Typhoid Toxin and Salmonella Typhi pathogenesis

伤寒毒素和伤寒沙门氏菌发病机制

基本信息

批准号：
8799676
负责人：
Jorge E Galan
金额：
$ 50.54万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-16 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8799676
关键词：
Accounting Animal Model Applications Grants Bacteria Binding Biology Cells Cessation of life Data Deoxyribonucleases Developing Countries Development Disease Disease Outbreaks Exhibits Food Poisoning Foundations Gastroenteritis Genetic Genome Growth Health Homologous Gene Human Infection Knowledge Laboratories Lead Life Link Location Molecular Mus Neuraminic Acids Pathogenesis Pathway interactions Pertussis Pertussis Toxin Polysaccharides Prevention Prevention strategy Production Publishing Recording of previous events Research Role Salmonella Salmonella enterica Salmonella paratyphi Salmonella typhi Series Site Solutions Specificity Structure Surface Symptoms Therapeutic Toxin Transferase Typhoid Fever United States Vaccines Vacuole Vertebrates Vesicle Virulence Virulence Factors Work autocrine base combat cytolethal distending toxin extracellular genome sequencing insight mouse model novel novel therapeutics paracrine pathogen public health relevance receptor

项目摘要

DESCRIPTION (provided by applicant): Salmonella enterica serovar Typhi (S. Typhi) and the related serovar S. Paratyphi cause typhoid fever in humans, a devastating disease that results in ~500,000 deaths every year. Although most of the cases occur in developing countries, outbreaks occasionally occur in the United States. Unlike other Salmonella enterica serovars, which can infect a variety of hosts and can cause limited gastroenteritis (e. g. food poisoning), S. Typhi and S. Paratyphi are exclusive human pathogen and causes systemic, often lethal, disease. Despite being one of the earliest recognized pathogens in human history, the pathogenesis of S. Typhi still remains poorly understood. The molecular bases for S. Typhi's remarkable host specificity are also poorly understood. Genome sequence data suggest that a combination of genome degradation and acquisition of unique genetic information may account for S. Typhi's unique biology. One of the very few virulence factors that are unique to typhoidal serovars of S. enterica is Typhoid toxin, which was recently discovered in our laboratory. Typhoid toxin is an atypical AB toxin in that it has two enzymatically active subunits: an ADP ribosyl transferase (PltA) and a deoxyribonuclease (CdtB), which are homologs of the active subunits of pertussis and cytolethal distending toxins, respectively. These two subunits are covalently linked to one another and are associated to a homopentameric B subunit composed of PltB. We have recently discovered that systemic administration of purified typhoid toxin can recapitulate many of the symptoms of typhoid fever in mice. This is a very exciting discovery since it not only links typhoid toxin to the pathogenesis of typhoid fever but also provides concrete bases for the development of novel prevention as well as potentially life-saving therapeutic strategies. Typhoid toxin exhibits a remarkable biology in that it is only produced by intracellularly located bacteria, and after its synthesis and assembly, it is released into the Salmonella-containing vacuole. From this location, the toxin is then packaged into vesicle carriers and exported to the extracellular medium, from where it finds its way into target cells by interacting with specific surface receptors. Our laboratory has recently identified the surface receptors for typhoid toxin, which revealed unique insights into the biology of this toxin. In addition, we have discovered that a Rab32 and BLOC-3-dependent pathogen surveillance mechanism restricts the growth of S. Typhi in mice. We intend to leverage these exciting findings to carry out a series of research objectives that, through the study of typhoid toxin, we hope will deepen our understanding of typhoid fever and the pathogenesis of S. Typhi infection.

描述（由申请人提供）：伤寒沙门氏菌（S. Typhi）和相关血清型副伤寒沙门氏菌会引起人类伤寒，这是一种毁灭性的疾病，每年导致约 500,000 人死亡。尽管大多数病例发生在发展中国家，但美国偶尔也会爆发疫情。与其他可感染多种宿主并可引起有限胃肠炎（例如食物中毒）的肠沙门氏菌血清型不同，伤寒沙门氏菌和副伤寒沙门氏菌是人类独有的病原体，可引起全身性疾病，通常是致命的疾病。尽管伤寒沙门氏菌是人类历史上最早认识的病原体之一，但其发病机制仍然知之甚少。伤寒沙门氏菌显着的宿主特异性的分子基础也知之甚少。基因组序列数据表明，基因组降解和独特遗传信息的获取相结合可能解释了伤寒沙门氏菌独特的生物学特性。伤寒毒素是肠沙门氏菌伤寒血清型特有的极少数毒力因子之一，是我们实验室最近发现的。伤寒毒素是一种非典型 AB 毒素，因为它具有两个酶活性亚基：ADP 核糖基转移酶 (PltA) 和脱氧核糖核酸酶 (CdtB)，它们分别是百日咳和细胞致死膨胀毒素活性亚基的同源物。这两个亚基彼此共价连接，并与由 PltB 组成的同五聚体 B 亚基缔合。我们最近发现，全身施用纯化的伤寒毒素可以在小鼠身上重现伤寒的许多症状。这是一个非常令人兴奋的发现，因为它不仅将伤寒毒素与伤寒的发病机制联系起来，而且还为开发新型预防以及可能挽救生命的治疗策略提供了具体基础。伤寒毒素具有显着的生物学特性，因为它仅由细胞内的细菌产生，在合成和组装后，它被释放到含有沙门氏菌的液泡中。从这个位置，毒素被包装到囊泡载体中并输出到细胞外介质，从那里它通过以下方式进入靶细胞：与特定的表面受体相互作用。我们的实验室最近鉴定了伤寒毒素的表面受体，这揭示了对该毒素生物学的独特见解。此外，我们还发现 Rab32 和 BLOC-3 依赖性病原体监测机制限制了小鼠中伤寒沙门氏菌的生长。我们打算利用这些令人兴奋的发现来开展一系列研究目标，希望通过对伤寒毒素的研究，加深我们对伤寒和伤寒沙门氏菌感染发病机制的了解。