Mechanism of innate immune recognition of cyclic-di-GMP

环二GMP的先天免疫识别机制

• 批准号: 8107576
• 负责人: Dara L Burdette
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107576
• 关键词: Adjuvant Therapy; Bacteria; Bacterial Infections; Bacterial RNA; Binding; Binding Proteins; Brucella abortus; Cell Line; Cell Wall; Cell surface; Cells; Cytosol; DNA; Data; Detection; Drug Design; Enzymes; Eukaryotic Cell; Francisella tularensis; Gene Expression; Genes; Goals; Grant; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Interferon Inducers; Interferon Type I; Interferons; Invaded; Learning; Legionella pneumophila; Ligand Binding; Lipopolysaccharides; Listeria monocytogenes; Measures; Mediating; Microbial Biofilms; Molecular; Mycobacterium tuberculosis; Nucleic Acids; Organism; Pathway interactions; Pattern; Pattern recognition receptor; Peptidoglycan; Physiological; Production; RNA Interference; Radiolabeled; Research; Role; Signal Pathway; Signaling Molecule; Testing; Transfection; Vaccine Adjuvant; Vaccines; Validation; Viral; Virulence; Virulence Factors; Work; bis(3' ,5' )-cyclic diguanylic acid; cell motility; cellular transduction; cytokine; design; diguanylate cyclase; extracellular; gene induction; interest; macrophage; microbial; microorganism; mutant; novel; novel vaccines; pathogen; phosphoric diester hydrolase; promoter; public health relevance; radiotracer; receptor; research study; response; sensor

DESCRIPTION (provided by applicant): The innate immune system detects the presence of invading microorganisms through a panel of pattern recognition receptors. These receptors can sense the presence of intracellular or extracellular microbial patterns such as DNA, RNA, and bacterial cell wall components. Activation of signaling pathways downstream of ligand binding leads to the induction of pro-inflammatory cytokines such as type I Interferons (IFN). While the induction of IFN is typically considered an anti-viral mechanism, bacterial pathogens also induce type I interferon during infection. Interestingly, the mechanisms underlying IFN induction during infection are largely unknown. In general, we are interested in mechanisms by which recognition of bacteria by the innate immune results in the induction of IFN. Our specific interest focuses on cyclic-di-GMP (c-di-GMP), a bacterial signaling molecule that regulates biofilm formation, motility and virulence. This molecule has recently been proposed to induce a type I interferon response following translocation into host cells. However, the direct host intracellular molecular sensor has yet to be identified. The proposed works seeks to confirm the cytosolic sensing of c-di-GMP, identify bacterial pathogens that induce IFN through cytosolic sensing of c-di-GMP, and identify the eukaryotic molecule(s) essential for cytosolic recognition of c-di-GMP and induction of IFN. C-di-GMP is a molecule produced exclusively by bacteria and eukaryotic organisms do not appear to possess the enzymes required for its synthesis. Therefore, this molecule represents a unique target for drug design. Research into understanding the mechanism of cytosolic detection of c-di-GMP will aid in generating better vaccines, adjuvants and therapies. PUBLIC HEALTH RELEVANCE: Bacterial pathogens use cyclic-di-GMP to regulate virulence factors. In addition, host cells sense this molecule during infection leading to a potent immune response against the bacteria. The goal of this application is to identify the essential host components required to respond to cyclic-di-GMP during infection. Understanding the innate immune system's response to cyclic-di-GMP is an essential aspect of designing effective vaccines against bacterial pathogens.

描述（由申请人提供）：先天免疫系统通过一系列模式识别受体检测出入侵的微生物的存在。这些受体可以感觉到存在细胞内或细胞外微生物模式，例如DNA，RNA和细菌细胞壁成分。配体结合下游信号通路的激活导致促炎性细胞因子（例如I型干扰素）的诱导（IFN）。虽然IFN的诱导通常被认为是一种抗病毒机制，但细菌病原体也会在感染过程中诱导I型干扰素。有趣的是，感染过程中IFN诱导的基础机制在很大程度上未知。通常，我们对通过先天免疫对细菌识别的机制感兴趣，从而导致IFN诱导。我们的具体兴趣集中在环状-DI-GMP（C-DI-GMP）上，这是一种调节生物膜形成，运动性和毒力的细菌信号分子。最近提出了该分子诱导I型干扰素反应后，转移到宿主细胞中。但是，直接宿主细胞内分子传感器尚未鉴定。拟议的作品旨在确认C-DI-GMP的胞质感应，鉴定通过C-DI-GMP诱导IFN的细菌病原体，并确定对C-DI-GMP胞质识别必不可少的真核分子（S）和IFN的诱导。 C-DI-GMP是仅由细菌产生的分子，而真核生物似乎没有其合成所需的酶。因此，该分子代表了药物设计的独特目标。研究了解C-DI-GMP的胞质检测机制将有助于产生更好的疫苗，佐剂和疗法。 公共卫生相关性：细菌病原体使用环状-DI-GMP调节毒力因素。此外，宿主细胞在感染过程中感觉到该分子导致对细菌的有效免疫反应。该应用程序的目的是确定感染过程中对环状-DI-GMP响应所需的基本宿主组件。了解先天免疫系统对环状-DI-GMP的反应是针对细菌病原体设计有效疫苗的重要方面。