Department of Medicine, McGill University, Montréal, QC H3A 1B1, Canada.
Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 1B1, Canada.
Cell Host Microbe. 2014 Jan 15;15(1):23-35. doi: 10.1016/j.chom.2013.12.003.
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.
细胞凋亡抑制蛋白（cIAPs）是细胞死亡和免疫的重要调节剂。IAPs 对应激感染性疾病结果的贡献相对未知。我们发现，缺乏 cIAP2 的小鼠对甲型流感病毒感染的易感性和死亡率增加。这种致死性不是由于抗病毒免疫功能受损，而是由于死亡受体诱导的气道上皮细胞程序性坏死，导致严重的细支气管上皮退化，尽管病毒复制得到控制。RIPK1 的药理学抑制或参与程序性坏死的激酶 Ripk3 的基因缺失均可挽救 cIAP2 缺陷型小鼠免受流感诱导的致死性。从造血细胞中删除死亡受体激动剂 Fas 配体或 TRAIL 也可逆转 cIAP2 缺陷型小鼠的易感性。因此，cIAP2 依赖性拮抗 RIPK3 介导的程序性坏死通过维持肺组织稳态而不是通过免疫系统控制病原体，从而使宿主免受流感感染的严重影响。
