Typhoid Toxin and Salmonella Typhi pathogenesis

伤寒毒素和伤寒沙门氏菌发病机制

• 批准号: 9330055
• 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
• 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/9330055
• 关键词: Animal Model; Applications Grants; Bacteria; Binding; Biology; Cells; Cessation of life; Crystallization; 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; Pathogenicity; Pathway interactions; Pertussis; Pertussis Toxin; Polysaccharides; Prevention; Prevention strategy; Production; Publishing; Recording of previous events; Research; Role; Salmonella; Salmonella enterica; Salmonella paratyphi; Salmonella typhi; Savings; 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; insight; mouse model; novel; novel therapeutics; paracrine; pathogen; public health relevance; receptor

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(伤寒沙门氏菌)和相关的副伤寒沙门氏菌在人类中引起伤寒，这是一种毁灭性的疾病，每年导致约500,000人死亡。虽然大多数病例发生在发展中国家，但美国偶尔也会爆发疫情。伤寒沙门氏菌和副伤寒沙门氏菌不同于其他沙门氏菌血清型，它们可以感染多种宿主并引起局限性胃肠炎(如食物中毒)，它们是人类独有的病原体，可引起系统性疾病，通常是致命的。尽管伤寒沙门氏菌是人类历史上最早发现的病原体之一，但其发病机制仍然知之甚少。伤寒沙门氏菌显著的宿主特异性的分子基础也鲜为人知。基因组序列数据表明，基因组退化和独特遗传信息的获取相结合可能是伤寒沙门氏菌独特生物学的原因。伤寒毒素是我们实验室最近发现的为数不多的伤寒血清型独有的毒力因子之一。伤寒毒素是一种非典型的AB毒素，因为它有两个具有酶活性的亚基：ADP核糖基转移酶(PltA)和脱氧核糖核酸酶(CDtB)，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亚基相连。我们最近发现，全身注射纯化的伤寒毒素可以重现小鼠伤寒的许多症状。这是一个非常令人振奋的发现，因为它不仅将伤寒毒素与伤寒的发病机制联系起来，而且为开发新的预防以及潜在的挽救生命的治疗策略提供了具体的基础。伤寒毒素有一个显著的生物学特性，它只由细胞内的细菌产生，合成和组装后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，在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。我们实验室最近发现了伤寒毒素的表面受体，这为伤寒毒素的生物学提供了独特的见解。此外，我们还发现依赖Rab32和BLOC-3的病原体监控机制限制了伤寒沙门氏菌在小鼠体内的生长。我们打算利用这些令人振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感染发病机制的理解。