Mechanism of innate immune recognition of cyclic-di-GMP

环二GMP的先天免疫识别机制

• 批准号: 8287085
• 负责人: Dara L Burdette
• 金额: $ 5.39万
• 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/8287085
• 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; radiotracer; receptor; research study; response; sensor

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.

先天免疫系统通过一组模式识别受体检测入侵微生物的存在。这些受体可以感知细胞内或细胞外微生物模式的存在，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细胞因子的诱导，例如 I 型干扰素 (IFN)。虽然诱导干扰素通常被认为是一种抗病毒机制，但细菌病原体在感染过程中也会诱导 I 型干扰素。有趣的是，感染期间诱导干扰素的机制在很大程度上尚不清楚。一般来说，我们感兴趣的是先天免疫识别细菌导致干扰素诱导的机制。我们的具体兴趣集中在环二 GMP (c-di-GMP)，这是一种调节生物膜形成、运动性和毒力的细菌信号分子。最近有人提出，这种分子在易位到宿主细胞后可诱导 I 型干扰素反应。然而，直接宿主细胞内分子传感器尚未确定。拟议的工作旨在确认 c-di-GMP 的细胞溶质感应，识别通过 c-di-GMP 的细胞溶质感应诱导 IFN 的细菌病原体，并鉴定细胞溶质识别 c-di-GMP 所必需的真核分子和IFN的诱导。 C-di-GMP 是一种仅由细菌产生的分子，真核生物似乎不具备合成其所需的酶。因此，该分子代表了药物设计的独特靶点。研究了解 c-di-GMP 的胞质检测机制将有助于生产更好的疫苗、佐剂和疗法。