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

1摘要 布鲁氏菌病是世界上最常见的人畜共患病之一，有50多万人感染 每年新增3例人类感染病例。巴西的人类布鲁氏菌病代表着另一种 4由于医疗费用造成的经济负担，以及由于以下原因造成的重大社会影响 5生产力和生活质量下降，偶尔会丧失工作能力或死亡。 6流产布鲁氏菌19株疫苗是用于预防传播的主要疫苗 7布鲁氏菌病在世界范围内从牛到人，在巴西，它不是一个选择的病原体。 8对19号菌株的保护机制知之甚少。寄主 9控制感染的疫苗诱导天然免疫的机制仍然存在 10个不起眼。此外，疫苗还含有几种对宿主有抑制作用的特性。 11豁免权。我们已经证明，流产杆菌、细菌DNA和内毒素可以导致 12通过STING/GBP(鸟巢结合蛋白)轴激活炎症体 13布鲁氏菌复制。相反，流产杆菌可以诱导未折叠的蛋白质反应。 14(UPR)，有利于布鲁氏菌在宿主中存活。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导致宿主抵抗细菌对免疫反应的颠覆。 17基于这些令人信服的初步数据，我们建议检验中心假设 布鲁氏菌19株通过激活保护性天然免疫介质 19刺痛/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)确定哪些刺突介导的鸟苷结合蛋白 21(Gbps)是释放细菌DNA和内毒素进入宿主细胞激活的重要因素 22个炎症体受体；2)确定未折叠的蛋白 布鲁氏菌诱导的UPR对巨噬细胞极化的调节作用 24促进细菌持久性；3)确定转录因子是否 布鲁氏菌感染诱导巨噬细胞α依赖的HIF-1代谢变化 26炎症小体激活和细菌清除。我们相信，我们的做法将 27阐明了这一重要的免疫和/或发病机制 28人和动物病原体。最后，对这一提案的调查人员有很强的 29布鲁氏菌病研究的记录和在以下领域的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。

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.