期刊
CELL HOST & MICROBE
卷 17, 期 6, 页码 811-819出版社
CELL PRESS
DOI: 10.1016/j.chom.2015.05.004
关键词
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资金
- NIH [PO1 AI063302, U19 AI109725]
- Crohn's and Colitis Foundation of America [274415]
- Arnold and Mabel Beckman Foundation
- HHMI
- Damon Runyon Cancer Research Foundation
- NSF Graduate Research Fellowships
- NIGMS Cell and Molecular Biology Training Grant [GM007067]
Type I interferons (IFNs) are critical mediators of antiviral defense, but their elicitation by bacterial pathogens can be detrimental to hosts. Many intracellular bacterial pathogens, including Mycobacterium tuberculosis, induce type I IFNs following phagosomal membrane perturbations. Cytosolic M. tuberculosis DNA has been implicated as a trigger for IFN production, but the mechanisms remain obscure. We report that the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), is required for activating IFN production via the STING/TBK1/IRF3 pathway during M. tuberculosis and L. pneumophila infection of macrophages, whereas L. monocytogenes short-circuits this pathway by producing the STING agonist, c-di-AMP. Upon sensing cytosolic DNA, cGAS also activates cell-intrinsic antibacterial defenses, promoting autophagic targeting of M. tuberculosis. Importantly, we show that cGAS binds M. tuberculosis DNA during infection, providing direct evidence that this unique host-pathogen interaction occurs in vivo. These data uncover a mechanism by which IFN is likely elicited during active human infections.
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