The Pathogenesis of Enteric Fever

肠热病的发病机制

• 批准号: 10557903
• 负责人: Ferric C Fang
• 金额: $ 69.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-24 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557903
• 关键词: Animal Model; Apoptotic; Aromatic Amino Acids; Biochemical; Blood Cells; CASP3 gene; Cell Death; Cells; Cessation of life; Chronic; Clinical; Cytoplasm; Engraftment; Foundations; Genetic; Hematopoietic; Hematopoietic System; Human; In Vitro; Induction of Apoptosis; Infection; Intestines; Iron; Laboratories; Lactobacillus; Macrophage; Molecular; Mononuclear; Morbidity - disease rate; Mus; Natural Immunity; Observational Study; Paratyphoid Fever; Pathogenesis; Pathogenicity Island; Pathway interactions; Phagocytes; Play; Prevention; Research; Resistance; Role; STAT1 gene; Salmonella; Salmonella infections; Salmonella paratyphi; Salmonella typhi; Salmonella typhimurium; Serum; Stress; System; Testing; Type III Secretion System Pathway; Typhoid Fever; Vi capsular polysaccharide; Virulence; aminoacid biosynthesis; antagonist; antimicrobial peptide; biological adaptation to stress; cell envelope; chronic infection; cytotoxic; cytotoxicity; deprivation; emerging pathogen; genome-wide analysis; gut colonization; gut inflammation; gut microbiota; humanized mouse; microbiota; mortality; mouse model; non-typhoidal Salmonella; novel; novel strategies; novel therapeutic intervention; prevent; response; transplant model; treatment strategy; vaccine trial

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.

项目摘要/摘要 由沙门氏菌血清S. typhi和S. paratyphi引起的肠发烧，占近1500万 每年感染和136,000人死亡。我们已经开发了一种新型的致命小动物模型 使用与功能性人类造血系统的人源化小鼠发烧。 S. typhi的能力 和副链球菌A在与人造血细胞接合的人源性小鼠中引起致命感染 表明人类巨噬细胞是肠发烧的发病机理所必需的，可能会提供 持续感染的水库。人性化小鼠中斑链球菌的全基因组分析证实了一些 怀疑的基本病毒确定了，但也揭示了鼠伤寒和 非细类沙门氏菌血清射手。此外，我们发现S. typhi持续存在于文化的人类中 由于缺乏多个SPI-2 III型分泌系统，巨噬细胞通过预防凋亡细胞死亡 在非锥状沙门氏菌发病机理中起着核心作用的效应子。 NF-κB抑制选择性杀死S。 Typhi感染的巨噬细胞，提出了一种治疗慢性启动子发烧的新策略。最近 我们还发现，肠发烧和非细类沙门氏菌的反应有显着差异 铁剥夺，观察到肠道微生物群拮抗孢子链球菌肠道定殖，并且 在与人类的相互作用中，帕托氏链球菌A和S. typhi之间表现出了重要的相似之处 巨噬细胞和人性化小鼠。 我们的中心假设是肠发烧沙门氏菌血清射手的病毒取决于 逃避先天免疫力和巨噬细胞的持久性。研究计划将检查三个 具体目的： 1。避免肠发烧沙门氏菌血清射击巨噬细胞死亡。遗传和生化 方法将阐明链球菌促进巨噬细胞存活和 评估巨噬细胞存活与人性化小鼠中Typhi病毒的相关性。 2。鼠伤寒沙门氏菌与肠道菌群的相互作用。外质应力的贡献 反应，菌群拮抗和避免巨噬细胞细胞毒性对伤寒链球菌的能力 将研究持续定植的肠道。 3。沙门氏菌的毒力。对链球菌的系统分析确定及其 将执行血清耐药性，采集和巨噬细胞持久性的机制。 拟议的研究将提高我们对肠发烧发病机理的理解，并导致新颖 预防和治疗的策略。