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, and Maya Saleh

Cell Host Microbe (2014) 1, 23-35

Speaker: Chieh-Yu Lin (林倢妤)                                          Time: 13:00~14:00, May 7, 2014

Commentator: Dr. Guey-Chuen Perng (彭貴春老師)  Place: Room 601

Abstract:

Cell death is one of the strategies for host to defense pathogen infections. Cell death must be tightly controlled since it will exacerbate tissue injury as a cost for host to clear pathogens. In regulating cell death, apoptosis and necrosis are two complementary pathways controlled by a common upstream regulator, cellular inhibitor of apoptosis proteins (cIAPs) (1). In addition, cIAPs are essential regulators to induce innate immune responses. To address the roles of cIAPs in virus infection, the authors infected wild-type and cIAP2-deficient (Birc3^-/-) mice with influenza A virus and found that the mortality of Birc3^-/- mice was significantly higher than that of wild-type mice. However, the viral loads, cytokine levels, and numbers of infiltrating leukocytes in infected lungs were comparable in Birc3^-/- and wild-type mice, suggesting that lethality of Birc3^-/- mice was not due to compromised immune responses against virus infection. Influenza A virus infects and induces death of lung epithelial cells. In infected lung of Birc3^-/- mice, the authors found more serious destruction when compared with that in wild-type mice, indicating that cIAP plays an important role in regulating cell death following virus infection. The death of lung epithelial cells in Birc3^-/- mice was dependent on receptor-interacting protein kinase (RIPK) 1 and 3, the key regulators to induce necroptosis, a programmed necrosis, but independent of caspases. Inhibition of necroptosis or knocking down death receptor agonists, Fas ligand or TRAIL, in Birc3^-/- mice improved the survival of infected mice. Collectively, this study demonstrates that cIAP2 antagonizes the RIPK3-mediated programmed necrosis and protects mice from influenza A virus-induced death by maintaining pulmonary tissue homeostasis rather than through pathogen control mediated by immune responses.

Reference:

1.     Vanlangenakker N, Vanden Berghe T, Bogaert P. Laukens B, Zobel K, Deshayes K, Vucic D, Fulda S, Vandenabeele P, and Bertrand MJM. cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent reactive oxygen species production. Cell Death Differ (2011) 18, 656–665.