The Pathogenesis of Enteric Fever

项目概要/摘要 由沙门氏菌血清型S.伤寒和沙门氏菌。副伤寒，占近1500万 每年有13.6万人感染和死亡。我们已经开发了一种新的致命的小动物模型， 使用移植有功能性人类造血系统的人源化小鼠的发热。S.伤寒 和S.甲型副伤寒在植入人造血细胞的人源化小鼠中引起致死性感染 提示人类巨噬细胞是肠热病发病所必需的，并可能提供一种 持续感染的储存库。对S.人源化小鼠中的伤寒证实了一些 怀疑的基本毒力决定因子，但也揭示了意想不到的差异之间的S。伤寒和 非伤寒沙门氏菌血清型。此外，我们还发现S.伤寒在培养的人中持续存在 由于缺乏多个SPI-2 III型分泌系统， 在非伤寒沙门氏菌发病机制中发挥核心作用的效应物。NF-κB抑制选择性地杀死S. 伤寒感染的巨噬细胞，提示一种新的策略，用于治疗慢性肠热病。最近 我们还发现，伤寒沙门氏菌和非伤寒沙门氏菌对 铁剥夺，观察到肠道微生物群拮抗S.伤寒肠内定植，以及 证明了S之间的重要相似之处。甲型副伤寒和甲型副伤寒伤寒与人类的相互作用 巨噬细胞和人源化小鼠。 我们的中心假设是，伤寒沙门氏菌血清型的毒力取决于 逃避先天免疫和在巨噬细胞中的持久性。该研究计划将研究三个 具体目标： 1.肠热沙门氏菌血清型对巨噬细胞死亡的避免。遗传和生化 的方法将阐明S.伤寒促进巨噬细胞存活， 评估巨噬细胞存活与S.人源化小鼠中的伤寒毒力。 2.伤寒沙门氏菌与肠道微生物群的相互作用。细胞质外应激的作用 反应、微生物群拮抗作用和避免巨噬细胞对S.伤寒至 将研究持续定殖于肠道的细菌。 3.甲型副伤寒沙门氏菌毒力系统分析了S.甲型副伤寒毒力决定因子及其临床意义 将进行血清抗性、铁获得和巨噬细胞持久性的机制。 这些研究将促进我们对肠热病发病机制的理解，并导致新的 预防和治疗的策略。

PROJECT SUMMARY/ABSTRACT Enteric fever, caused by the Salmonella serovars S. Typhi and S. Paratyphi, accounts for nearly 15 million infections and 136,000 deaths each year. We have developed a novel lethal small animal model for enteric fever using humanized mice engrafted with a functional human hematopoietic system. The ability of S. Typhi and S. Paratyphi A to cause lethal infections in humanized mice engrafted with human hematopoietic cells suggests that human macrophages are required for the pathogenesis of enteric fever and may provide a reservoir for persistent infection. A genome-wide analysis of S. Typhi in humanized mice confirms some suspected essential virulence determinants but also reveals unexpected differences between S. Typhi and non-typhoidal Salmonella serovars. Moreover, we have discovered that S. Typhi persists in cultured human macrophages by preventing apoptotic cell death, due to the absence of multiple SPI-2 type III secretion system effectors that play a central role in non-typhoidal Salmonella pathogenesis. NF-κB inhibition selectively kill S. Typhi-infected macrophages, suggesting a novel strategy for the treatment of chronic enteric fever. Recently we have also found significant differences in the responses of enteric fever and non-typhoidal Salmonella to iron deprivation, observed that the gut microbiota antagonizes S. Typhi intestinal colonization, and demonstrated important parallels between S. Paratyphi A and S. Typhi in their interactions with human macrophages and humanized mice. Our central hypothesis is that the virulence of enteric fever Salmonella serovars depends on the evasion of innate immunity and persistence in macrophages. The research plan will examine three specific aims: 1. Avoidance of Macrophage Cell Death by Enteric Fever Salmonella Serovars. Genetic and biochemical approaches will elucidate the molecular mechanisms by which S. Typhi promotes macrophage survival and assess the relevance of macrophage survival to S. Typhi virulence in humanized mice. 2. Interactions of Salmonella Typhi with the Gut Microbiota. The contributions of extracytoplasmic stress responses, microbiota antagonism and avoidance of macrophage cytotoxicity to the ability of S. Typhi to persistently colonize the intestinal tract will be investigated. 3. Salmonella Paratyphi A Virulence. A systematic analysis of S. Paratyphi A virulence determinants and its mechanisms of serum resistance, iron acquisition and macrophage persistence will be performed. The proposed studies will advance our understanding of enteric fever pathogenesis and lead to novel strategies for its prevention and treatment.