Mechanisms of Inflammasome Defense against Cytosol-invasive Bacteria

摘要 炎性小体调查细胞溶质的扰动或细菌污染的迹象，并启动 微生物防御过程中的炎症或炎性疾病。NLRC 4炎性小体检测 细菌III型分泌系统（T3 SS）以及鞭毛蛋白的活性，然后激活caspase-1， 将IL-1β和IL-18加工成成熟形式，并启动一种称为 焦亡，以防止细胞内复制生态位的建立。Caspase-11，非经典 炎性小体，检测胞质溶胶中的LPS并触发焦亡，但不能单独加工IL-1β原或IL-18。 利用类鼻疽伯克霍尔德氏菌的胞质侵入性筛选模型--泰国伯克霍尔德氏菌， 发现B. Thailandensis主要通过caspase-11清除，而caspase-1在防御中起次要作用。 具体来说，我发现T3 SS激活caspase-1提供了一个启动信号，IL-18诱导的IFN-γ， 在防御B过程中caspase-11表达的上游。泰国，导致在24小时内清除。 相比之下，在没有caspase-1驱动的IL-18的情况下，细菌负荷持续数天，最终 触发其他信号，诱导IFN-γ和下游caspase-11表达。在这份提案中，我将 研究为什么caspase-1和-11依赖性焦亡是不等价的，以及什么是细胞来源， IFN-γ启动caspase-11以保护免受B. thailandensis。这些研究将提供新的见解， 炎症体介导的抗感染防御机制，从而有助于未来的治疗， 对宿主先天免疫系统的治疗性操纵。

Abstract Inflammasomes survey the cytosol for signs of perturbation or bacterial contamination and initiate inflammation during microbial defense or inflammatory diseases. The NLRC4 inflammasome detects the activity of bacterial type III secretion systems (T3SS) as well as flagellin, and then activates caspase-1, which processes IL-1β and IL-18 to their mature forms, and initiates a form of programmed lytic cell death called pyroptosis to prevent the establishment of an intracellular replication niche. Caspase-11, the non-canonical inflammasome, detects LPS in the cytosol and triggers pyroptosis, but cannot process pro-IL-1β or IL-18 alone. Using Burkholderia thailandensis, a model for the cytosol invasive select agent Burkholderia pseudomallei, I found that B. thailandensis is primarily cleared via caspase-11, while caspase-1 plays a minor role in defense. Specifically, I found that caspase-1 activation by the T3SS provides a priming signal, IL-18-induced IFN-γ, upstream of caspase-11 expression during defense against B. thailandensis, leading to clearance in 24 hours. By contrast, in the absence of caspase-1-driven IL-18, bacterial burdens persist for several days, eventually triggering other signals that induce IFN-γ and downstream caspase-11 expression. In this proposal, I will investigate why caspase-1 and -11 dependent pyroptosis are not equivalent, and what is the cellular source of IFN-γ that prime caspase-11 to protect against B.thailandensis. These studies will provide new insights into the mechanisms behind inflammasome-mediated defense against infection, and thus aid future treatments aimed at therapeutic manipulation of the host innate immune system.