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

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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article numbere01986-18
Number of pages22
JournalJournal of Virology
Volume93
Issue number6
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • Epithelial cell
  • Influenza
  • Lung
  • Macrophage
  • Mouse model
  • RNA sequencing

Cite this

Ma, Joel Z. ; Ng, Wy Ching ; Zappia, Luke ; Gearing, Linden J. ; Olshansky, Moshe ; Pham, Kym ; Cheong, Karey ; Hsu, Arthur ; Turner, Stephen J. ; Wijburg, Odilia ; Londrigan, Sarah L. ; Brooks, Andrew G. ; Reading, Patrick C. / Unique transcriptional architecture in airway epithelial cells and macrophages shapes distinct responses following influenza virus infection Ex vivo. In: Journal of Virology. 2019 ; Vol. 93, No. 6.
@article{6fac6cf329dd49378a6f5d719f8f982f,
title = "Unique transcriptional architecture in airway epithelial cells and macrophages shapes distinct responses following influenza virus infection Ex vivo",
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.",
keywords = "Epithelial cell, Influenza, Lung, Macrophage, Mouse model, RNA sequencing",
author = "Ma, {Joel Z.} and Ng, {Wy Ching} and Luke Zappia and Gearing, {Linden J.} and Moshe Olshansky and Kym Pham and Karey Cheong and Arthur Hsu and Turner, {Stephen J.} and Odilia Wijburg and Londrigan, {Sarah L.} and Brooks, {Andrew G.} and Reading, {Patrick C.}",
year = "2019",
month = "3",
day = "1",
doi = "10.1128/JVI.01986-18",
language = "English",
volume = "93",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "6",

}

Ma, JZ, Ng, WC, Zappia, L, Gearing, LJ, Olshansky, M, Pham, K, Cheong, K, Hsu, A, Turner, SJ, Wijburg, O, Londrigan, SL, Brooks, AG & Reading, PC 2019, 'Unique transcriptional architecture in airway epithelial cells and macrophages shapes distinct responses following influenza virus infection Ex vivo', Journal of Virology, vol. 93, no. 6, e01986-18. https://doi.org/10.1128/JVI.01986-18

Unique transcriptional architecture in airway epithelial cells and macrophages shapes distinct responses following influenza virus infection Ex vivo. / Ma, Joel Z.; Ng, Wy Ching; Zappia, Luke; Gearing, Linden J.; Olshansky, Moshe; Pham, Kym; Cheong, Karey; Hsu, Arthur; Turner, Stephen J.; Wijburg, Odilia; Londrigan, Sarah L.; Brooks, Andrew G.; Reading, Patrick C.

In: Journal of Virology, Vol. 93, No. 6, e01986-18, 01.03.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Unique transcriptional architecture in airway epithelial cells and macrophages shapes distinct responses following influenza virus infection Ex vivo

AU - Ma, Joel Z.

AU - Ng, Wy Ching

AU - Zappia, Luke

AU - Gearing, Linden J.

AU - Olshansky, Moshe

AU - Pham, Kym

AU - Cheong, Karey

AU - Hsu, Arthur

AU - Turner, Stephen J.

AU - Wijburg, Odilia

AU - Londrigan, Sarah L.

AU - Brooks, Andrew G.

AU - Reading, Patrick C.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

KW - Epithelial cell

KW - Influenza

KW - Lung

KW - Macrophage

KW - Mouse model

KW - RNA sequencing

UR - http://www.scopus.com/inward/record.url?scp=85062916700&partnerID=8YFLogxK

U2 - 10.1128/JVI.01986-18

DO - 10.1128/JVI.01986-18

M3 - Article

VL - 93

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 6

M1 - e01986-18

ER -