Defining human noncanonical inflammasome responses to Legionella pneumophila

定义人类对嗜肺军团菌的非典型炎症反应

基本信息

批准号：
9214308
负责人：
Sunny Shin
金额：
$ 40.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9214308
关键词：
Anti-Bacterial Agents Bacterial Infections Binding Biochemical Biological Blood Pressure CASP1 gene Caspase Cell Death Cells Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Community Hospitals Cytoplasm Cytosol Data Detection Disease Drops Endotoxic Shock Failure Family Flagellin Gene Silencing Genetic Genetic Transcription Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Host Defense Human Immune Immune response Immunomodulators Infection Infection Control Inflammasome Inflammation Inflammatory Inflammatory Response Innate Immune Response Integration Host Factors Interferons Interleukin-1 Interleukin-1 alpha Interleukin-1 beta Interleukin-18 Knowledge Laboratories Lead Legionella Legionella pneumophila Legionnaires&apos Disease Light Lipopolysaccharides Mastigophora Mediating Methods Molecular Multiprotein Complexes Mus Nosocomial pneumonia Orthologous Gene Outcome Pathologic Pathology Pathway interactions Play Pneumonia Process Public Health Publishing Role Sepsis Septic Shock Signal Transduction Small Interfering RNA System Testing Type IV Secretion System Pathway Virulence Factors aposome base cytokine defined contribution design effective therapy insight macrophage microbial mortality novel novel therapeutic intervention pathogen public health relevance response sensor septic

项目摘要

DESCRIPTION (provided by applicant): Gram-negative bacterial infections remain an enormous public health challenge. Failure to control infection can lead to sepsis, a severe pathology driven by dysregulated immune responses to lipopolysaccharide (LPS) and other microbial products. Sepsis can progress to multi-organ failure, a severe drop in blood pressure, and septic shock. Gram-negative infections are responsible for over 10 million cases of sepsis worldwide each year, with a greater than 30% mortality rate. Critically, more than a hundred clinical trials of immunomodulators that successfully treat sepsis in mice have failed, resulting i a shortage of effective treatments for human sepsis. The basis for these failures is unclear, but fundamental differences in human and mouse innate immune responses to infection likely play an important role. Our long-term goal is to elucidate the molecular mechanisms underlying human-specific innate immune responses to infection, as this knowledge is essential for developing new treatments for sepsis. To this end, we study the gram-negative pathogen Legionella pneumophila. Legionella causes the severe pneumonia Legionnaires' disease, which can develop into sepsis if not promptly treated. To initiate disease, Legionella infects and replicates within macrophages by delivering bacterial virulence factors into the host cell cytosol. Cytosolic immune detection of translocated bacterial products triggers assembly of inflammasomes, multiprotein complexes that activate caspases to induce host cell death and release of IL-1 family cytokines. We and other groups recently identified two types of inflammasomes in murine cells that respond to Legionella and other gram-negative pathogens: canonical inflammasomes activate caspase-1 (CASP1), while noncanonical inflammasomes engage caspase-11 (mCASP11), which directly detects cytosolic LPS. Although mCASP11 is critical for host defense, mCASP11 also mediates endotoxic shock. Intriguingly, humans express two mCASP11 orthologs, hCASP4 and hCASP5, both of which also recognize LPS, but how they control inflammasome responses to bacterial infection is poorly understood. Our recently published and new findings reveal major differences in mouse and human noncanonical inflammasomes and indicate that hCASP4 and hCASP5 have distinct roles. We thus hypothesize that hCASP4- and hCASP5-mediated responses to bacterial infection drive human-specific inflammatory responses. Thus, we will pursue two aims that will examine how hCASP4 and hCASP5 regulate human inflammasome responses to infection and define the bacterial and host factors required for noncanonical inflammasome activation in primary human macrophages. These studies will provide fundamental insight into how noncanonical inflammasomes function in human cells, and will shed critical light on human-specific mechanisms that regulate anti-bacterial immune responses and sepsis.

描述（适用提供）：革兰氏阴性细菌感染仍然是巨大的公共卫生挑战。无法控制感染会导致败血症，这是一种严重的病理学，由对脂多糖（LPS）和其他微生物产物的免疫调查失调。败血症可以发展为多器官衰竭，血压严重下降和化粪池休克。革兰氏阴性感染每年在全球范围内造成超过1000万例败血症病例，死亡率大于30％。至关重要的是，在小鼠中成功治疗败血症的免疫调节剂的一百多个临床试验失败了，导致对人类败血症的有效治疗短缺。这些失败的基础尚不清楚，但是人类和小鼠对感染的先天免疫反应的根本差异可能起重要作用。我们的长期目标是阐明基本的分子机制。人类特异性的先天免疫反应对感染，因为这种知识对于为败血症开发新的治疗方法至关重要。为此，我们研究了革兰氏阴性病原体肺炎。军团菌会引起严重的肺炎军团疾病，如果不及时治疗，可能会发展为败血症。为了引发疾病，通过将细菌病毒因子输送到宿主细胞细胞质中，军团菌感染和在巨噬细胞内复制。翻译细菌产物的胞质免疫检测触发炎症体的组装，多动蛋白复合物激活Cassapase以诱导宿主细胞死亡和IL-1家族细胞因子的释放。我们和其他小组最近发现了对鼠类细胞中对军团菌和其他革兰氏阴性病原体反应的两种类型的炎症：典型的炎性症激活了caspase-1（CASP1），而非官方炎症症可以参与CASPASE-11（MCASP11）（MCASP11）（MCASP11），从而直接检测细胞质LPS。尽管MCASP11对于宿主防御至关重要，但MCASP11也介导了内毒性休克。有趣的是，人类表达了两个MCASP11直系同源物HCASP4和HCASP5，这两者都认可了LP，但是他们如何控制对细菌感染的炎性体反应的理解很少。我们最近发表的新发现揭示了小鼠和人类非教育炎症中的主要差异，并表明HCASP4和HCASP5具有不同的作用。因此，我们假设HCASP4和HCASP5介导的对细菌感染的反应驱动了人类特异性炎性体反应。这是我们将追求两个目标，这些目标将研究HCASP4和HCASP5如何调节人类对感染的炎症反应，并定义原代人类巨噬细胞中非官方炎症体激活所需的细菌和宿主因素。这些研究将提供有关非规范炎症在人类细胞中如何发挥作用的基本见解，并将对调节抗细菌免疫反应和败血症的人类特异性机制进行批判性阐明。