Influenza A virus (IAV) activates ZBP1-initiated RIPK3-dependent parallel pathways of necroptosis and apoptosis in infected cells. Although mice deficient in both pathways fail to control IAV and succumb to lethal respiratory infection, RIPK3-mediated apoptosis by itself can limit IAV, without need for necroptosis. However, whether necroptosis, conventionally considered a fail-safe cell death mechanism to apoptosis, can restrict IAV—or indeed any virus—in the absence of apoptosis is not known. Here, we use mice selectively deficient in IAV-activated apoptosis to show that necroptosis drives robust antiviral immune responses and promotes effective virus clearance from infected lungs when apoptosis is absent. We also demonstrate that apoptosis and necroptosis are mutually exclusive fates in IAV-infected cells. Thus, necroptosis is an independent, “stand-alone” cell death mechanism that fully compensates for the absence of apoptosis in antiviral host defense.
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2 November 2020
Brief Definitive Report|
August 14 2020
Necroptosis restricts influenza A virus as a stand-alone cell death mechanism
Maria Shubina,
Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing - original draft, Writing - review & editing
1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA
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Bart Tummers,
Investigation, Methodology, Project administration, Resources, Validation, Writing - original draft, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
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David F. Boyd,
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
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Ting Zhang,
1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA
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Chaoran Yin,
Chaoran Yin
Investigation, Writing - review & editing
1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA
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Avishekh Gautam,
Avishekh Gautam
Investigation, Writing - review & editing
1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA
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Xi-zhi J. Guo,
Xi-zhi J. Guo
Investigation
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
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Diego A. Rodriguez,
Diego A. Rodriguez
Investigation, Methodology, Visualization, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
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William J. Kaiser,
William J. Kaiser
Conceptualization
3
University of Texas Health Science Center at San Antonio, San Antonio, TX
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Peter Vogel,
Peter Vogel
Formal analysis, Investigation, Methodology, Resources, Visualization, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
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Douglas R. Green,
Douglas R. Green
Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
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Paul G. Thomas,
Paul G. Thomas
Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
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Siddharth Balachandran
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA
Correspondence to Siddharth Balachandran: siddharth.balachandran@fccc.edu
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Maria Shubina
Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing - original draft, Writing - review & editing
1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA
Bart Tummers
Investigation, Methodology, Project administration, Resources, Validation, Writing - original draft, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
David F. Boyd
Investigation, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
Ting Zhang
Investigation
1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA
Chaoran Yin
Investigation, Writing - review & editing
1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA
Avishekh Gautam
Investigation, Writing - review & editing
1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA
Xi-zhi J. Guo
Investigation
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
Diego A. Rodriguez
Investigation, Methodology, Visualization, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
William J. Kaiser
Conceptualization
3
University of Texas Health Science Center at San Antonio, San Antonio, TX
Peter Vogel
Formal analysis, Investigation, Methodology, Resources, Visualization, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
Douglas R. Green
Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
Paul G. Thomas
Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing - review & editing
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN
Siddharth Balachandran
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA
Correspondence to Siddharth Balachandran: siddharth.balachandran@fccc.edu
*
M. Shubina, B. Tummers, D.F. Boyd, and T. Zhang contributed equally to this paper.
Received:
July 09 2019
Revision Received:
May 08 2020
Accepted:
July 02 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
National Institute of Allergy and Infectious Diseases
(HHSN272201400006C)
National Institutes of Health
(CA168621, CA190542, AI135025, P30CA006927, AI44828, CA231620, R01 AI121832)
© 2020 Shubina et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2020) 217 (11): e20191259.
Article history
Received:
July 09 2019
Revision Received:
May 08 2020
Accepted:
July 02 2020
Citation
Maria Shubina, Bart Tummers, David F. Boyd, Ting Zhang, Chaoran Yin, Avishekh Gautam, Xi-zhi J. Guo, Diego A. Rodriguez, William J. Kaiser, Peter Vogel, Douglas R. Green, Paul G. Thomas, Siddharth Balachandran; Necroptosis restricts influenza A virus as a stand-alone cell death mechanism. J Exp Med 2 November 2020; 217 (11): e20191259. doi: https://doi.org/10.1084/jem.20191259
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