Natural killer cell cytotoxicity against intracellular bacteria

摘要 自然杀伤细胞对病毒感染的细胞和癌细胞具有细胞毒性，但从来没有 显示在体内杀死携带细胞内细菌的宿主细胞。我们发现了前两个例子 NK细胞的基本功能，可以杀死被单核细胞增生李斯特菌或色杆菌感染的肝细胞 紫罗兰。这种活性分别需要外源性或内源性IL-18。 这一发现源于我们对细菌的研究，这些细菌在体内无法逃避caspase-1的检测。 vivo.一系列的逻辑步骤使我们发现C。紫孢菌对caspase-1缺陷型细胞是极其致命的 小鼠，其死于低至100 CFU。与之形成鲜明对比的是，WT小鼠完全具有抵抗力， 1，000，000 CFU全身攻毒。这个新模型使我们有了一个惊人的新发现。约 半胱天冬酶-1定向防御的一半是通过IL-18，其刺激NK细胞杀死C。紫色菌感染 肝细胞通过穿孔素介导的细胞毒性。脊椎动物适应的病原体具有很强的选择压力 以逃避炎性小体-我们先前已经表明L.单核细胞增多症这导致我们 假设L.单核细胞增多症通过阻止IL-18的分泌来逃避NK细胞，事实上，当我们治疗 在用治疗性IL-18处理的小鼠中，NK细胞毒性应答恢复。 在这项研究中，我们探讨了NK细胞的细胞毒性如何驱动L。单核细胞增多症和C. 紫罗兰。我们研究了NKG2D在识别感染细胞中的作用，探索了NKG2D靶向的蛋白质。 颗粒酶在目标感染的肝细胞，并研究感染的肝细胞被杀死后的命运。

ABSTRACT Natural killer cells are cytotoxic against virally infected cells and cancerous cells, but had never been shown to kill host cells harboring intracellular bacteria in vivo. We discovered the first two examples of this basic function of NK cells, which can kill hepatocytes infected by Listeria monocytogenes or Chromobacterium violaceum. This activity required exogenous or endogenous IL-18, respectively. This discovery originated from our search for bacteria that would fail to evade caspase-1 detection in vivo. A series of logical steps led us to discover that C. violaceum is extremely lethal to caspase-1 deficient mice, which succumb to as few as 100 CFUs. In stark contrast, WT mice are fully resistant, surviving 1,000,000 CFU systemic challenge. This new model led us to make a surprising new discovery. Approximately half of the caspase-1 directed defense was via IL-18, which stimulates NK cells to kill C. violaceum infected hepatocytes via perforin mediated cytotoxicity. Vertebrate adapted pathogens have strong selective pressure to evade inflammasomes – we have previously show this is the case for L. monocytogenes. This led us to postulate that L. monocytogenes evades NK cells by preventing IL-18 secretion, and indeed, when we treated mice with therapeutic IL-18, the NK cytotoxic response is restored. In this grant we explore how NK cytotoxicity drives the clearance of L. monocytogenes and C. violaceum. We study the role of NKG2D in identifying infected cells, explore the proteins that are targeted by granzymes in the target infected hepatocytes, and study the fate of infected hepatocytes after they are killed.