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: 10401750
• 负责人: Glen N. Barber
• 金额: $ 14.49万
• 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/10401750
• 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; Cytosol; DNA; Data; Disease; Economic Burden; Equilibrium; 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; Light; Measures; Mediating; Metabolic; Microbiology; Mitochondria; Mus; Natural Immunity; Pathogenesis; Pathway interactions; Phenotype; Production; Productivity; Property; Proteins; Quality of life; Research; Research Personnel; Resistance; Resistance to infection; Respiration; Role; Secure; Small Interfering RNA; Social Impacts; Succinates; Testing; Vaccines; Vacuole; Zoonoses; base; chronic infection; conditional knockout; disorder control; experimental study; glucose uptake; guanylate; immune activation; in vivo; inhibitor; innate immune pathways; macrophage; pathogen; prevent; protein expression; receptor; response; sensor; tauroursodeoxycholic acid; transcription factor; transmission process; vaccine efficacy; vaccine-induced immunity; 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; Cytosol; DNA; Data; Disease; Economic Burden; Equilibrium; 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; Light; Measures; Mediating; Metabolic; Microbiology; Mitochondria; Mus; Natural Immunity; Pathogenesis; Pathway interactions; Phenotype; Production; Productivity; Property; Proteins; Quality of life; Research; Research Personnel; Resistance; Resistance to infection; Respiration; Role; Secure; Small Interfering RNA; Social Impacts; Succinates; Testing; Vaccines; Vacuole; Zoonoses; base; chronic infection; conditional knockout; disorder control; experimental study; glucose uptake; guanylate; immune activation; in vivo; inhibitor; innate immune pathways; macrophage; 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个摘要 2巴布鲁病是世界上最常见的人畜共患病之一，超过500,000 每年3种新的人类感染。巴西的人布鲁克病代表 4由于医疗保健成本而造成的经济烧伤，由于 5降低生产力和生活质量，偶尔丧失能力或死亡。 6布鲁氏菌流产菌株19疫苗是用于防止传播的主要疫苗 从牛到巴西的人类和巴西的人性病中有7个，这不是精选的药物。 8对菌株19介导保护的机制知之甚少。主持人 9疫苗诱导的对照感染诱导的先天免疫机制仍然存在 10晦涩。此外，该疫苗包含几种抑制性宿主的特性 11免疫。我们已经证明了B. abortus，细菌DNA和LPS 12通过刺激/GBP（鸟苷结合蛋白）轴的炎症体激活 13布鲁氏菌复制。相比之下，Abortus诱导展开的蛋白质反应 14（UPR）有利于宿主中布鲁氏菌的生存。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导致宿主抗性与免疫响应的细菌颠覆。 17基于这些引人入胜的初步数据，我们建议测试中心假设 18布鲁氏菌菌株19通过 19 Sting/GBP途径并触发UPR以确保细胞内复制。我们的 20个具体目标是：1）定义哪个刺激介导的鸟苷结合蛋白 21（GBP）对于将细菌DNA和LP释放到宿主细胞中很重要以激活 22个炎性体受体； 2）确定是否展开的蛋白质 23布鲁氏菌诱导的反应（UPR）调节巨噬细胞极化 24个最喜欢的细菌持久性； 3）确定转录因子是否 25 HIF-1α依赖性代谢变化在布鲁氏菌诱导的巨噬细胞中 26炎性体激活和细菌清除率。我们相信我们的方法会 27阐明了这种重要的免疫和/或发病机理的机制 28人类和动物病原体。最后，该提案的调查人员有很强的 29布鲁氏菌病研究的往绩以及关键专业知识的独特组合 30微生物学，先天免疫学和细胞生物学。