title: STING-dependent recognition of cyclic di-AMP mediates type I interferon responses during Chlamydia trachomatis infection.
abstract: STING (stimulator of interferon [IFN] genes) initiates type I IFN responses in mammalian cells through the detection of microbial nucleic acids. The membrane-bound obligate intracellular bacterium Chlamydia trachomatis induces a STING-dependent type I IFN response in infected cells, yet the IFN-inducing ligand remains unknown. In this report, we provide evidence that Chlamydia synthesizes cyclic di-AMP (c-di-AMP), a nucleic acid metabolite not previously identified in Gram-negative bacteria, and that this metabolite is a prominent ligand for STING-mediated activation of IFN responses during infection. We used primary mouse lung fibroblasts and HEK293T cells to compare IFN-β responses to Chlamydia infection, c-di-AMP, and other type I IFN-inducing stimuli. Chlamydia infection and c-di-AMP treatment induced type I IFN responses in cells expressing STING but not in cells expressing STING variants that cannot sense cyclic dinucleotides but still respond to cytoplasmic DNA. The failure to induce a type I IFN response to Chlamydia and c-di-AMP correlated with the inability of STING to relocalize from the endoplasmic reticulum to cytoplasmic punctate signaling complexes required for IFN activation. We conclude that Chlamydia induces STING-mediated IFN responses through the detection of c-di-AMP in the host cell cytosol and propose that c-di-AMP is the ligand predominantly responsible for inducing such a response in Chlamydia-infected cells.
  
  
  OBJECTIVE
  This study shows that the Gram-negative obligate pathogen Chlamydia trachomatis, a major cause of pelvic inflammatory disease and infertility, synthesizes cyclic di-AMP (c-di-AMP), a nucleic acid metabolite that thus far has been described only in Gram-positive bacteria. We further provide evidence that the host cell employs an endoplasmic reticulum (ER)-localized cytoplasmic sensor, STING (stimulator of interferon [IFN] genes), to detect c-di-AMP synthesized by Chlamydia and induce a protective IFN response. This detection occurs even though Chlamydia is confined to a membrane-bound vacuole. This raises the possibility that the ER, an organelle that innervates the entire cytoplasm, is equipped with pattern recognition receptors that can directly survey membrane-bound pathogen-containing vacuoles for leaking microbe-specific metabolites to mount type I IFN responses required to control microbial infections.
authors: Department of Molecular Genetics and Microbiology, Center for Microbial Pathogenesis, Duke University, Durham, North Carolina, USA.
authors: Jeffrey R
authors: JR
authors: Barker
authors: Benjamin J
authors: BJ
authors: Koestler
authors: Victoria K
authors: VK
authors: Carpenter
authors: Dara L
authors: DL
authors: Burdette
authors: Christopher M
authors: CM
authors: Waters
authors: Russell E
authors: RE
authors: Vance
authors: Raphael H
authors: RH
authors: Valdivia
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002690:Chlamydia Infections / Q000276:immunology*; D002692:Chlamydia trachomatis / Q000276:immunology* / Q000378:metabolism*; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000099197:STING Protein
chemical_list: D015226:Dinucleoside Phosphates; D016899:Interferon-beta; D008565:Membrane Proteins; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C528998:cyclic diadenosine phosphate
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