Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection

ABSTRACT Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single-cell level and how it impacts virus-host interactions at a system level are not well understood. To charac...

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Autores principales:	Chang Wang, Christian V. Forst, Tsui-wen Chou, Adam Geber, Minghui Wang, Wissam Hamou, Melissa Smith, Robert Sebra, Bin Zhang, Bin Zhou, Elodie Ghedin
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	influenza A virus defective viral genome host immune response single-cell RNA-seq viral transcription Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/165b5bd82b01438b8ac0b0922c02913d
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spelling	oai:doaj.org-article:165b5bd82b01438b8ac0b0922c02913d2021-11-15T15:56:57ZCell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection10.1128/mBio.02880-192150-7511https://doaj.org/article/165b5bd82b01438b8ac0b0922c02913d2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02880-19https://doaj.org/toc/2150-7511ABSTRACT Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single-cell level and how it impacts virus-host interactions at a system level are not well understood. To characterize the dynamics of viral transcription and host responses, we used single-cell RNA sequencing to quantify at multiple time points the host and viral transcriptomes of human A549 cells and primary bronchial epithelial cells infected with influenza A virus. We observed substantial variability in viral transcription between cells, including the accumulation of defective viral genomes (DVGs) that impact viral replication. We show (i) a correlation between DVGs and virus-induced variation of the host transcriptional program and (ii) an association between differential inductions of innate immune response genes and attenuated viral transcription in subpopulations of cells. These observations at the single-cell level improve our understanding of the complex virus-host interplay during influenza virus infection. IMPORTANCE Defective influenza virus particles generated during viral replication carry incomplete viral genomes and can interfere with the replication of competent viruses. These defective genomes are thought to modulate the disease severity and pathogenicity of an influenza virus infection. Different defective viral genomes also introduce another source of variation across a heterogeneous cell population. Evaluating the impact of defective virus genomes on host cell responses cannot be fully resolved at the population level, requiring single-cell transcriptional profiling. Here, we characterized virus and host transcriptomes in individual influenza virus-infected cells, including those of defective viruses that arise during influenza A virus infection. We established an association between defective virus transcription and host responses and validated interfering and immunostimulatory functions of identified dominant defective viral genome species in vitro. This study demonstrates the intricate effects of defective viral genomes on host transcriptional responses and highlights the importance of capturing host-virus interactions at the single-cell level.Chang WangChristian V. ForstTsui-wen ChouAdam GeberMinghui WangWissam HamouMelissa SmithRobert SebraBin ZhangBin ZhouElodie GhedinAmerican Society for Microbiologyarticleinfluenza A virusdefective viral genomehost immune responsesingle-cell RNA-seqviral transcriptionMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	influenza A virus defective viral genome host immune response single-cell RNA-seq viral transcription Microbiology QR1-502
spellingShingle	influenza A virus defective viral genome host immune response single-cell RNA-seq viral transcription Microbiology QR1-502 Chang Wang Christian V. Forst Tsui-wen Chou Adam Geber Minghui Wang Wissam Hamou Melissa Smith Robert Sebra Bin Zhang Bin Zhou Elodie Ghedin Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection
description	ABSTRACT Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single-cell level and how it impacts virus-host interactions at a system level are not well understood. To characterize the dynamics of viral transcription and host responses, we used single-cell RNA sequencing to quantify at multiple time points the host and viral transcriptomes of human A549 cells and primary bronchial epithelial cells infected with influenza A virus. We observed substantial variability in viral transcription between cells, including the accumulation of defective viral genomes (DVGs) that impact viral replication. We show (i) a correlation between DVGs and virus-induced variation of the host transcriptional program and (ii) an association between differential inductions of innate immune response genes and attenuated viral transcription in subpopulations of cells. These observations at the single-cell level improve our understanding of the complex virus-host interplay during influenza virus infection. IMPORTANCE Defective influenza virus particles generated during viral replication carry incomplete viral genomes and can interfere with the replication of competent viruses. These defective genomes are thought to modulate the disease severity and pathogenicity of an influenza virus infection. Different defective viral genomes also introduce another source of variation across a heterogeneous cell population. Evaluating the impact of defective virus genomes on host cell responses cannot be fully resolved at the population level, requiring single-cell transcriptional profiling. Here, we characterized virus and host transcriptomes in individual influenza virus-infected cells, including those of defective viruses that arise during influenza A virus infection. We established an association between defective virus transcription and host responses and validated interfering and immunostimulatory functions of identified dominant defective viral genome species in vitro. This study demonstrates the intricate effects of defective viral genomes on host transcriptional responses and highlights the importance of capturing host-virus interactions at the single-cell level.
format	article
author	Chang Wang Christian V. Forst Tsui-wen Chou Adam Geber Minghui Wang Wissam Hamou Melissa Smith Robert Sebra Bin Zhang Bin Zhou Elodie Ghedin
author_facet	Chang Wang Christian V. Forst Tsui-wen Chou Adam Geber Minghui Wang Wissam Hamou Melissa Smith Robert Sebra Bin Zhang Bin Zhou Elodie Ghedin
author_sort	Chang Wang
title	Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection
title_short	Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection
title_full	Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection
title_fullStr	Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection
title_full_unstemmed	Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection
title_sort	cell-to-cell variation in defective virus expression and effects on host responses during influenza virus infection
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/165b5bd82b01438b8ac0b0922c02913d
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Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection

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