The Chlamydia trachomatis Inclusion Membrane Protein CpoS Counteracts STING-Mediated Cellular Surveillance and Suicide Programs

• Published in: Cell host & microbe Vol. 21; no. 1; pp. 113 - 121
• Main Authors: Sixt, Barbara S., Bastidas, Robert J., Finethy, Ryan, Baxter, Ryan M., Carpenter, Victoria K., Kroemer, Guido, Coers, Jörn, Valdivia, Raphael H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.01.2017
• Subjects: Animals; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Cell Death - immunology; Chlamydia trachomatis - genetics; Chlamydia trachomatis - immunology; Chlamydia trachomatis - pathogenicity; Chlorocebus aethiops; Female; HeLa Cells; Humans; Interferon Regulatory Factor-3 - metabolism; Interferon Type I - immunology; Life Sciences; Medicin och hälsovetenskap; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Protein-Serine-Threonine Kinases - metabolism; Vero Cells
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2016.12.002

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. [Display omitted] •A genetic screen identifies C. trachomatis effector CpoS as a regulator of cell death•Loss of CpoS on the inclusion causes enhanced death in infected cells•DNA sensor STING modulates IFN responses and death in cells infected with cpoS mutants•cpoS mutants are defective for propagation in cell culture and in mice Evading cell death is critical for Chlamydia trachomatis to maintain a replicative niche. Sixt et al. show that the Chlamydia effector protein CpoS counteracts STING-mediated pro-death signals and type I IFN responses in response to Chlamydia-containing vacuoles, which enables optimal intracellular bacterial growth and survival in the murine genital tract.