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：
9079707
负责人：
Sunny Shin
金额：
$ 40.15万
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/9079707
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 Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Host Defense Human Immune Immune response Immunomodulators Infection Infection Control Inflammation Inflammatory Inflammatory 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 Organ failure Orthologous Gene Outcome 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 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（由申请人提供）：革兰氏阴性细菌感染仍然是一个巨大的公共卫生挑战，无法控制感染可能会导致脓毒症，这是一种由脂多糖（LPS）和其他微生物产物的免疫反应失调引起的严重病理学，脓毒症可能会发展为脓毒症。多器官衰竭、血压严重下降和感染性休克每年导致全世界超过 1000 万例败血症，死亡率超过 30%。重要的是，成功治疗小鼠脓毒症的免疫调节剂的一百多项临床试验都失败了，导致人类脓毒症缺乏有效的治疗方法。这些失败的原因尚不清楚，但人类和小鼠对感染的先天免疫反应可能存在根本差异。我们的长期目标是阐明人类对感染的特异性先天免疫反应的分子机制，因为这些知识对于开发败血症的新疗法至关重要。为此，我们研究了革兰氏阴性病原体军团菌。嗜肺军团菌会引起严重的军团菌肺炎，如果不及时治疗，可能会发展为败血症，军团菌会通过将细菌毒力因子传递到宿主细胞胞浆中来感染并在巨噬细胞内复制。对易位细菌产物的胞质免疫检测会触发炎症小体的组装，这是一种多蛋白复合物，可激活半胱天冬酶，诱导宿主细胞死亡并释放 IL-1 家族细胞因子，我们和其他小组最近在小鼠细胞中发现了两种类型的炎症小体，它们对军团菌和其他细菌有反应。革兰氏阴性病原体：典型炎症小体激活 caspase-1 (CASP1)，而非典型炎症小体则参与caspase-11 (mCASP11)，直接检测胞质 LPS。虽然 mCASP11 对于宿主防御至关重要，但 mCASP11 也介导内毒素休克。有趣的是，人类表达两种 mCASP11 直向同源物，hCASP4 和 hCASP5，它们也识别 LPS，但它们如何控制。我们对炎症小体对细菌感染的反应知之甚少，我们最近发表的新发现揭示了小鼠和人类的主要差异。并表明 hCASP4 和 hCASP5 具有不同的作用，因此我们观察到 hCASP4 和 hCASP5 介导的细菌感染反应驱动人类特异性炎症反应，因此，我们将追求两个目标，即检查 hCASP4 和 hCASP5 如何调节人类炎症体。对感染的反应并确定原代人类巨噬细胞中非典型炎症小体激活所需的细菌和宿主因素。这些研究将为了解如何激活提供基础见解。非典型炎症小体在人类细胞中发挥作用，将为调节抗菌免疫反应和败血症的人类特异性机制提供重要线索。