title: The Chlamydia trachomatis Inclusion Membrane Protein CpoS Counteracts STING-Mediated Cellular Surveillance and Suicide Programs.
abstract: 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.
authors.affiliation: 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.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Sixt
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bastidas
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Finethy
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Baxter
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Carpenter
authors.affiliation: 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; Pôle de Biologie, Hôpital Européen Georges-Pompidou, AP-HP, Paris 75015, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm 17176, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA.
authors.forename: Jörn
authors.initials: J
authors.lastname: Coers
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA. Electronic address: raphael.valdivia@duke.edu.
authors.forename: Raphael H
authors.initials: RH
authors.lastname: Valdivia
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000276:immunology*; D002692:Chlamydia trachomatis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D002522:Chlorocebus aethiops; D005260:Female; D006367:HeLa Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014709:Vero Cells; D000099197:STING Protein
chemical_list: D001426:Bacterial Proteins; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C000622460:CpoS protein, Chlamydia trachomatis; C494232:IRF3 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C403191:TBK1 protein, human