Brucella induces STING-mediated Guanylate-Binding Protein expression and Unfolded Protein Response: Balancing Bacterial Elimination, Inflammation and Disease

布鲁氏菌诱导 STING 介导的鸟苷酸结合蛋白表达和未折叠蛋白反应：平衡细菌消除、炎症和疾病

• 批准号: 10617266
• 负责人: Glen N. Barber
• 金额: $ 14.48万
• 依托单位: FOUNDATION FOR RESEARCH DEVELOPMENT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-20 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617266
• 关键词: ATF6 gene; Acids; Adjuvant; Affect; Animals; Anti-Bacterial Agents; Bacterial DNA; Binding Proteins; Biological Response Modifiers; Brazil; Brucella; Brucella abortus; Brucella abortus infection; Brucellosis; CASP1 gene; Caspase; Cattle; Cell Line; Cells; Cellular biology; Cessation of life; Chromosome 3; Cytoplasm; Cytosol; DNA; Data; Disease; Economic Burden; Flow Cytometry; GBP1 gene; Genetically Engineered Mouse; Goals; Health Care Costs; Host resistance; Human; ITGAX gene; Immune; Immune response; Immunity; Infection; Infection Control; Inflammasome; Inflammation; Innate Immune Response; Interferons; Interleukin-1 beta; Interleukin-4; Knockout Mice; Ligands; Macrophage; Measures; Mediating; Metabolic; Microbiology; Mitochondria; Mus; Natural Immunity; Pathogenesis; Pathway interactions; Phenotype; Production; Productivity; Proliferating; Property; Proteins; Quality of life; Research; Research Personnel; Resistance; Resistance to infection; Respiration; Role; Secure; Small Interfering RNA; Social Impacts; Succinates; Testing; Transfection; Vaccines; Vacuole; Zoonoses; chronic infection; conditional knockout; disorder control; experimental study; glucose uptake; guanylate; immune activation; in vivo; inhibitor; innate immune pathways; pathogen; prevent; protein expression; receptor; response; sensor; tauroursodeoxycholic acid; transcription factor; transmission process; vaccine efficacy; vaccine-induced immunity

1 Summary 2 Brucellosis is one of the world’s most frequent zoonotic diseases with over 500,000 3 new human infections every year. Human brucellosis in Brazil represents an additional 4 economic burden due to health care costs and has a major social impact due to 5 decreased productivity and quality of life and occasionally incapacitation or death. 6 Brucella abortus strain 19 vaccine is the principal vaccine used to prevent transmission 7 of brucellosis from cattle to humans worldwide and in Brazil and it is not a select agent. 8 The mechanisms that mediate protection by strain 19 are poorly understood. Host 9 mechanisms of innate immunity induced by the vaccine that control infection remain 10 obscure. Additionally, the vaccine contains several properties that are inhibitory to host 11 immunity. We have demonstrated that B. abortus, bacterial DNA and LPS leads to 12 inflammasome activation via STING/GBP (guanylate-binding protein) axis that limits 13 Brucella replication. In contrast, B. abortus induces the Unfolded Protein Response 14 (UPR) that favors Brucella survival in the host. Therefore, our long-term goal is to 15 resolve the black box of how Brucella activates innate immune components that 16 results in host resistance versus bacterial subversion of the immune response. 17 Based on these compelling preliminary data, we propose to test the central hypothesis 18 that Brucella abortus strain 19 activates protective innate immune mediators via 19 STING/GBP pathway and triggers the UPR to secure intracellular replication. Our 20 specific aims are: 1) To define which STING-mediated guanylated-binding proteins 21 (GBPs) are important to release bacterial DNA and LPS into host cells to activate 22 inflammasome receptors; 2) To determine whether the Unfolded Protein 23 Response (UPR) induced by Brucella regulates macrophage polarization to 24 facilitate bacterial persistence; 3) To determine whether the transcription factor 25 HIF-1α-dependent metabolic changes in macrophages induced by Brucella affect 26 inflammasome activation and bacterial clearance. We believe that our approach will 27 shed light on the mechanisms of immunity and/or pathogenesis of this important 28 human and animal pathogen. Finally, the investigators on this proposal have a strong 29 track record in brucellosis research and a unique combination of key expertise in 30 microbiology, innate immunity and cell biology.

1 总结 2 布鲁氏菌病是世界上最常见的人畜共患疾病之一，有超过 500,000 例 每年新增 3 例人类感染病例。巴西的人类布鲁氏菌病是另一种 4 由于医疗保健费用造成经济负担，并由于以下原因产生重大社会影响 5 生产力和生活质量下降，偶尔会导致丧失能力或死亡。 6 流产布鲁氏菌 19 株疫苗是用于预防传播的主要疫苗 7 布鲁氏菌病从牛传染给全世界和巴西的人类，它不是一种选择性病原体。 8 对菌株 19 介导保护的机制知之甚少。主持人 疫苗诱导的先天免疫控制感染的 9 种机制仍然存在 10 晦涩难懂。此外，该疫苗还含有多种抑制宿主的特性。 11 免疫力。我们已经证明，流产布鲁氏菌、细菌 DNA 和 LPS 会导致 12 通过 STING/GBP（鸟苷酸结合蛋白）轴激活炎症小体，限制 13 布鲁氏菌复制。相反，流产芽孢杆菌诱导未折叠蛋白反应 14 (UPR) 有利于布鲁氏菌在宿主体内存活。因此，我们的长期目标是 15 解决布鲁氏菌如何激活先天免疫成分的黑匣子 16导致宿主抵抗与细菌破坏免疫反应。 17 基于这些令人信服的初步数据，我们建议检验中心假设 18 流产布鲁氏菌菌株 19 通过激活保护性先天免疫介质 19 STING/GBP 通路并触发 UPR 以确保细胞内复制。我们的 20 个具体目标是： 1) 定义哪些 STING 介导的鸟苷酸结合蛋白 21 (GBP) 对于将细菌 DNA 和 LPS 释放到宿主细胞中以激活 22个炎性体受体； 2) 判断是否未折叠蛋白 23 布鲁氏菌诱导的反应 (UPR) 调节巨噬细胞极化 24 促进细菌持久存在； 3) 判断转录因子是否存在 25 布鲁氏菌诱导的巨噬细胞 HIF-1α 依赖性代谢变化影响 26 炎症小体激活和细菌清除。我们相信我们的方法将 27 揭示了这一重要疾病的免疫机制和/或发病机制 28 种人类和动物病原体。最后，这项提案的研究人员有很强的 29 条布鲁氏菌病研究记录和关键专业知识的独特组合 30 微生物学、先天免疫和细胞生物学。