Watson Robert O, Bell Samantha L, MacDuff Donna A, Kimmey Jacqueline M, Diner Elie J, Olivas Joanna, Vance Russell E, Stallings Christina L, Virgin Herbert W, Cox Jeffery S
Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Cell Host Microbe. 2015 Jun 10;17(6):811-819. doi: 10.1016/j.chom.2015.05.004. Epub 2015 Jun 2.
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.
I型干扰素（IFN）是抗病毒防御的关键介质，但细菌病原体引发的I型干扰素对宿主可能有害。许多细胞内细菌病原体，包括结核分枝杆菌，在吞噬体膜受到扰动后会诱导产生I型干扰素。胞质中的结核分枝杆菌DNA被认为是干扰素产生的触发因素，但其机制仍不清楚。我们报告称，在巨噬细胞受到结核分枝杆菌和嗜肺军团菌感染期间，胞质DNA传感器——环磷酸鸟苷-腺苷酸合成酶（cGAS）是通过STING/TBK1/IRF3途径激活干扰素产生所必需的，而单核细胞增生李斯特菌通过产生STING激动剂环二腺苷酸（c-di-AMP）使该途径短路。在感知到胞质DNA后，cGAS还会激活细胞内在的抗菌防御，促进对结核分枝杆菌的自噬靶向作用。重要的是，我们表明在感染过程中cGAS与结核分枝杆菌DNA结合，提供了这种独特的宿主-病原体相互作用在体内发生的直接证据。这些数据揭示了在人类活动性感染期间可能引发干扰素的一种机制。
