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Cellular Inhibitor of Apoptosis Protein cIAP2 Protects against Pulmonary Tissue Necrosis during Influenza Virus Infection to Promote Host Survival
Ian Ga?l Rodrigue-Gervais1, 6, Katherine Labb?2, 6, Maryse Dagenais3, Jeremy Dupaul-Chicoine3, Claudia Champagne1, Alexandre Morizot1, Alexander Skeldon3, Erik L. Brincks5, Silvia M. Vidal4, Thomas S. Griffith5 and Maya Saleh1, 2, 3, Go To Corresponding Author,
1 Department of Medicine, McGill University, Montr?al, QC H3A 1B1, Canada
2 Department of Microbiology and Immunology, McGill University, Montr?al, QC H3A 1B1, Canada
3 Department of Biochemistry, McGill University, Montr?al, QC H3A 1B1, Canada
4 Department of Human Genetics, McGill University, Montr?al, QC H3A 1B1, Canada
5 Department of Urology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
Corresponding author
6 These authors contributed equally to this work
Graphical Abstract
Highlights
cIAP2−/− mice show enhanced susceptibility to influenza infection despite virus control
cIAP2−/− epithelial cell necrosis during infection underlies impaired airway integrity
RIPK1 inhibition or RIPK3 deletion improves survival of influenza infected cIAP2−/− mice
Hematopoietic deficiency of Fas ligand or TRAIL reversed susceptibility of cIAP2−/− mice
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.
Ian Ga?l Rodrigue-Gervais1, 6, Katherine Labb?2, 6, Maryse Dagenais3, Jeremy Dupaul-Chicoine3, Claudia Champagne1, Alexandre Morizot1, Alexander Skeldon3, Erik L. Brincks5, Silvia M. Vidal4, Thomas S. Griffith5 and Maya Saleh1, 2, 3, Go To Corresponding Author,
1 Department of Medicine, McGill University, Montr?al, QC H3A 1B1, Canada
2 Department of Microbiology and Immunology, McGill University, Montr?al, QC H3A 1B1, Canada
3 Department of Biochemistry, McGill University, Montr?al, QC H3A 1B1, Canada
4 Department of Human Genetics, McGill University, Montr?al, QC H3A 1B1, Canada
5 Department of Urology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
Corresponding author
6 These authors contributed equally to this work
Graphical Abstract
Highlights
cIAP2−/− mice show enhanced susceptibility to influenza infection despite virus control
cIAP2−/− epithelial cell necrosis during infection underlies impaired airway integrity
RIPK1 inhibition or RIPK3 deletion improves survival of influenza infected cIAP2−/− mice
Hematopoietic deficiency of Fas ligand or TRAIL reversed susceptibility of cIAP2−/− mice
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.
