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J Virol. 2019 Jan 9. pii: JVI.01986-18. doi: 10.1128/JVI.01986-18. [Epub ahead of print]

Unique transcriptional architecture in airway epithelial cells and macrophages shapes distinct responses following influenza virus infection ex vivo.

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Department of Microbiology and Immunology, University of Melbourne, Victoria, 3010, Australia.
Department of Microbiology and Immunology, University of Melbourne, Victoria, 3010, Australia.
Department of Pathology, The University of Melbourne, Parkville, Victoria, 3010, Australia.
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Department of Molecular and Translational Science, School of Clinical Science, Monash University, 27-31 Wright St, Clayton, Victoria, 3168, Australia.
Department of Microbiology, Monash University, Clayton, Victoria, 3800, Australia.
WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory, at The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Victoria 3000, Australia.


Airway epithelial cells and macrophages differ markedly in their responses to influenza A virus (IAV) infection. To investigate transcriptional responses underlying these differences, purified subsets of type II airway epithelial cells (ATII) and alveolar macrophages (AM) recovered from the lungs of mock- or IAV-infected mice at 9 hours post-infection were subjected to RNA sequencing. This time point was chosen to allow for characterization of cell types first infected with virus inoculum, prior to multicycle virus replication and the infiltration of inflammatory cells into the airways. In the absence of infection, AM predominantly expressed genes related to immunity whereas ATII expressed genes consistent with their physiological roles in the lung. Following IAV infection, AM almost exclusively activated cell-intrinsic antiviral pathways that were dependent on interferon regulatory factor (IRF)3/7 and/or type I interferon (IFN) signaling. In contrast, IAV-infected ATII activated a broader range of physiological responses, including cell-intrinsic antiviral pathways, which were both independent and dependent on IRF3/7 and/or type I IFN. These data suggest that transcriptional profiles hardwired during development are a major determinant underlying the different responses of ATII and AM to IAV infection.IMPORTANCE Airway epithelial cells (AEC) and airway macrophages (AM) represent major targets of influenza A virus (IAV) infection in the lung, yet the two cell types respond very differently to IAV infection. We have used RNA sequencing to define the host transcriptional responses in each cell type under steady-state conditions, as well as following IAV infection. To do this, different cell subsets isolated from the lungs of mock- and IAV-infected mice were subjected to RNA sequencing. Under steady-state conditions, AM and AEC express distinct transcriptional activity, consistent with distinct physiological roles in the airways. Not surprisingly, these also exhibited major differences in transcriptional responses following IAV infection. These studies shed light on how the different transcriptional architecture of airway cells from two different lineages drive transcriptional responses to IAV infection.


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