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：
9121477
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/9121477
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 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 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 genetic information genome sequencing insight mouse model novel novel therapeutics paracrine pathogen 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）：肠道沙门氏菌血清鼠伤寒（S. typhi）和相关的血清链球菌在人类中引起伤寒，这是一种毁灭性的疾病，每年造成约500,000人死亡。尽管大多数案件发生在发展中国家，但爆发偶尔发生在美国。与其他可以感染各种宿主并可能导致胃肠炎有限（例如食物中毒）的肠道肠道血清射手不同，typhi链球菌和副链球菌是人类病原体的独家病原体，并引起全身性，通常是致命的，疾病。尽管是人类历史上最早公认的病原体之一，但鼠伤寒沙门氏菌的发病机理仍然知之甚少。 S. typhi显着的宿主特异性的分子碱基也很少了解。基因组序列数据表明，基因组降解和对独特遗传信息的获取的结合可能解释了S. typhi的独特生物学。肠形肠链球菌伤寒的毒力因子极少数是伤寒毒素，最近在我们的实验室中发现了伤寒毒素。伤寒毒素是一种非典型的AB毒素，它具有两个酶活性亚基：ADP核糖基转移酶（PLTA）和一个脱氧核糖核酸酶（CDTB），它们是百日咳和细胞降低差异毒素的活性亚基的同源物。这两个亚基相互共价链接，并与由PLTB组成的同型B亚基相关联。我们最近发现，纯化伤寒毒素的全身给药可以概括小鼠伤寒的许多症状。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发烧的发病机理联系起来，而且还为开发新型预防以及潜在的挽救生命的治疗策略提供了具体基础。伤寒毒素表现出显着的生物学，因为它仅由细胞内细菌产生，在其合成和组装后，它被释放到含沙门氏菌的液泡中。然后从这个位置将毒素包装到囊泡载体中，并导出到细胞外培养基中，从那里从那里找到了它的方式与特定的表面受体相互作用。我们的实验室最近确定了伤寒毒素的表面受体，该受体揭示了对这种毒素的生物学的独特见解。此外，我们发现RAB32和BLOC-3依赖性病原体监测机制限制了小鼠孢子链球菌的生长。我们打算利用这些令人兴奋的发现来实现一系列研究目标，通过研究伤寒毒素，我们希望我们将加深对伤寒和伤寒链球菌感染的发病机理的理解。