Typhoid Toxin and Salmonella Typhi pathogenesis

描述（由申请方提供）：伤寒沙门氏菌（S.伤寒）和相关血清型S.副伤寒引起人类伤寒，这是一种毁灭性的疾病，每年导致约50万人死亡。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。与其他肠道沙门氏菌血清型不同，它可以感染各种宿主，并可引起有限的胃肠炎（如。G.食物中毒）、S.伤寒和沙门氏菌。副伤寒是人类独有的病原体，引起全身性疾病，通常是致命的。尽管是人类历史上最早认识到的病原体之一，但S.人们对伤寒仍然知之甚少。S.伤寒显著的宿主特异性也知之甚少。基因组序列数据表明，基因组降解和获得独特的遗传信息的组合可能解释了S。伤寒独特的生物学特性。伤寒沙门氏菌是伤寒血清型特有的极少数毒力因子之一。enterica是我们实验室最近发现的伤寒毒素。伤寒毒素是一种非典型的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性膨胀毒素的活性亚基的同源物。这两个亚基彼此共价连接，并与由Plt B组成的同型五聚体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中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。伤寒毒素表现出显著的生物学特性，因为它仅由位于细胞内的细菌产生，并且在其合成和组装之后，其被释放到含有沙门氏菌的液泡中。从这个位置，毒素然后被包装到囊泡载体中并输出到细胞外介质，从那里它通过以下途径进入靶细胞： 与特定的表面受体相互作用。我们的实验室最近确定了伤寒毒素的表面受体，这揭示了对这种毒素生物学的独特见解。此外，我们发现Rab 32和BLOC-3依赖的病原体监视机制限制了S.小鼠伤寒。我们打算利用这些令人兴奋的发现来开展一系列的研究目标，通过对伤寒毒素的研究，我们希望加深我们对伤寒和S.伤寒感染。

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.