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