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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：
10348115
负责人：
Edward A Miao
金额：
$ 40.67万
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/10348115
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