Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival

Ian Gaël Rodrigue-Gervais; Katherine Labbé; Maryse Dagenais; Jeremy Dupaul-Chicoine; Claudia Champagne; Alexandre Morizot; Alexander Skeldon; Erik L. Brincks; Silvia M. Vidal; Thomas S. Griffith; Maya Saleh

doi:10.1016/j.chom.2013.12.003

Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival

Ian Gaël Rodrigue-Gervais, Katherine Labbé, Maryse Dagenais, Jeremy Dupaul-Chicoine, Claudia Champagne, Alexandre Morizot, Alexander Skeldon, Erik L. Brincks, Silvia M. Vidal, Thomas S. Griffith, Maya Saleh

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Abstract

Summary Cellular inhibitors of apoptosis proteins (cIAPs) are essential regulators of cell death and immunity. The corresponding contributions of IAPs to infectious disease outcomes are relatively unexplored. We find that mice deficient in cIAP2 exhibit increased susceptibility and mortality to influenza A virus infection. The lethality was not due to impaired antiviral immune functions, but rather because of death-receptor-induced programmed necrosis of airway epithelial cells that led to severe bronchiole epithelial degeneration, despite control of viral replication. Pharmacological inhibition of RIPK1 or genetic deletion of Ripk3, both kinases involved in programmed necrosis, rescued cIAP2-deficient mice from influenza-induced lethality. Genetic deletion of the death receptor agonists Fas ligand or TRAIL from the hematopoietic compartment also reversed the susceptibility of cIAP2-deficient mice. Thus, cIAP2-dependent antagonism of RIPK3-mediated programmed necrosis critically protects the host from influenza infection through maintenance of pulmonary tissue homeostasis rather than through pathogen control by the immune system.

Original language	English (US)
Pages (from-to)	23-35
Number of pages	13
Journal	Cell Host and Microbe
Volume	15
Issue number	1
DOIs	https://doi.org/10.1016/j.chom.2013.12.003
State	Published - Jan 15 2014

Bibliographical note

Funding Information:
We thank V. Dixit and Genentech for providing Ripk3 −/− , Nlrp3 −/− , Asc −/− , Casp11 −/− mice; R. Korneluk for Birc3 −/− mice and caspase-11 PCR genotyping protocol; P. Barker for Birc3 −/− Casp11 +/+ mice; R. Flavell for Ripk2 −/− and Casp1 −/− mice; M. Divangahi for the NP 366–374 tetramer; D. Lamarre for purified PR/8 virus; and J. Rinz for animal husbandry. This work was supported by grants from the Canadian Institutes for Health Research (CIHR-MOP 79410) and the Burroughs Wellcome Fund to M.S., who is a Fonds de Recherche en Santé du Québec (FRSQ) Senior Investigator and a McGill University William Dawson Scholar. I.G.R.G. is supported by postdoctoral fellowships from the FRSQ, CIHR, and by the Strauss Foundation. K.L., J.D., and A.S. are supported by CIHR studentships/fellowships. M.D. is supported by a FRSQ studentship, and A.M. is supported by a CIHR/CAG/Abbott fellowship. E.L.B. is supported by a postdoctoral fellowship from the Kidney Cancer Association and National Institutes of Health grant CA109446 (to T.S.G.).

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Rodrigue-Gervais, I. G., Labbé, K., Dagenais, M., Dupaul-Chicoine, J., Champagne, C., Morizot, A., Skeldon, A., Brincks, E. L., Vidal, S. M., Griffith, T. S., & Saleh, M. (2014). Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival. Cell Host and Microbe, 15(1), 23-35. https://doi.org/10.1016/j.chom.2013.12.003

Rodrigue-Gervais, IG, Labbé, K, Dagenais, M, Dupaul-Chicoine, J, Champagne, C, Morizot, A, Skeldon, A, Brincks, EL, Vidal, SM, Griffith, TS & Saleh, M 2014, 'Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival', Cell Host and Microbe, vol. 15, no. 1, pp. 23-35. https://doi.org/10.1016/j.chom.2013.12.003

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title = "Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival",

abstract = "Summary Cellular inhibitors of apoptosis proteins (cIAPs) are essential regulators of cell death and immunity. The corresponding contributions of IAPs to infectious disease outcomes are relatively unexplored. We find that mice deficient in cIAP2 exhibit increased susceptibility and mortality to influenza A virus infection. The lethality was not due to impaired antiviral immune functions, but rather because of death-receptor-induced programmed necrosis of airway epithelial cells that led to severe bronchiole epithelial degeneration, despite control of viral replication. Pharmacological inhibition of RIPK1 or genetic deletion of Ripk3, both kinases involved in programmed necrosis, rescued cIAP2-deficient mice from influenza-induced lethality. Genetic deletion of the death receptor agonists Fas ligand or TRAIL from the hematopoietic compartment also reversed the susceptibility of cIAP2-deficient mice. Thus, cIAP2-dependent antagonism of RIPK3-mediated programmed necrosis critically protects the host from influenza infection through maintenance of pulmonary tissue homeostasis rather than through pathogen control by the immune system.",

author = "Rodrigue-Gervais, {Ian Ga{\"e}l} and Katherine Labb{\'e} and Maryse Dagenais and Jeremy Dupaul-Chicoine and Claudia Champagne and Alexandre Morizot and Alexander Skeldon and Brincks, {Erik L.} and Vidal, {Silvia M.} and Griffith, {Thomas S.} and Maya Saleh",

note = "Funding Information: We thank V. Dixit and Genentech for providing Ripk3 −/− , Nlrp3 −/− , Asc −/− , Casp11 −/− mice; R. Korneluk for Birc3 −/− mice and caspase-11 PCR genotyping protocol; P. Barker for Birc3 −/− Casp11 +/+ mice; R. Flavell for Ripk2 −/− and Casp1 −/− mice; M. Divangahi for the NP 366–374 tetramer; D. Lamarre for purified PR/8 virus; and J. Rinz for animal husbandry. This work was supported by grants from the Canadian Institutes for Health Research (CIHR-MOP 79410) and the Burroughs Wellcome Fund to M.S., who is a Fonds de Recherche en Sant{\'e} du Qu{\'e}bec (FRSQ) Senior Investigator and a McGill University William Dawson Scholar. I.G.R.G. is supported by postdoctoral fellowships from the FRSQ, CIHR, and by the Strauss Foundation. K.L., J.D., and A.S. are supported by CIHR studentships/fellowships. M.D. is supported by a FRSQ studentship, and A.M. is supported by a CIHR/CAG/Abbott fellowship. E.L.B. is supported by a postdoctoral fellowship from the Kidney Cancer Association and National Institutes of Health grant CA109446 (to T.S.G.). ",

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doi = "10.1016/j.chom.2013.12.003",

language = "English (US)",

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T1 - Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival

AU - Rodrigue-Gervais, Ian Gaël

AU - Labbé, Katherine

AU - Dagenais, Maryse

AU - Dupaul-Chicoine, Jeremy

AU - Champagne, Claudia

AU - Morizot, Alexandre

AU - Skeldon, Alexander

AU - Brincks, Erik L.

AU - Vidal, Silvia M.

AU - Griffith, Thomas S.

AU - Saleh, Maya

N1 - Funding Information: We thank V. Dixit and Genentech for providing Ripk3 −/− , Nlrp3 −/− , Asc −/− , Casp11 −/− mice; R. Korneluk for Birc3 −/− mice and caspase-11 PCR genotyping protocol; P. Barker for Birc3 −/− Casp11 +/+ mice; R. Flavell for Ripk2 −/− and Casp1 −/− mice; M. Divangahi for the NP 366–374 tetramer; D. Lamarre for purified PR/8 virus; and J. Rinz for animal husbandry. This work was supported by grants from the Canadian Institutes for Health Research (CIHR-MOP 79410) and the Burroughs Wellcome Fund to M.S., who is a Fonds de Recherche en Santé du Québec (FRSQ) Senior Investigator and a McGill University William Dawson Scholar. I.G.R.G. is supported by postdoctoral fellowships from the FRSQ, CIHR, and by the Strauss Foundation. K.L., J.D., and A.S. are supported by CIHR studentships/fellowships. M.D. is supported by a FRSQ studentship, and A.M. is supported by a CIHR/CAG/Abbott fellowship. E.L.B. is supported by a postdoctoral fellowship from the Kidney Cancer Association and National Institutes of Health grant CA109446 (to T.S.G.).

PY - 2014/1/15

Y1 - 2014/1/15

N2 - Summary Cellular inhibitors of apoptosis proteins (cIAPs) are essential regulators of cell death and immunity. The corresponding contributions of IAPs to infectious disease outcomes are relatively unexplored. We find that mice deficient in cIAP2 exhibit increased susceptibility and mortality to influenza A virus infection. The lethality was not due to impaired antiviral immune functions, but rather because of death-receptor-induced programmed necrosis of airway epithelial cells that led to severe bronchiole epithelial degeneration, despite control of viral replication. Pharmacological inhibition of RIPK1 or genetic deletion of Ripk3, both kinases involved in programmed necrosis, rescued cIAP2-deficient mice from influenza-induced lethality. Genetic deletion of the death receptor agonists Fas ligand or TRAIL from the hematopoietic compartment also reversed the susceptibility of cIAP2-deficient mice. Thus, cIAP2-dependent antagonism of RIPK3-mediated programmed necrosis critically protects the host from influenza infection through maintenance of pulmonary tissue homeostasis rather than through pathogen control by the immune system.

AB - Summary Cellular inhibitors of apoptosis proteins (cIAPs) are essential regulators of cell death and immunity. The corresponding contributions of IAPs to infectious disease outcomes are relatively unexplored. We find that mice deficient in cIAP2 exhibit increased susceptibility and mortality to influenza A virus infection. The lethality was not due to impaired antiviral immune functions, but rather because of death-receptor-induced programmed necrosis of airway epithelial cells that led to severe bronchiole epithelial degeneration, despite control of viral replication. Pharmacological inhibition of RIPK1 or genetic deletion of Ripk3, both kinases involved in programmed necrosis, rescued cIAP2-deficient mice from influenza-induced lethality. Genetic deletion of the death receptor agonists Fas ligand or TRAIL from the hematopoietic compartment also reversed the susceptibility of cIAP2-deficient mice. Thus, cIAP2-dependent antagonism of RIPK3-mediated programmed necrosis critically protects the host from influenza infection through maintenance of pulmonary tissue homeostasis rather than through pathogen control by the immune system.

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Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival

Abstract

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