Non-lytic clearance of influenza B virus from infected cells preserves epithelial barrier function

Rebekah E. Dumm; Jessica K. Fiege; Barbara M. Waring; Chay T. Kuo; Ryan A. Langlois; Nicholas S. Heaton

doi:10.1038/s41467-019-08617-z

Non-lytic clearance of influenza B virus from infected cells preserves epithelial barrier function

Rebekah E. Dumm, Jessica K. Fiege, Barbara M. Waring, Chay T. Kuo, Ryan A. Langlois, Nicholas S. Heaton

Microbiology

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Influenza B virus (IBV) is an acute, respiratory RNA virus that has been assumed to induce the eventual death of all infected cells. We and others have shown however, that infection with apparently cytopathic viruses does not necessarily lead to cell death; some cells can intrinsically clear the virus and persist in the host long-term. To determine if any cells can survive direct IBV infection, we here generate a recombinant IBV capable of activating a host-cell reporter to permanently label all infected cells. Using this system, we demonstrate that IBV infection leads to the formation of a survivor cell population in the proximal airways that are ciliated-like, but transcriptionally and phenotypically distinct from both actively infected and bystander ciliated cells. We also show that survivor cells are critical to maintain respiratory barrier function. These results highlight a host response pathway that preserves the epithelium to limit the severity of IBV disease.

Original language	English (US)
Article number	779
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08617-z
State	Published - Dec 1 2019

Bibliographical note

Funding Information:
We would like to acknowledge assistance from Mike Cook and the Duke Cancer Institute Flow Cytometry Core. The high-resolution microscopy was performed at the Duke Light Microscopy Core Facility with assistance from Dr. Yasheng Gao. Lung physiology measurements were performed using Duke Rodent Inhalation Core by Barbara Theriot and Dr. Loretta Que. The 10x Genomics pipeline for single-cell RNA-sequencing was performed at the Duke University Molecular Genomics Core by Emily Grass and Karen Abramson. Next-generation sequencing was done at the Duke Center for Genomic and Computational Biology. Sequencing reads were mapped to the mouse transcriptome and the influenza genome using applications developed by David Sachs. We thank Khadar Abdi for his contributions to the FoxJ1-CreER mouse line development. We would also like to thank Brook Heaton for cloning the PB1-Cre segment and Alfred Harding for rescue of the virus as well as Brook Heaton, Griffin Haas, and Heather Froggatt for critical reading of the manuscript. N.S.H. is partially supported by NIH 1K22-AI116509-01, 1R21-AI133444-01, 1R01-HL142985-01 and the Duke School of Medicine Whitehead Scholarship. R.E.D. is supported by the NIH Training grant T32-GM007184-41. R.A.L. is partially supported by NIH 1K22-AI110581 and R01 AI-132962. J.F.K. is supported by the NIH Training grant T32-HL007741. C.T.K. is supported by NIH 5R01-NS078192-07.

Publisher Copyright:
© 2019, The Author(s).

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Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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title = "Non-lytic clearance of influenza B virus from infected cells preserves epithelial barrier function",

abstract = "Influenza B virus (IBV) is an acute, respiratory RNA virus that has been assumed to induce the eventual death of all infected cells. We and others have shown however, that infection with apparently cytopathic viruses does not necessarily lead to cell death; some cells can intrinsically clear the virus and persist in the host long-term. To determine if any cells can survive direct IBV infection, we here generate a recombinant IBV capable of activating a host-cell reporter to permanently label all infected cells. Using this system, we demonstrate that IBV infection leads to the formation of a survivor cell population in the proximal airways that are ciliated-like, but transcriptionally and phenotypically distinct from both actively infected and bystander ciliated cells. We also show that survivor cells are critical to maintain respiratory barrier function. These results highlight a host response pathway that preserves the epithelium to limit the severity of IBV disease.",

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AU - Heaton, Nicholas S.

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Non-lytic clearance of influenza B virus from infected cells preserves epithelial barrier function

Abstract

Bibliographical note

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