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

IG Rodrigue-Gervais, K Labbé, M Dagenais… - Cell host & …, 2014 - cell.com
IG Rodrigue-Gervais, K Labbé, M Dagenais, J Dupaul-Chicoine, C Champagne, A Morizot…
Cell host & microbe, 2014cell.com
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 …
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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