STING-dependent recognition of cyclic di-AMP mediates type I interferon responses during Chlamydia trachomatis infection.

Abstract

UNLABELLED:

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.

IMPORTANCE:

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: Jeffrey R Barker, Benjamin J Koestler, Victoria K Carpenter, Dara L Burdette, Christopher M Waters, Russell E Vance, Raphael H Valdivia
• Journal: mBio (mBio) Vol. 4 Issue 3 Pg. e00018-13 (Apr 30 2013) ISSN: 2150-7511 [Electronic] United States
• PMID: 23631912 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Dinucleoside Phosphates
• Membrane Proteins
• STING1 protein, human
• Sting1 protein, mouse
• cyclic diadenosine phosphate
• Interferon-beta

Topics

• Animals
• Cells, Cultured
• Chlamydia Infections (immunology)
• Chlamydia trachomatis (immunology, metabolism)
• Dinucleoside Phosphates (metabolism)
• Humans
• Interferon-beta (metabolism)
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL