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.
Bibliographical noteFunding 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.).