcriptase inhibitors. A small minority of patients achieve seroclearance after treatment with type-I interferons, defined as sustained absence of detectable HBV DNA and surface antigen (HBsAg) antigenemia. However, type-I interferons cause significant side effects, are costly, must be administered for months, and most patients have viral rebound or non-response. Nucleos(t)ide reverse transcriptase inhibitors reduce HBV viral load and improve liver-related outcomes, but do not lower HBsAg levels or impart seroclearance. Thus, new therapeutics are urgently needed. Lambda interferons (IFNLs) have been tested as an alternative strategy to stimulate host antiviral pathways to treat HBV infection. IFNLs comprise an evolutionarily conserved innate immune pathway and have cell-type specific activity on hepatocytes, other epithelial cells found at mucosal surfaces, and some immune cells due to restricted cellular expression of the IFNL receptor. This article will review work that examined expression of IFNLs during acute and chronic HBV infection, the impact of IFNLs on HBV replication in vitro and in vivo, the association of polymorphisms in IFNL genes with clinical outcomes, and the therapeutic evaluation of IFNLs for the treatment of chronic HBV infection.
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Affiliation(s)
- Laura A. Novotny
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
| | - John Grayson Evans
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
| | - Lishan Su
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology, Microbiology, and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Haitao Guo
- Department of Microbiology and Molecular Genetics, Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA;
| | - Eric G. Meissner
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
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34
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Quench me if you can: Alpha-2-macroglobulin trypsin complexes enable serum biomarker analysis by MALDI mass spectrometry. Biochimie 2021; 185:87-95. [PMID: 33744341 DOI: 10.1016/j.biochi.2021.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 02/15/2021] [Accepted: 03/08/2021] [Indexed: 12/11/2022]
Abstract
One of the main functions of alpha-2-macroglobulin (A2M) in human blood serum is the binding of all classes of protease. It is known that trypsin, after such interaction, possesses modified proteolytic activity. Trypsin first hydrolyzes two bonds in A2M's 'bait region', and the peptide 705VGFYESDVMGR715 is released from A2M. In this work, specifics of the A2M-trypsin interaction were used to determine A2M concentration directly in human blood serum using MALDI mass-spectrometry. Following exogenous addition of trypsin to human blood serum in vitro, the concentration of the VGFYESDVMGR peptide was measured, using its isotopically-labeled analogue (18O), and A2M concentration was calculated. The optimized mass spectrometric approach was verified using a standard method for A2M concentration determination (ELISA) and the relevant statistical analysis methods. It was also shown that trypsin's modified proteolytic activity in the presence of serum A2M can be used to analyze other serum proteins, including potential biomarkers of pathological processes. Thus, this work describes a promising approach to serum biomarker analysis that can be technically extended in several useful directions.
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35
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Protective cellular and mucosal immune responses following nasal administration of a whole gamma-irradiated influenza A (subtype H1N1) vaccine adjuvanted with interleukin-28B in a mouse model. Arch Virol 2021; 166:545-557. [PMID: 33409549 PMCID: PMC7787640 DOI: 10.1007/s00705-020-04900-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 10/14/2020] [Indexed: 12/22/2022]
Abstract
The use of gamma-irradiated influenza A virus (γ-Flu), retains most of the viral structural antigens, represent a promising option for vaccine development. However, despite the high effectiveness of γ-Flu vaccines, the need to incorporate an adjuvant to improve vaccine-mediated protection seems inevitable. Here, we examined the protective efficacy of an intranasal gamma-irradiated HIN1 vaccine co-administered with a plasmid encoding mouse interleukin-28B (mIL-28B) as a novel adjuvant in BALB/c mice. Animals were immunized intranasally three times at one-week intervals with γ-Flu, alone or in combination with the mIL-28B adjuvant, followed by viral challenge with a high lethal dose (10 LD50) of A/PR/8/34 (H1N1) influenza virus. Virus-specific antibody, cellular and mucosal responses, and the balance of cytokines in the spleen IFN-γ, IL-12, and IL-4) and in lung homogenates (IL-6 and IL-10) were measured by ELISA. The lymphoproliferative activity of restimulated spleen cells was also determined by MTT assay. Furthermore, virus production in the lungs of infected mice was estimated using the Madin-Darby canine kidney (MDCK)/hemagglutination assay (HA). Our data showed that intranasal immunization with adjuvanted γ-Flu vaccine efficiently promoted humoral, cellular, and mucosal immune responses and efficiently decreased lung virus titers, all of which are associated with protection against challenge. This combination also reduced IL-6 and IL-10 levels in lung homogenates. The results suggest that IL-28B can enhance the ability of the vaccine to elicit virus-specific immune responses and could potentially be used as an effective adjuvant.
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36
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Fulop T, Tripathi S, Rodrigues S, Desroches M, Bunt T, Eiser A, Bernier F, Beauregard PB, Barron AE, Khalil A, Plotka A, Hirokawa K, Larbi A, Bocti C, Laurent B, Frost EH, Witkowski JM. Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer's Disease. Neuropsychiatr Dis Treat 2021; 17:1311-1339. [PMID: 33976546 PMCID: PMC8106529 DOI: 10.2147/ndt.s264910] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.
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Affiliation(s)
- Tamas Fulop
- Research Center on Aging, Geriatric Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Shreyansh Tripathi
- Cluster Innovation Centre, North Campus, University of Delhi, Delhi, 110007, India.,Ikerbasque, The Basque Foundation for Science, Bilbao, Spain
| | - Serafim Rodrigues
- Ikerbasque, The Basque Foundation for Science, Bilbao, Spain.,Mathematical Computational and Experimental Neuroscience (MCEN), BCAM - The Basque Center for Applied Mathematics, Bilbao, Spain
| | - Mathieu Desroches
- MathNeuro Team, Inria Sophia Antipolis Méditerranée, Sophia Antipolis, France.,Department of Mathematics, Université Côte d'Azur, Nice, France
| | - Ton Bunt
- Izumi Biosciences, Inc., Lexington, MA, USA
| | - Arnold Eiser
- Leonard Davis Institute, University of Pennsylvania, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Francois Bernier
- Morinaga Milk Industry Co., Ltd, Next Generation Science Institute, Kanagawa, Japan
| | - Pascale B Beauregard
- Department of Biology, Faculty of Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Annelise E Barron
- Department of Bioengineering, Stanford School of Medicine, Stanford, CA, USA
| | - Abdelouahed Khalil
- Research Center on Aging, Geriatric Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Adam Plotka
- Department of Pathophysiology, Medical University of Gdansk, Gdansk, Poland
| | - Katsuiku Hirokawa
- Institute of Health and Life Science, Tokyo Med. Dent. University, Tokyo and Nito-Memory Nakanosogo Hospital, Department of Pathology, Tokyo, Japan
| | - Anis Larbi
- Singapore Immunology Network (SIgN), Agency for Science Technology and Research (ASTAR), Immunos Building, Biopolis, Singapore, Singapore
| | - Christian Bocti
- Research Center on Aging, Department of Medicine, Division of Neurology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Benoit Laurent
- Research Center on Aging, Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Eric H Frost
- Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Jacek M Witkowski
- Department of Pathophysiology, Medical University of Gdansk, Gdansk, Poland
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Arayasongsak U, Naka I, Ohashi J, Patarapotikul J, Nuchnoi P, Kalambaheti T, Sa-Ngasang A, Chanama S, Chaorattanakawee S. Genetic association study of interferon lambda 3, CD27, and human leukocyte antigen-DPB1 with dengue severity in Thailand. BMC Infect Dis 2020; 20:948. [PMID: 33308178 PMCID: PMC7731073 DOI: 10.1186/s12879-020-05636-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Dengue patients develop different disease severity ranging from mild (dengue fever [DF]) to severe forms (dengue hemorrhagic fever [DHF] and the fatal dengue shock syndrome [DSS]). Host genetics are considered to be one factor responsible for the severity of dengue outcomes. To identify genes associated with dengue severity that have not been studied yet, we performed genetic association analyses of interferon lambda 3 (IFNL3), CD27, and human leukocyte antigen-DPB1 (HLA-DPB1) genes in Thai dengue patients. METHODS A case-control association study was performed in 877 children (age ≤ 15 years) with dengue infection (DF, n = 386; DHF, n = 416; DSS, n = 75). A candidate single nucleotide polymorphism of each of IFNL3, CD27, and HLA-DPB1 was selected to be analyzed. Genotyping was performed by TaqMan real-time PCR assay, and the association with dengue severity was examined. RESULTS The rs9277534 variant of HLA-DPB1 was weakly associated with DHF. The genotype GG and G allele conferred protection against DHF (p = 0.04, odds ratio 0.74 for GG genotype, p = 0.03, odds ratio 0.79 for G allele). The association became borderline significant after adjusting for confounders (p = 0.05, odds ratio 0.82). No association was detected for IFNL3 or CD27. CONCLUSIONS The present study demonstrated the weak association of the rs9277534 variant of HLA-DPB1 with protection against DHF. This variant is in the 3' untranslated region and affects HLA-DPB1 surface protein expression. Our finding suggests that HLA-DPB1 may be involved in DHF pathogenesis.
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Affiliation(s)
- Unchana Arayasongsak
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Ratchawithi Road, Bangkok, 10400, Thailand
| | - Izumi Naka
- Laboratory of Human Genome Diversity, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Jun Ohashi
- Laboratory of Human Genome Diversity, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Jintana Patarapotikul
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Ratchawithi Road, Bangkok, 10400, Thailand
| | - Pornlada Nuchnoi
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, 10700, Thailand
| | - Thareerat Kalambaheti
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Ratchawithi Road, Bangkok, 10400, Thailand
| | - Areerat Sa-Ngasang
- National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand
| | - Sumalee Chanama
- National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand
| | - Suwanna Chaorattanakawee
- Department of Parasitology and Entomology, Faculty of Public Health, Mahidol University, Ratchawithi Road, Bangkok, 10400, Thailand.
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38
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Orr C, Xu W, Masur H, Kottilil S, Meissner EG. Peripheral blood correlates of virologic relapse after Sofosbuvir and Ribavirin treatment of Genotype-1 HCV infection. BMC Infect Dis 2020; 20:929. [PMID: 33276734 PMCID: PMC7718661 DOI: 10.1186/s12879-020-05657-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 11/24/2020] [Indexed: 12/11/2022] Open
Abstract
Background Treatment of chronic hepatitis C virus infection with direct acting antiviral therapy results in viral elimination in over 90% of cases. The duration of treatment required to achieve cure differs between individuals and relapse can occur. We asked whether cellular and transcriptional profiling of peripheral blood collected during treatment could identify biomarkers predictive of treatment outcome. Methods We analyzed peripheral blood collected during treatment of genotype 1 HCV with 24 weeks of sofosbuvir and weight-based or low dose ribavirin in a trial in which 29% of patients relapsed. Changes in host immunity during treatment were assessed by flow cytometry and whole blood gene expression profiling. Differences in expression of immune-relevant transcripts based on treatment outcome were analyzed using the Nanostring Human Immunology V2 panel. Results Multiple cellular populations changed during treatment, but pre-treatment neutrophil counts were lower and natural post-treatment killer cell counts were higher in patients who relapsed. Pre-treatment expression of genes associated with interferon-signaling, T-cell dysfunction, and T-cell co-stimulation differed by treatment outcome. We identified a pre- and post-treatment gene expression signature with high predictive capacity for distinguishing treatment outcome, but neither signature was sufficiently robust to suggest viability for clinical use. Conclusions Patients who relapse after hepatitis C virus therapy differ immunologically from non-relapsers based on expression of transcripts related to interferon signaling and T-cell dysfunction, as well as by peripheral neutrophil and NK-cell concentrations. These data provide insight into the host immunologic basis of relapse after DAA therapy for HCV and suggests mechanisms which may be relevant for understanding outcomes with currently approved regimens.
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Affiliation(s)
- Cody Orr
- Division of Infectious Diseases, Medical University of South Carolina, 135 Rutledge Ave, MSC752, Charleston, SC, 29425, USA
| | - Wenjie Xu
- Nanostring Technologies, Seattle, WA, USA
| | - Henry Masur
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Eric G Meissner
- Division of Infectious Diseases, Medical University of South Carolina, 135 Rutledge Ave, MSC752, Charleston, SC, 29425, USA. .,Department of Microbiology and Immunology, Medical University of South Carolina, 135 Rutledge Ave, MSC752, Charleston, SC, 29425, USA.
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Lozhkov AA, Klotchenko SA, Ramsay ES, Moshkoff HD, Moshkoff DA, Vasin AV, Salvato MS. The Key Roles of Interferon Lambda in Human Molecular Defense against Respiratory Viral Infections. Pathogens 2020; 9:pathogens9120989. [PMID: 33255985 PMCID: PMC7760417 DOI: 10.3390/pathogens9120989] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/18/2022] Open
Abstract
Interferons (IFN) are crucial for the innate immune response. Slightly more than two decades ago, a new type of IFN was discovered: the lambda IFN (type III IFN). Like other IFN, the type III IFN display antiviral activity against a wide variety of infections, they induce expression of antiviral, interferon-stimulated genes (MX1, OAS, IFITM1), and they have immuno-modulatory activities that shape adaptive immune responses. Unlike other IFN, the type III IFN signal through distinct receptors is limited to a few cell types, primarily mucosal epithelial cells. As a consequence of their greater and more durable production in nasal and respiratory tissues, they can determine the outcome of respiratory infections. This review is focused on the role of IFN-λ in the pathogenesis of respiratory viral infections, with influenza as a prime example. The influenza virus is a major public health problem, causing up to half a million lethal infections annually. Moreover, the virus has been the cause of four pandemics over the last century. Although IFN-λ are increasingly being tested in antiviral therapy, they can have a negative influence on epithelial tissue recovery and increase the risk of secondary bacterial infections. Therefore, IFN-λ expression deserves increased scrutiny as a key factor in the host immune response to infection.
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Affiliation(s)
- Alexey A. Lozhkov
- Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (A.A.L.); (D.A.M.); (A.V.V.)
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 196376 St. Petersburg, Russia; (S.A.K.); (E.S.R.)
| | - Sergey A. Klotchenko
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 196376 St. Petersburg, Russia; (S.A.K.); (E.S.R.)
| | - Edward S. Ramsay
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 196376 St. Petersburg, Russia; (S.A.K.); (E.S.R.)
| | - Herman D. Moshkoff
- Russian Technological University (MIREA), 119454 Moscow, Russia;
- US Pharma Biotechnology, Inc., 5000 Thayer Center, Suite C, Oakland, MD 21550, USA
| | - Dmitry A. Moshkoff
- Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (A.A.L.); (D.A.M.); (A.V.V.)
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 196376 St. Petersburg, Russia; (S.A.K.); (E.S.R.)
- US Pharma Biotechnology, Inc., 5000 Thayer Center, Suite C, Oakland, MD 21550, USA
- Global Virus Network(GVN), 725 W Lombard St, Baltimore, MD 21201, USA
| | - Andrey V. Vasin
- Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (A.A.L.); (D.A.M.); (A.V.V.)
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 196376 St. Petersburg, Russia; (S.A.K.); (E.S.R.)
- Global Virus Network(GVN), 725 W Lombard St, Baltimore, MD 21201, USA
- St. Petersburg State Chemical-Pharmaceutical Academy, 197022 St. Petersburg, Russia
| | - Maria S. Salvato
- Global Virus Network(GVN), 725 W Lombard St, Baltimore, MD 21201, USA
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Correspondence:
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Bamunuarachchi G, Yang X, Huang C, Liang Y, Guo Y, Liu L. MicroRNA-206 inhibits influenza A virus replication by targeting tankyrase 2. Cell Microbiol 2020; 23:e13281. [PMID: 33099847 DOI: 10.1111/cmi.13281] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 10/08/2020] [Accepted: 10/16/2020] [Indexed: 12/31/2022]
Abstract
Due to the frequent mutations, influenza A virus (IAV) becomes resistant to anti-viral drugs targeting influenza viral proteins. There are increasing interests in anti-viral agents that target host cellular proteins required for virus replication. Tankyrase (TNKS) has poly (ADP-ribose) polymerase activity and is a negative regulator of many host proteins. The objectives of this study are to study the role of TNKS2 in IAV infection, identify the microRNAs targeting TNKS2, and to understand the mechanisms involved. We found that TNKS2 expression was elevated in human lung epithelial cells and mouse lungs during IAV infection. Knock-down of TNKS2 by RNA interference reduced viral replication. Using a computation approach and 3'-untranslation regions (3'-UTR) reporter assay, we identified miR-206 as the microRNA that targeted TNKS2. Overexpression of miR-206 reduced viral protein levels and virus production in cell culture. The effect of miR-206 on IAV replication was strain-independent. miR-206 activated JNK/c-Jun signalling, induced type I interferon expression and enhanced Stat signalling. Finally, the delivery of an adenovirus expressing miR-206 into the lung of mice challenged with IAV increased type I interferon response, suppressed viral load in the lungs and increased survival. Our results indicate that miR-206 has anti-influenza activity by targeting TNKS2 and subsequently activating the anti-viral state.
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Affiliation(s)
- Gayan Bamunuarachchi
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA.,Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Xiaoyun Yang
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA.,Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Chaoqun Huang
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA.,Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Yurong Liang
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA.,Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, USA
| | | | - Lin Liu
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA.,Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, USA
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Interferon-λ Enhances the Differentiation of Naive B Cells into Plasmablasts via the mTORC1 Pathway. Cell Rep 2020; 33:108211. [DOI: 10.1016/j.celrep.2020.108211] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 06/24/2020] [Accepted: 09/09/2020] [Indexed: 01/21/2023] Open
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42
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Hetland G, Johnson E, Bernardshaw SV, Grinde B. Can medicinal mushrooms have prophylactic or therapeutic effect against COVID-19 and its pneumonic superinfection and complicating inflammation? Scand J Immunol 2020; 93:e12937. [PMID: 32657436 PMCID: PMC7404338 DOI: 10.1111/sji.12937] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/04/2020] [Accepted: 07/06/2020] [Indexed: 12/18/2022]
Abstract
Medicinal mushrooms have documented effects against different diseases, including infections and inflammatory disorders. The related Basidiomycota Agaricus blazei Murill (AbM), Hericium erinaceus (HE), and Grifola frondosa (GF) have been shown to exert antimicrobial activity against viral agents, Gram‐positive and Gram‐negative bacteria, and parasites in vitro and in vivo. Since the mechanism is immunomodulatory and not antibiotical, the mushrooms should be active against multi‐drug resistant microbes as well. Moreover, since these Basidiomycota also have anti‐inflammatory properties, they may be suited for treatment of the severe lung inflammation that often follows COVID‐19 infection. An AbM‐based mushroom extract (Andosan™), also containing HE and GF, has been shown to significantly reduce bacteraemia and increase survival in mice with pneumococcal sepsis, and to improve symptoms and quality of life in IBD patients via an anti‐inflammatory effect. Hence, such mushroom extracts could have prophylactic or therapeutic effect against the pneumonic superinfection and severe lung inflammation that often complicates COVID‐19 infection. Here, we review antimicrobial and anti‐inflammatory properties of AbM, HE and GF mushrooms, which could be used for the battle against COVID‐19.
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Affiliation(s)
- Geir Hetland
- Department of Immunology and Transfusion Medicine, Oslo University Hospital (OUH), Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Egil Johnson
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Gastrointestinal and Pediatric Surgery, Oslo University Hospital, Oslo, Norway
| | | | - Bjørn Grinde
- Norwegian Institute of Public Health, Oslo, Norway
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43
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Mihm S. COVID-19: Possible Impact of the Genetic Background in IFNL Genes on Disease Outcomes. J Innate Immun 2020; 12:273-274. [PMID: 32344401 PMCID: PMC7251566 DOI: 10.1159/000508076] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 04/14/2020] [Indexed: 11/19/2022] Open
Affiliation(s)
- Sabine Mihm
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany,
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44
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Santer DM, Minty GES, Golec DP, Lu J, May J, Namdar A, Shah J, Elahi S, Proud D, Joyce M, Tyrrell DL, Houghton M. Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells. PLoS Pathog 2020; 16:e1008515. [PMID: 32353085 PMCID: PMC7217487 DOI: 10.1371/journal.ppat.1008515] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 05/12/2020] [Accepted: 04/03/2020] [Indexed: 12/12/2022] Open
Abstract
Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8+ T cells, but not monocytes, neutrophils, natural killer cells, and CD4+ T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4+ T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.
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Affiliation(s)
- Deanna M. Santer
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Gillian E. S. Minty
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Dominic P. Golec
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Julia Lu
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Julia May
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Afshin Namdar
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
- School of Dentistry, University of Alberta, Edmonton, Alberta, Canada
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Juhi Shah
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Shokrollah Elahi
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
- School of Dentistry, University of Alberta, Edmonton, Alberta, Canada
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - David Proud
- Department of Physiology and Pharmacology and Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Michael Joyce
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - D. Lorne Tyrrell
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Michael Houghton
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
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Choobin H, Bamdad T, Shekarabi M. The pattern of antiviral protein expression induced by interferon λ1 in peripheral blood mononuclear cells of patients with chronic hepatitis C virus infection. Arch Virol 2020; 165:583-592. [PMID: 31927635 DOI: 10.1007/s00705-019-04438-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 09/12/2019] [Indexed: 12/28/2022]
Abstract
Interferon lambda was discovered in recent years to be an antiviral agent, and research on different aspects of this antiviral factor in viral infection and investigations of its effectiveness are also progressing. The immunological effects of interferon lambda on different cell populations is not precisely known, which may be due to its use of a heterodimeric receptor consisting of IL-10R2 and IFN-λR1, which are not broadly expressed in all types of cells. In the present study, signaling by interferon lambda and its effect on the expression of hepatitis C virus (HCV) proteins were measured, and the expression pattern of some antiviral proteins and IL-10 levels were investigated in peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 50 patients with chronic genotype 1a HCV infection and 10 healthy individuals as controls. The PBMCs were treated with various doses of interferon lambda at different times of cultivation. Real-time PCR was used for relative quantification of Mxa, PKR, OAS, ISG15 and HCV core mRNAs. Expression of the NS5A protein was measured by flow cytometry, and IL-10 production was assessed by ELISA. A significant increase in the expression of mRNA encoding antiviral proteins and a decrease in the expression of mRNAs encoding the HCV core protein were observed when cells were treated with interferon lambda in an intermittent manner. The expression of HCV NS5A protein and interleukin 10 levels were also lower than in the control group. It was shown that the maximum antiviral effect of interferon lambda in PBMCs is dependent on the dose and treatment time.
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Affiliation(s)
- Hamzeh Choobin
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Taravat Bamdad
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mehdi Shekarabi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Romagnoli M, Porcellini E, Carbone I, Veerhuis R, Licastro F. Impaired Innate Immunity Mechanisms in the Brain of Alzheimer's Disease. Int J Mol Sci 2020; 21:E1126. [PMID: 32046242 PMCID: PMC7038145 DOI: 10.3390/ijms21031126] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 01/27/2020] [Accepted: 02/05/2020] [Indexed: 12/11/2022] Open
Abstract
Among environmental factors likely associated with Alzheimer's disease (AD), persistent virus infections, and age-related progressive decline of immune competence might play a pivotal role. However, AD antimicrobial brain immune responses are poorly investigated. The present study focused on genes involved in antimicrobial defenses, especially against virus infections, in the AD brain. In particular, mRNA levels of IRF7, MED23, IL28B, and IFN-α genes were analyzed in hippocampus and temporal cortex brain samples from AD and non-demented controls. All subjects were also genotyped for APOE ε, IRF7, MED23, and IL28B gene polymorphisms. Most AD patients showed decreased mRNA levels of all investigated genes in the hippocampus and temporal cortex. However, a small group of AD patients showed increased hippocampal mRNA expression of MED23, IL28B, and IFN-α. mRNA levels of MED23, IL28B, IFN-α from the hippocampus and those of MED23 from the temporal cortex were further decreased in APOE ε4 allele AD carriers. Moreover, rs6598008 polymorphism of IRF7 was significantly associated with decreased hippocampal expression of IRF7, MED23, IL28B, and IFN-α. These findings suggest that AD brains show impaired innate antimicrobial gene expression profiles, and individual genetic makeup, such as positivity for the APOE ε4 and IRF7 A alleles, might affect brain immune efficiency.
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Affiliation(s)
- Martina Romagnoli
- Department of Experimental, Diagnostic and Specialty Medicine, School of Medicine, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy; (M.R.); (I.C.); (F.L.)
| | - Elisa Porcellini
- Department of Experimental, Diagnostic and Specialty Medicine, School of Medicine, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy; (M.R.); (I.C.); (F.L.)
| | - Ilaria Carbone
- Department of Experimental, Diagnostic and Specialty Medicine, School of Medicine, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy; (M.R.); (I.C.); (F.L.)
| | - Robert Veerhuis
- Department of Clinical Chemistry, Vrije Universiteit Amsterdam, Amsterdam UMC, 1105 Amsterdam, The Netherlands;
- Department of Psychiatry, Vrije Universiteit Amsterdam, Amsterdam UMC, 1105 Amsterdam, The Netherlands
| | - Federico Licastro
- Department of Experimental, Diagnostic and Specialty Medicine, School of Medicine, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy; (M.R.); (I.C.); (F.L.)
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Broquet A, Besbes A, Martin J, Jacqueline C, Vourc'h M, Roquilly A, Caillon J, Josien R, Asehnoune K. Interleukin-22 regulates interferon lambda expression in a mice model of pseudomonas aeruginosa pneumonia. Mol Immunol 2020; 118:52-59. [PMID: 31855807 DOI: 10.1016/j.molimm.2019.12.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 10/29/2019] [Accepted: 12/08/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Interleukin (IL)-22 is a cytokine involved in tissue protection and repair following lung pathologies. Interferon (IFN)-λ cytokines displayed similar properties during viral infection and a synergy of action between these two players has been documented in the intestine. We hypothesize that during Pseudomonas aeruginosa challenge, IL-22 up-regulates IFN-λ and that IFN-λ exhibits protective functions during Pseudomonas aeruginosa acute pneumonia model in mice. METHODS Using an in vitro human alveolar epithelial cell line A549, we assessed the ability of IL-22 to enhance IFN-λ expression during infection. IFN-λ protective function was evaluated in an acute mouse pneumonia model. RESULTS We first demonstrated in murine lungs that only type-II alveolar cells express IL-22 receptor and that IL-22 treatment of A549 cell line up-regulates IFN-λ expression. In a murine acute pneumonia model, IL-22 administration maintained significant IFN-λ levels in the broncho-alveolar fluids whereas IL-22 neutralization abolished IFN-λ up-regulation. In vivo administration of IFN-λ during Pseudomonas aeruginosa pneumonia improves mice outcome by dampening neutrophil recruitment and decreasing epithelium damages. DISCUSSION We show here that IL-22 regulates IFN-λ levels during Pseudomonas aeruginosa pneumonia.
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Affiliation(s)
- Alexis Broquet
- Laboratoire UPRES EA3826 « Thérapeutiques Cliniques Et Expérimentales Des Infections », IRS2 - Nantes Biotech, Université De Nantes, Nantes, France
| | - Anissa Besbes
- Laboratoire UPRES EA3826 « Thérapeutiques Cliniques Et Expérimentales Des Infections », IRS2 - Nantes Biotech, Université De Nantes, Nantes, France
| | - Jérôme Martin
- Centre De Recherche En Transplantation Et Immunologie UMR1064, INSERM, Université De Nantes, Nantes, France; Institut De Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; Laboratoire d'Immunologie, CHU Nantes, Nantes, France
| | - Cédric Jacqueline
- Laboratoire UPRES EA3826 « Thérapeutiques Cliniques Et Expérimentales Des Infections », IRS2 - Nantes Biotech, Université De Nantes, Nantes, France
| | - Mickaël Vourc'h
- Laboratoire UPRES EA3826 « Thérapeutiques Cliniques Et Expérimentales Des Infections », IRS2 - Nantes Biotech, Université De Nantes, Nantes, France; CHU Nantes, Pôle Anesthésie Réanimations, Service d'Anesthésie Réanimation Chirurgicale, Hôtel Dieu, Nantes, F-44093, France
| | - Antoine Roquilly
- Laboratoire UPRES EA3826 « Thérapeutiques Cliniques Et Expérimentales Des Infections », IRS2 - Nantes Biotech, Université De Nantes, Nantes, France; CHU Nantes, Pôle Anesthésie Réanimations, Service d'Anesthésie Réanimation Chirurgicale, Hôtel Dieu, Nantes, F-44093, France
| | - Jocelyne Caillon
- Laboratoire UPRES EA3826 « Thérapeutiques Cliniques Et Expérimentales Des Infections », IRS2 - Nantes Biotech, Université De Nantes, Nantes, France
| | - Régis Josien
- Centre De Recherche En Transplantation Et Immunologie UMR1064, INSERM, Université De Nantes, Nantes, France; Institut De Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; Laboratoire d'Immunologie, CHU Nantes, Nantes, France
| | - Karim Asehnoune
- Laboratoire UPRES EA3826 « Thérapeutiques Cliniques Et Expérimentales Des Infections », IRS2 - Nantes Biotech, Université De Nantes, Nantes, France; CHU Nantes, Pôle Anesthésie Réanimations, Service d'Anesthésie Réanimation Chirurgicale, Hôtel Dieu, Nantes, F-44093, France.
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48
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Marchese AM, Chiale C, Moshkani S, Robek MD. Mechanisms of Innate Immune Activation by a Hybrid Alphavirus-Rhabdovirus Vaccine Platform. J Interferon Cytokine Res 2019; 40:92-105. [PMID: 31633442 DOI: 10.1089/jir.2019.0123] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Virus-like vesicles (VLV) are infectious, self-propagating alphavirus-vesiculovirus hybrid vaccine vectors that can be engineered to express foreign antigens to elicit a protective immune response. VLV are highly immunogenic and nonpathogenic in vivo, and we hypothesize that the unique replication and structural characteristics of VLV efficiently induce an innate antiviral response that enhances immunogenicity and limits replication and spread of the vector. We found that VLV replication is inhibited by interferon (IFN)-α, IFN-γ, and IFN-λ, but not by tumor necrosis factor-α. In cell culture, VLV infection activated IFN production and expression of IFN-stimulated genes (ISGs), such as MXA, ISG15, and IFI27, which were dependent on replication of the evolved VLV-encoded Semliki Forest virus replicon. Knockdown of the pattern recognition receptors, retinoic acid-inducible gene I and melanoma differentiation-associated protein 5 or their intermediary signaling protein mitochondrial antiviral-signaling protein (MAVS) blocked IFN production. Furthermore, ISG expression in VLV-infected cells was dependent on IFN receptor signaling through the Janus kinase (JAK) tyrosine kinases and phosphorylation of the STAT1 protein, and JAK inhibition restored VLV replication in otherwise uninfectable cell lines. This work provides new insight into the mechanism of innate antiviral responses to a hybrid virus-based vector and provides the basis for future characterization of the platform's safety and adjuvant-like effects in vivo. [Figure: see text].
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Affiliation(s)
- Anthony M Marchese
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York
| | - Carolina Chiale
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York
| | - Safiehkhatoon Moshkani
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York
| | - Michael D Robek
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York
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49
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Nelemans T, Kikkert M. Viral Innate Immune Evasion and the Pathogenesis of Emerging RNA Virus Infections. Viruses 2019; 11:v11100961. [PMID: 31635238 PMCID: PMC6832425 DOI: 10.3390/v11100961] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/15/2019] [Accepted: 10/16/2019] [Indexed: 02/07/2023] Open
Abstract
Positive-sense single-stranded RNA (+ssRNA) viruses comprise many (re-)emerging human pathogens that pose a public health problem. Our innate immune system and, in particular, the interferon response form the important first line of defence against these viruses. Given their genetic flexibility, these viruses have therefore developed multiple strategies to evade the innate immune response in order to optimize their replication capacity. Already many molecular mechanisms of innate immune evasion by +ssRNA viruses have been identified. However, research addressing the effect of host innate immune evasion on the pathology caused by viral infections is less prevalent in the literature, though very relevant and interesting. Since interferons have been implicated in inflammatory diseases and immunopathology in addition to their protective role in infection, antagonizing the immune response may have an ambiguous effect on the clinical outcome of the viral disease. Therefore, this review discusses what is currently known about the role of interferons and host immune evasion in the pathogenesis of emerging coronaviruses, alphaviruses and flaviviruses.
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Affiliation(s)
- Tessa Nelemans
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
| | - Marjolein Kikkert
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
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50
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Feng K, Deng F, Hu Z, Wang H, Ning YJ. Heartland virus antagonizes type I and III interferon antiviral signaling by inhibiting phosphorylation and nuclear translocation of STAT2 and STAT1. J Biol Chem 2019; 294:9503-9517. [PMID: 31040183 DOI: 10.1074/jbc.ra118.006563] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 04/17/2019] [Indexed: 01/30/2023] Open
Abstract
Heartland virus (HRTV) is a pathogenic phlebovirus recently identified in the United States and related to severe fever with thrombocytopenia syndrome virus (SFTSV) emerging in Asia. We previously reported that SFTSV disrupts host antiviral responses directed by interferons (IFNs) and their downstream regulators, signal transducer and activator of transcription (STAT) proteins. However, whether HRTV infection antagonizes the IFN-STAT signaling axis remains unclear. Here, we show that, similar to SFTSV, HRTV also inhibits IFN-α- and IFN-λ-mediated antiviral responses. As expected, the nonstructural protein (NSs) of HRTV (HNSs) robustly antagonized both type I and III IFN signaling. Protein interaction analyses revealed that a common component downstream of type I and III IFN signaling, STAT2, is the target of HNSs. Of note, the DNA-binding and linker domains of STAT2 were required for an efficient HNSs-STAT2 interaction. Unlike the NSs of SFTSV (SNSs), which blocks both STAT2 and STAT1 nuclear accumulation, HNSs specifically blocked IFN-triggered nuclear translocation only of STAT2. However, upon HRTV infection, IFN-induced nuclear translocation of both STAT2 and STAT1 was suppressed, suggesting that STAT1 is an additional HRTV target for IFN antagonism. Consistently, despite HNSs inhibiting phosphorylation only of STAT2 and not STAT1, HRTV infection diminished both STAT2 and STAT1 phosphorylation. These results suggest that HRTV antagonizes IFN antiviral signaling by dampening both STAT2 and STAT1 activities. We propose that HNSs-specific targeting of STAT2 likely plays an important role but is not all of the "tactics" of HRTV in its immune evasion.
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Affiliation(s)
- Kuan Feng
- From the State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China and.,the University of Chinese Academy of Sciences, Beijing 101408, China
| | - Fei Deng
- From the State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China and
| | - Zhihong Hu
- From the State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China and
| | - Hualin Wang
- From the State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China and
| | - Yun-Jia Ning
- From the State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China and
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