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

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...

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Autores principales: Shartouny, Jessica R., Lee, Chung-Young, Delima, Gabrielle K., Lowen, Anice C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9521904/
https://www.ncbi.nlm.nih.gov/pubmed/36121893
http://dx.doi.org/10.1371/journal.ppat.1010865
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author Shartouny, Jessica R.
Lee, Chung-Young
Delima, Gabrielle K.
Lowen, Anice C.
author_facet Shartouny, Jessica R.
Lee, Chung-Young
Delima, Gabrielle K.
Lowen, Anice C.
author_sort Shartouny, Jessica R.
collection PubMed
description 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.
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spelling pubmed-95219042022-09-30 Beneficial effects of cellular coinfection resolve inefficiency in influenza A virus transcription Shartouny, Jessica R. Lee, Chung-Young Delima, Gabrielle K. Lowen, Anice C. PLoS Pathog Research Article 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. Public Library of Science 2022-09-19 /pmc/articles/PMC9521904/ /pubmed/36121893 http://dx.doi.org/10.1371/journal.ppat.1010865 Text en © 2022 Shartouny et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Shartouny, Jessica R.
Lee, Chung-Young
Delima, Gabrielle K.
Lowen, Anice C.
Beneficial effects of cellular coinfection resolve inefficiency in influenza A virus transcription
title Beneficial effects of cellular coinfection resolve inefficiency in influenza A virus transcription
title_full Beneficial effects of cellular coinfection resolve inefficiency in influenza A virus transcription
title_fullStr Beneficial effects of cellular coinfection resolve inefficiency in influenza A virus transcription
title_full_unstemmed Beneficial effects of cellular coinfection resolve inefficiency in influenza A virus transcription
title_short Beneficial effects of cellular coinfection resolve inefficiency in influenza A virus transcription
title_sort beneficial effects of cellular coinfection resolve inefficiency in influenza a virus transcription
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9521904/
https://www.ncbi.nlm.nih.gov/pubmed/36121893
http://dx.doi.org/10.1371/journal.ppat.1010865
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