Natural killer cell cytotoxicity against intracellular bacteria

自然杀伤细胞对细胞内细菌的细胞毒性

• 批准号: 10168917
• 负责人: Edward A Miao
• 金额: $ 5.3万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/10168917
• 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

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.

抽象的 自然杀伤细胞对病毒感染的细胞和癌细胞具有细胞毒性，但从未被研究过。 显示可杀死体内含有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多性李斯特氏菌或色杆菌感染的肝细胞 紫罗兰。该活性分别需要外源或内源 IL-18。 这一发现源于我们寻找无法逃避 caspase-1 检测的细菌 体内。一系列逻辑步骤使我们发现 C. violaceum 对 caspase-1 缺陷具有极高的致死率 小鼠，仅 100 个 CFU 就会死亡。与此形成鲜明对比的是，WT 小鼠具有完全抵抗力，能够存活下来 1,000,000 CFU 系统性挑战。这个新模型让我们有了一个令人惊讶的新发现。大约 caspase-1 定向防御的一半是通过 IL-18，它刺激 NK 细胞杀死受紫罗兰色念珠菌感染的细胞 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 逃避炎症小体——我们之前已经证明单核细胞增生利斯特氏菌就是这种情况。这导致我们 假设单增李斯特氏菌通过阻止 IL-18 分泌来逃避 NK 细胞，事实上，当我们治疗时 使用IL-18治疗的小鼠，NK细胞毒性反应得以恢复。 在这笔资助中，我们探索 NK 细胞毒性如何驱动单核细胞增生李斯特菌和艰难梭菌的清除。 紫罗兰。我们研究 NKG2D 在识别感染细胞中的作用，探索 NKG2D 所针对的蛋白质 目标感染肝细胞中的颗粒酶，并研究感染肝细胞被杀死后的命运。