Sixt Barbara S, Bastidas Robert J, Finethy Ryan, Baxter Ryan M, Carpenter Victoria K, Kroemer Guido, Coers Jörn, Valdivia Raphael H
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA; INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris 75006, France; Université Paris Descartes, Paris 75006, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif 94800, France.
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
Cell Host Microbe. 2017 Jan 11;21(1):113-121. doi: 10.1016/j.chom.2016.12.002. Epub 2016 Dec 29.
Evading cell death is critical for Chlamydia to maintain a replicative niche, but the underlying mechanisms are unknown. We screened a library of Chlamydia mutants for modulators of cell death. Inactivation of the inclusion membrane protein CpoS (Chlamydia promoter of survival) induced rapid apoptotic and necrotic death in infected cells. The protection afforded by CpoS is limited to the inclusion in which it resides, indicating that it counteracts a spatially restricted pro-death signal. CpoS-deficient Chlamydia induced an exacerbated type I interferon response that required the host cGAS/STING/TBK1/IRF3 signaling pathway. Disruption of STING, but not cGAS or IRF3, attenuated cell death, suggesting that STING mediates Chlamydia-induced cell death independent of its role in regulating interferon responses. CpoS-deficient strains are attenuated in their ability to propagate in cell culture and are cleared faster from the murine genital tract, highlighting the importance of CpoS for Chlamydia pathogenesis.
逃避细胞死亡对于衣原体维持复制龛至关重要，但其潜在机制尚不清楚。我们筛选了衣原体突变体文库以寻找细胞死亡调节剂。包涵体膜蛋白CpoS（衣原体生存促进因子）失活会诱导受感染细胞迅速发生凋亡和坏死性死亡。CpoS提供的保护仅限于其所在的包涵体，这表明它可抵消空间受限的促死亡信号。缺乏CpoS的衣原体诱导了加剧的I型干扰素反应，这需要宿主cGAS/STING/TBK1/IRF3信号通路。STING的破坏而非cGAS或IRF3的破坏减弱了细胞死亡，这表明STING介导衣原体诱导的细胞死亡，与其在调节干扰素反应中的作用无关。缺乏CpoS的菌株在细胞培养中的繁殖能力减弱，并且从鼠生殖道中清除得更快，这突出了CpoS对衣原体发病机制的重要性。
