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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：
10097967
负责人：
Edward A Miao
金额：
$ 49.08万
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/10097967
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 Cleaved cell 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 therapeutic cytokines 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，但从来没有这样的作用。被证明能在体内杀死含有胞内细菌的宿主细胞。我们发现了头两个这样的例子 NK细胞的基本功能，可杀死单核细胞增多性李斯特菌或嗜铬杆菌感染的肝细胞紫罗兰科。这一活动分别需要外源性或内源性IL-18。这一发现源于我们寻找无法逃脱caspase-1检测的细菌。活着。一系列合乎逻辑的步骤使我们发现，紫罗兰对caspase-1缺陷是极其致命的。老鼠，它们屈从于100个CFU。与之形成鲜明对比的是，WT小鼠完全耐受，存活了下来 100万CFU的系统性挑战。这一新模型使我们有了一个令人惊讶的新发现。大致 Caspase-1定向防御的一半是通过IL-18，它刺激NK细胞杀死感染的Vioraceum 穿孔素对肝细胞的细胞毒作用。脊椎动物适应的病原体有很强的选择压力为了躲避炎性小体--我们之前已经证明，单核细胞增多性李斯特菌就是这种情况。这让我们找到了假设单核细胞增多性乳杆菌通过阻止IL-18的分泌而逃避NK细胞，实际上，当我们治疗小鼠经治疗性IL-18治疗后，NK细胞毒性反应恢复。在这笔赠款中，我们探索了NK细胞毒性如何推动单核细胞增多性乳杆菌和C. 紫罗兰科。我们研究了NKG2D在识别感染细胞中的作用，探索了NKG2D靶向的蛋白质在靶感染的肝细胞中发现颗粒酶，并研究感染的肝细胞在被杀死后的命运。