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Natural killer cell cytotoxicity against intracellular bacteria

自然杀伤细胞对细胞内细菌的细胞毒性

基本信息

批准号：
10411544
负责人：
Edward A Miao
金额：
$ 3.62万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411544
关键词：
Apoptosis Apoptotic Automobile Driving Bacteria Bacterial Infections Bacteriophages Biological Response Modifiers CASP1 gene CASP3 gene CASP7 gene CD94 Antigen Cancerous Caspase Categories Cell physiology Cells Chromobacterium Cytolysis Data Detection Grant Granzyme Hepatocyte Immune Infection Infectious Agent Inflammasome Innate Immune System Interleukin-18 Knowledge Lead Listeria monocytogenes Malignant Neoplasms Mediating Modeling Mus Natural Killer Cell toxicity Natural Killer Cells Occupations Phase Poxviridae Predisposition Proteins Resistance Role Safety Series Specificity Therapeutic Therapeutic Intervention Viral Virus Work bactericide cell killing cell type combat cytokine cytokine release syndrome cytotoxic cytotoxicity fight against improved in vivo macrophage neutrophil pathogen perforin pressure prevent response tool

项目摘要

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.

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，但从未如此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NKG 2D在识别感染细胞中的作用，探索了NKG 2D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。