STING-Dependent Recognition of Cyclic di-AMP Mediates Type I Interferon Responses during <named-content content-type="genus-species">Chlamydia trachomatis</named-content> 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...

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Autores principales:	Jeffrey R. Barker, Benjamin J. Koestler, Victoria K. Carpenter, Dara L. Burdette, Christopher M. Waters, Russell E. Vance, Raphael H. Valdivia
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bdb5532bc2164aa296238bf6a6386812
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spelling	oai:doaj.org-article:bdb5532bc2164aa296238bf6a63868122021-11-15T15:40:05ZSTING-Dependent Recognition of Cyclic di-AMP Mediates Type I Interferon Responses during <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Infection10.1128/mBio.00018-132150-7511https://doaj.org/article/bdb5532bc2164aa296238bf6a63868122013-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00018-13https://doaj.org/toc/2150-7511ABSTRACT 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.Jeffrey R. BarkerBenjamin J. KoestlerVictoria K. CarpenterDara L. BurdetteChristopher M. WatersRussell E. VanceRaphael H. ValdiviaAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 3 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Jeffrey R. Barker Benjamin J. Koestler Victoria K. Carpenter Dara L. Burdette Christopher M. Waters Russell E. Vance Raphael H. Valdivia STING-Dependent Recognition of Cyclic di-AMP Mediates Type I Interferon Responses during <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Infection
description	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. 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.
format	article
author	Jeffrey R. Barker Benjamin J. Koestler Victoria K. Carpenter Dara L. Burdette Christopher M. Waters Russell E. Vance Raphael H. Valdivia
author_facet	Jeffrey R. Barker Benjamin J. Koestler Victoria K. Carpenter Dara L. Burdette Christopher M. Waters Russell E. Vance Raphael H. Valdivia
author_sort	Jeffrey R. Barker
title	STING-Dependent Recognition of Cyclic di-AMP Mediates Type I Interferon Responses during <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Infection
title_short	STING-Dependent Recognition of Cyclic di-AMP Mediates Type I Interferon Responses during <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Infection
title_full	STING-Dependent Recognition of Cyclic di-AMP Mediates Type I Interferon Responses during <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Infection
title_fullStr	STING-Dependent Recognition of Cyclic di-AMP Mediates Type I Interferon Responses during <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Infection
title_full_unstemmed	STING-Dependent Recognition of Cyclic di-AMP Mediates Type I Interferon Responses during <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Infection
title_sort	sting-dependent recognition of cyclic di-amp mediates type i interferon responses during <named-content content-type="genus-species">chlamydia trachomatis</named-content> infection
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/bdb5532bc2164aa296238bf6a6386812
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STING-Dependent Recognition of Cyclic di-AMP Mediates Type I Interferon Responses during <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Infection

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