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The Pathogenesis of Enteric Fever

肠热病的发病机制

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘