Defective influenza a virus rna products mediate mavs-dependent upregulation of human leukocyte antigen class i proteins

Mir Munir A. Rahim, Brendon D. Parsons, Emma L. Price, Patrick D. Slaine, Becca L. Chilvers, Gregory S. Seaton, Andrew Wight, Daniel Medina-Luna, Sayanti Dey, Shannen L. Grandy, Lauryn E. Anderson, Natalia Zamorano Cuervo, Nathalie Grandvaux, Marta M. Gaglia, Alyson A. Kelvin, Denys A. Khaperskyy, Craig McCormick, Andrew P. Makrigiannis

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12 Citations (Scopus)

Abstract

kocyte 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- and IFN-1 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.

Original languageEnglish
Article number00165-20
JournalJournal of Virology
Volume94
Issue number13
DOIs
Publication statusPublished - 2020

Bibliographical note

Funding Information:
N.Z.C. was funded by a scholarship from Fonds de Recherche du Québec-Santé. This work was supported by Canadian Institutes for Health Research grants MOP-136817 (to C.M.), MOP-155906 (to A.P.M.), and MOP-130527 (to N.G.) and by National Institutes of Health grant R01 AI137358 (to M.M.G.).

Publisher Copyright:
© 2020 Rahim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

ASJC Scopus Subject Areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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