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

rna-seq
mouse
virus
immune
Authors

Joel Z Ma

Wy Ching Ng

Luke Zappia

Linden J Gearing

Moshe Olshansky

Kym Pham

Karey Cheong

Arthur Hsu

Stephen J Turner

Odilia Wijburg

Sarah L Londrigan

Andrew G Brooks

Patrick C Reading

Date

January 1, 2019

Links
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Abstract

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 h postinfection were subjected to RNA sequencing. This time point was chosen to allow for characterization of cell types first infected with the 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 (IFN) regulatory factor 3/7 (IRF3/7) and/or type I IFN signaling. In contrast, IAV-infected ATII activated a broader range of physiological responses, including cell-intrinsic antiviral pathways, which were both independent of 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 activities, consistent with distinct physiological roles in the airways. Not surprisingly, these cells also exhibited major differences in transcriptional responses following IAV infection. These studies shed light on how the different transcriptional architectures of airway cells from two different lineages drive transcriptional responses to IAV infection.

Citation

BibTeX citation:
@article{z_ma2019,
  author = {Z Ma, Joel and Ching Ng, Wy and Zappia, Luke and J Gearing,
    Linden and Olshansky, Moshe and Pham, Kym and Cheong, Karey and Hsu,
    Arthur and J Turner, Stephen and Wijburg, Odilia and L Londrigan,
    Sarah and G Brooks, Andrew and C Reading, Patrick},
  title = {Unique Transcriptional Architecture in Airway Epithelial
    Cells and Macrophages Shapes Distinct Responses Following Influenza
    Virus Infection Ex Vivo},
  journal = {Journal of virology},
  date = {2019-01-01},
  url = {https://lazappi.id.au/publications/2019-ma-influenza/},
  doi = {10.1128/JVI.01986-18},
  issn = {0022-538X, 1098-5514},
  langid = {en},
  abstract = {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 h postinfection were subjected to RNA sequencing. This
    time point was chosen to allow for characterization of cell types
    first infected with the 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 (IFN) regulatory factor 3/7
    (IRF3/7) and/or type I IFN signaling. In contrast, IAV-infected ATII
    activated a broader range of physiological responses, including
    cell-intrinsic antiviral pathways, which were both independent of
    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
    activities, consistent with distinct physiological roles in the
    airways. Not surprisingly, these cells also exhibited major
    differences in transcriptional responses following IAV infection.
    These studies shed light on how the different transcriptional
    architectures of airway cells from two different lineages drive
    transcriptional responses to IAV infection.}
}
For attribution, please cite this work as:
Z Ma, Joel, Wy Ching Ng, Luke Zappia, Linden J Gearing, Moshe Olshansky, Kym Pham, Karey Cheong, et al. 2019. “Unique Transcriptional Architecture in Airway Epithelial Cells and Macrophages Shapes Distinct Responses Following Influenza Virus Infection Ex Vivo.” Journal of Virology, January. https://doi.org/10.1128/JVI.01986-18.