PMID- 32321802 OWN - NLM STAT- MEDLINE DCOM- 20201217 LR - 20201217 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 94 IP - 13 DP - 2020 Jun 16 TI - Defective Influenza A Virus RNA Products Mediate MAVS-Dependent Upregulation of Human Leukocyte Antigen Class I Proteins. LID - 10.1128/JVI.00165-20 [doi] LID - e00165-20 AB - Influenza A virus (IAV) increases the presentation of class I human leukocyte antigen (HLA) proteins that limit antiviral responses mediated by natural killer (NK) cells, but molecular mechanisms for these processes have not yet been fully elucidated. We observed that infection with A/Fort Monmouth/1/1947(H1N1) IAV significantly increased the presentation of HLA-B, -C, and -E on lung epithelial cells. Virus entry was not sufficient to induce HLA upregulation because UV-inactivated virus had no effect. Aberrant internally deleted viral RNAs (vRNAs) known as mini viral RNAs (mvRNAs) and defective interfering RNAs (DI RNAs) expressed from an IAV minireplicon were sufficient for inducing HLA upregulation. These defective RNAs bind to retinoic acid-inducible gene I (RIG-I) and initiate mitochondrial antiviral signaling (MAVS) protein-dependent antiviral interferon (IFN) responses. Indeed, MAVS was required for HLA upregulation in response to IAV infection or ectopic mvRNA/DI RNA expression. The effect was partially due to paracrine signaling, as we observed that IAV infection or mvRNA/DI RNA-expression stimulated production of IFN-beta and IFN-lambda1 and conditioned media from these cells elicited a modest increase in HLA surface levels in naive epithelial cells. HLA upregulation in response to aberrant viral RNAs could be prevented by the Janus kinase (JAK) inhibitor ruxolitinib. While HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein; we determined that NS1 limits cell-intrinsic and paracrine mechanisms of HLA upregulation. Taken together, our findings indicate that aberrant IAV RNAs stimulate HLA presentation, which may aid viral evasion of innate immunity.IMPORTANCE Human leukocyte antigens (HLAs) are cell surface proteins that regulate innate and adaptive immune responses to viral infection by engaging with receptors on immune cells. Many viruses have evolved ways to evade host immune responses by modulating HLA expression and/or processing. Here, we provide evidence that aberrant RNA products of influenza virus genome replication can trigger retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS)-dependent remodeling of the cell surface, increasing surface presentation of HLA proteins known to inhibit the activation of an immune cell known as a natural killer (NK) cell. While this HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein, which limits RIG-I activation and interferon production by the infected cell. CI - Copyright (c) 2020 Rahim et al. FAU - Rahim, Mir Munir A AU - Rahim MMA AD - Department of Biomedical Sciences, University of Windsor, Windsor, Ontario, Canada. FAU - Parsons, Brendon D AU - Parsons BD AUID- ORCID: 0000-0002-9255-0290 AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Price, Emma L AU - Price EL AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Slaine, Patrick D AU - Slaine PD AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Chilvers, Becca L AU - Chilvers BL AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Seaton, Gregory S AU - Seaton GS AD - Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Wight, Andrew AU - Wight A AD - Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Medina-Luna, Daniel AU - Medina-Luna D AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Dey, Sayanti AU - Dey S AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Grandy, Shannen L AU - Grandy SL AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Anderson, Lauryn E AU - Anderson LE AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Zamorano Cuervo, Natalia AU - Zamorano Cuervo N AD - Centre Hospitalier de l'Universite de Montreal (CRCHUM), Montreal, Quebec, Canada. FAU - Grandvaux, Nathalie AU - Grandvaux N AD - Centre Hospitalier de l'Universite de Montreal (CRCHUM), Montreal, Quebec, Canada. AD - Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universite de Montreal, Montreal, Quebec, Canada. FAU - Gaglia, Marta M AU - Gaglia MM AUID- ORCID: 0000-0002-1791-0663 AD - Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA. FAU - Kelvin, Alyson A AU - Kelvin AA AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. AD - Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Khaperskyy, Denys A AU - Khaperskyy DA AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - McCormick, Craig AU - McCormick C AUID- ORCID: 0000-0003-2794-3722 AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada craig.mccormick@dal.ca andrew.makrigiannis@dal.ca. FAU - Makrigiannis, Andrew P AU - Makrigiannis AP AD - Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada craig.mccormick@dal.ca andrew.makrigiannis@dal.ca. LA - eng GR - R01 AI137358/AI/NIAID NIH HHS/United States GR - MOP-136817/CIHR/Canada GR - MOP-155906/CIHR/Canada GR - MOP-130527/CIHR/Canada PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200616 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (HLA Antigens) RN - 0 (MAVS protein, human) RN - 0 (RNA, Viral) RN - 0 (Viral Nonstructural Proteins) RN - EC 3.6.4.13 (DEAD Box Protein 58) SB - IM MH - A549 Cells MH - Adaptor Proteins, Signal Transducing/genetics MH - DEAD Box Protein 58/genetics MH - Databases, Genetic MH - Epithelial Cells/virology MH - Genes, MHC Class I/*genetics MH - HLA Antigens/*metabolism MH - Host-Pathogen Interactions/genetics MH - Humans MH - Immunity, Innate MH - Influenza A Virus, H1N1 Subtype/*genetics MH - Influenza A virus/genetics MH - Influenza, Human/genetics MH - Killer Cells, Natural/metabolism MH - Lung/virology MH - RNA, Viral/genetics MH - Signal Transduction MH - Transcriptional Activation MH - Viral Nonstructural Proteins/metabolism MH - Virus Replication/genetics PMC - PMC7307169 OTO - NOTNLM OT - DI RNAs OT - KIR OT - MAVS OT - NK cells OT - RIG-I OT - class I HLA OT - class I MHC OT - influenza A virus OT - interferon OT - mvRNAs EDAT- 2020/04/24 06:00 MHDA- 2020/12/18 06:00 PMCR- 2020/06/16 CRDT- 2020/04/24 06:00 PHST- 2020/01/30 00:00 [received] PHST- 2020/04/16 00:00 [accepted] PHST- 2020/04/24 06:00 [pubmed] PHST- 2020/12/18 06:00 [medline] PHST- 2020/04/24 06:00 [entrez] PHST- 2020/06/16 00:00 [pmc-release] AID - JVI.00165-20 [pii] AID - 00165-20 [pii] AID - 10.1128/JVI.00165-20 [doi] PST - epublish SO - J Virol. 2020 Jun 16;94(13):e00165-20. doi: 10.1128/JVI.00165-20. Print 2020 Jun 16.