Beneficial effects of cellular coinfection resolve inefficiency in influenza A virus transcription

• Type of Material: Article
• Authors: Anice Lowen, Emory University; JR Shartouny, Emory University School of Medicine; CY Lee, Emory University School of Medicine; GK Delima, Emory University School of Medicine
• Language: English
• Date: 2022-09-01
• Publisher: PLoS Pathogens
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Shartouny et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1010865
• Title of Journal or Parent Work: PLoS Pathogens
• Volume: 18
• Issue: 9
• Start Page: e1010865
• End Page: e1010865
• Grant/Funding Information: The work was supported by funding from NIH/NIAID under the Centers of Excellence for Influenza Research and Response contract no. 75N93021C00017 to ACL and R01 AI127799 to ACL. This research project was supported in part by the Emory University School of Medicine Flow Cytometry Core. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: Coinfection; Influenza A Virus, H9N2 Subtype; Humans; Viral Proteins; Influenza, Human; Ribonucleoproteins; Viral Transcription; Endonucleases; Animals; Amino Acids; Mammals
• Research Categories: Biology, Microbiology; Health Sciences, Medicine and Surgery; Health Sciences, Immunology

Abstract

For diverse viruses, cellular infection with single vs. multiple virions can yield distinct biological outcomes. We previously found that influenza A/guinea fowl/Hong Kong/WF10/99 (H9N2) virus (GFHK99) displays a particularly high reliance on multiple infection in mammalian cells. Here, we sought to uncover the viral processes underlying this phenotype. We found that the need for multiple infection maps to amino acid 26K of the viral PA protein. PA 26K suppresses endonuclease activity and viral transcription, specifically within cells infected at low multiplicity. In the context of the higher functioning PA 26E, inhibition of PA using baloxavir acid augments reliance on multiple infection. Together, these data suggest a model in which sub-optimal activity of the GFHK99 endonuclease results in inefficient priming of viral transcription, an insufficiency which can be overcome with the introduction of additional viral ribonucleoprotein templates to the cell. More broadly, the finding that deficiency in a core viral function is ameliorated through multiple infection suggests that the fitness effects of many viral mutations are likely to be modulated by multiplicity of infection, such that the shape of fitness landscapes varies with viral densities.