Finethy Ryan, Jorgensen Ine, Haldar Arun K, de Zoete Marcel R, Strowig Till, Flavell Richard A, Yamamoto Masahiro, Nagarajan Uma M, Miao Edward A, Coers Jörn
Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, North Carolina, USA.
Infect Immun. 2015 Dec;83(12):4740-9. doi: 10.1128/IAI.00856-15. Epub 2015 Sep 28.
Interferon (IFN)-inducible guanylate binding proteins (GBPs) mediate cell-autonomous host resistance to bacterial pathogens and promote inflammasome activation. The prevailing model postulates that these two GBP-controlled activities are directly linked through GBP-dependent vacuolar lysis. It was proposed that the rupture of pathogen-containing vacuoles (PVs) by GBPs destroyed the microbial refuge and simultaneously contaminated the host cell cytosol with microbial activators of inflammasomes. Here, we demonstrate that GBP-mediated host resistance and GBP-mediated inflammatory responses can be uncoupled. We show that PVs formed by the rodent pathogen Chlamydia muridarum, so-called inclusions, remain free of GBPs and that C. muridarum is impervious to GBP-mediated restrictions on bacterial growth. Although GBPs neither bind to C. muridarum inclusions nor restrict C. muridarum growth, we find that GBPs promote inflammasome activation in C. muridarum-infected macrophages. We demonstrate that C. muridarum infections induce GBP-dependent pyroptosis through both caspase-11-dependent noncanonical and caspase-1-dependent canonical inflammasomes. Among canonical inflammasomes, we find that C. muridarum and the human pathogen Chlamydia trachomatis activate not only NLRP3 but also AIM2. Our data show that GBPs support fast-kinetics processing and secretion of interleukin-1β (IL-1β) and IL-18 by the NLRP3 inflammasome but are dispensable for the secretion of the same cytokines at later times postinfection. Because IFN-γ fails to induce IL-1β transcription, GBP-dependent fast-kinetics inflammasome activation can drive the preferential processing of constitutively expressed IL-18 in IFN-γ-primed macrophages in the absence of prior Toll-like receptor stimulation. Together, our results reveal that GBPs control the kinetics of inflammasome activation and thereby shape macrophage responses to Chlamydia infections.
干扰素（IFN）诱导的鸟苷酸结合蛋白（GBP）介导细胞自主的宿主对细菌病原体的抗性，并促进炎性小体激活。目前流行的模型假定这两种GBP控制的活动通过GBP依赖的液泡裂解直接联系在一起。有人提出，GBP使含病原体液泡（PV）破裂，破坏了微生物的避难所，同时用炎性小体的微生物激活剂污染了宿主细胞胞质溶胶。在这里，我们证明GBP介导的宿主抗性和GBP介导的炎症反应可以解偶联。我们表明，由啮齿动物病原体鼠衣原体形成的PV，即所谓的包涵体，不含GBP，并且鼠衣原体不受GBP介导的对细菌生长的限制。尽管GBP既不与鼠衣原体包涵体结合也不限制鼠衣原体生长，但我们发现GBP促进鼠衣原体感染的巨噬细胞中的炎性小体激活。我们证明，鼠衣原体感染通过半胱天冬酶-11依赖的非经典和半胱天冬酶-1依赖的经典炎性小体诱导GBP依赖的细胞焦亡。在经典炎性小体中，我们发现鼠衣原体和人类病原体沙眼衣原体不仅激活NLRP3，还激活AIM2。我们的数据表明，GBP支持NLRP3炎性小体对白介素-1β（IL-1β）和IL-18的快速动力学加工和分泌，但在感染后期对相同细胞因子的分泌是可有可无的。因为IFN-γ不能诱导IL-1β转录，GBP依赖的快速动力学炎性小体激活可以在没有先前Toll样受体刺激的情况下，驱动IFN-γ预处理的巨噬细胞中组成性表达的IL-18的优先加工。总之，我们的结果揭示GBP控制炎性小体激活的动力学，从而塑造巨噬细胞对衣原体感染的反应。
