Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival.
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.
Department of Medicine, McGill University, Montréal, QC H3A 1B1, Canada.
Ian Gaël
IG
Rodrigue-Gervais
Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 1B1, Canada.
Katherine
K
Labbé
Department of Biochemistry, McGill University, Montréal, QC H3A 1B1, Canada.
Maryse
M
Dagenais
Department of Biochemistry, McGill University, Montréal, QC H3A 1B1, Canada.
Jeremy
J
Dupaul-Chicoine
Department of Medicine, McGill University, Montréal, QC H3A 1B1, Canada.
Claudia
C
Champagne
Department of Medicine, McGill University, Montréal, QC H3A 1B1, Canada.
Alexandre
A
Morizot
Department of Biochemistry, McGill University, Montréal, QC H3A 1B1, Canada.
Alexander
A
Skeldon
Department of Urology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
Erik L
EL
Brincks
Department of Human Genetics, McGill University, Montréal, QC H3A 1B1, Canada.
Silvia M
SM
Vidal
Department of Urology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
Thomas S
TS
Griffith
Department of Medicine, McGill University, Montréal, QC H3A 1B1, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 1B1, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1B1, Canada. Electronic address: maya.saleh@mcgill.ca.
Maya
M
Saleh
D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053222:Fas Ligand Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D016019:Survival Analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D044767:Ubiquitin-Protein Ligases
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D047428:Protein Kinase Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse