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Cell type- and replication stage-specific influenza virus responses in vivo

Influenza A viruses (IAVs) remain a significant global health burden. Activation of the innate immune response is important for controlling early virus replication and spread. It is unclear how early IAV replication events contribute to immune detection. Additionally, while many cell types in the lu...

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Autores principales: Fay, Elizabeth J., Aron, Stephanie L., Macchietto, Marissa G., Markman, Matthew W., Esser-Nobis, Katharina, Gale, Michael, Shen, Steven, Langlois, Ryan A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447048/
https://www.ncbi.nlm.nih.gov/pubmed/32790753
http://dx.doi.org/10.1371/journal.ppat.1008760
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author Fay, Elizabeth J.
Aron, Stephanie L.
Macchietto, Marissa G.
Markman, Matthew W.
Esser-Nobis, Katharina
Gale, Michael
Shen, Steven
Langlois, Ryan A.
author_facet Fay, Elizabeth J.
Aron, Stephanie L.
Macchietto, Marissa G.
Markman, Matthew W.
Esser-Nobis, Katharina
Gale, Michael
Shen, Steven
Langlois, Ryan A.
author_sort Fay, Elizabeth J.
collection PubMed
description Influenza A viruses (IAVs) remain a significant global health burden. Activation of the innate immune response is important for controlling early virus replication and spread. It is unclear how early IAV replication events contribute to immune detection. Additionally, while many cell types in the lung can be infected, it is not known if all cell types contribute equally to establish the antiviral state in the host. Here, we use single-cycle influenza A viruses (scIAVs) to characterize the early immune response to IAV in vitro and in vivo. We found that the magnitude of virus replication contributes to antiviral gene expression within infected cells prior to the induction of a global response. We also developed a scIAV that is only capable of undergoing primary transcription, the earliest stage of virus replication. Using this tool, we uncovered replication stage-specific responses in vitro and in vivo. Using several innate immune receptor knockout cell lines, we identify RIG-I as the predominant antiviral detector of primary virus transcription and amplified replication in vitro. Through a Cre-inducible reporter mouse, we used scIAVs expressing Cre-recombinase to characterize cell type-specific responses in vivo. Individual cell types upregulate unique sets of antiviral genes in response to both primary virus transcription and amplified replication. We also identified antiviral genes that are only upregulated in response to direct infection. Altogether, these data offer insight into the early mechanisms of antiviral gene activation during influenza A infection.
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spelling pubmed-74470482020-08-31 Cell type- and replication stage-specific influenza virus responses in vivo Fay, Elizabeth J. Aron, Stephanie L. Macchietto, Marissa G. Markman, Matthew W. Esser-Nobis, Katharina Gale, Michael Shen, Steven Langlois, Ryan A. PLoS Pathog Research Article Influenza A viruses (IAVs) remain a significant global health burden. Activation of the innate immune response is important for controlling early virus replication and spread. It is unclear how early IAV replication events contribute to immune detection. Additionally, while many cell types in the lung can be infected, it is not known if all cell types contribute equally to establish the antiviral state in the host. Here, we use single-cycle influenza A viruses (scIAVs) to characterize the early immune response to IAV in vitro and in vivo. We found that the magnitude of virus replication contributes to antiviral gene expression within infected cells prior to the induction of a global response. We also developed a scIAV that is only capable of undergoing primary transcription, the earliest stage of virus replication. Using this tool, we uncovered replication stage-specific responses in vitro and in vivo. Using several innate immune receptor knockout cell lines, we identify RIG-I as the predominant antiviral detector of primary virus transcription and amplified replication in vitro. Through a Cre-inducible reporter mouse, we used scIAVs expressing Cre-recombinase to characterize cell type-specific responses in vivo. Individual cell types upregulate unique sets of antiviral genes in response to both primary virus transcription and amplified replication. We also identified antiviral genes that are only upregulated in response to direct infection. Altogether, these data offer insight into the early mechanisms of antiviral gene activation during influenza A infection. Public Library of Science 2020-08-13 /pmc/articles/PMC7447048/ /pubmed/32790753 http://dx.doi.org/10.1371/journal.ppat.1008760 Text en © 2020 Fay et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://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
Fay, Elizabeth J.
Aron, Stephanie L.
Macchietto, Marissa G.
Markman, Matthew W.
Esser-Nobis, Katharina
Gale, Michael
Shen, Steven
Langlois, Ryan A.
Cell type- and replication stage-specific influenza virus responses in vivo
title Cell type- and replication stage-specific influenza virus responses in vivo
title_full Cell type- and replication stage-specific influenza virus responses in vivo
title_fullStr Cell type- and replication stage-specific influenza virus responses in vivo
title_full_unstemmed Cell type- and replication stage-specific influenza virus responses in vivo
title_short Cell type- and replication stage-specific influenza virus responses in vivo
title_sort cell type- and replication stage-specific influenza virus responses in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447048/
https://www.ncbi.nlm.nih.gov/pubmed/32790753
http://dx.doi.org/10.1371/journal.ppat.1008760
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