Deficiency of XIAP leads to sensitization for Chlamydophila pneumoniae pulmonary infection and dysregulation of innate immune response in mice.

Obligate intracellular Chlamydophila pneumoniae induce apoptosis resistance in host cells to escape eradication by immune effector cells. Apoptosis resistance depends on the increased expression and stabilization of cellular inhibitor of apoptosis proteins (cIAPs) and X-linked inhibitor of apoptosis protein (XIAP). Here we investigated the role of XIAP in experimental pulmonary infection of mice with C. pneumoniae. XIAP knock out (KO) mice were sensitized for C. pneumoniae infection compared with wild type mice. XIAP was involved in lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and endotoxin shock. Hyper-secretion of tumor necrosis factor-alpha and lower NO in LPS-treated KO mouse macrophages revealed its regulatory role in inflammatory responses. Unexpectedly, activating stimuli like LPS, tumor necrosis factor-alpha, or interferon-gamma very efficiently induced apoptotic cell death in KO macrophages but not in wild type macrophages. Cell survival transcription factor nuclear factor kappaB (NF-kappaB) p65 levels were reduced in lungs and pulmonary macrophages of infected KO mice. Furthermore, a reduced CD8 T cell population and their increased sensitivity for concanavalin A and chlamydial HSP60 stimulation revealed a defect in CD8 T cells in XIAP KO mice. These data demonstrated a role of XIAP for the integrity of both innate and cellular immune responses during C. pneumoniae infection.