Cracking Salmonella Typhis Secret Code: Understanding Pathogenic Mechanisms of Salmonella Typhi Toxin

项目摘要/摘要 伤寒是由伤寒沙门氏菌引起的最成功的传染病之一。 人类历史上最严重的疾病，仍是一个重大的全球健康威胁，发展中国家的疫情仍在持续。 国家。每年有20万人死于伤寒，2100万人患病。多药耐药株 伤寒沙门氏菌正在迅速蔓延。替代抗生素的最有效的对策之一是 针对伤寒的基本毒力机制。然而，人们对其致病机理知之甚少。 伤寒沙门氏菌特有的机制。伤寒沙门氏菌特有的一种基本毒力因子是最近发现的 毒素：伤寒毒素。伤寒毒素具有许多独特的结构和功能特征。这种毒素由三种毒素组成 亚基，CDtB(核酸酶)，PltA(单ADP核糖基转移酶)，以及PltB的同型五聚体(受体结合)， 导致其独特的A2B5化学计量比。当用在实验动物身上时，伤寒毒素会重现 伤寒的许多典型症状，如嗜睡、虚弱、昏迷、白细胞减少和 神经系统并发症。预计伤寒毒素在人类感染过程中也发挥类似的作用，如 临床报告显示，猪伤寒血清中存在大量抗伤寒毒素抗体，这支持了这一点 伤寒恢复期患者，以及我们最近的研究表明特定的糖链的表达 导致伤寒症状的细胞上的伤寒毒素受体。然而，我们仍然没有很好的 了解伤寒毒素的每个亚基是如何影响其毒力的。为了填补我们知识上的这一空白， 在这里，我们的目的是定义伤寒毒素亚单位在毒力中的确切作用(S)，重点是 PltA和PltB。拟议的研究具有重要意义，因为这项工作将为 针对伤寒沙门氏菌致病机制和减毒的有效策略的发展 伤寒沙门氏菌的毒力。

PROJECT SUMMARY/ABSTRACT Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), is one of the most successful infectious diseases in human history and remains a major global health threat with continuing outbreaks in developing countries. Typhoid fever kills 0.2 million and sickens 21 million people every year. Multidrug-resistant strains of S. Typhi is rapidly spreading. One of the most effective countermeasures alternative to antibiotics would be targeting essential virulence mechanisms of typhoid fever. However, little is known about the pathogenic mechanisms specific to S. Typhi. One such essential virulence factor specific to S. Typhi is a recently discovered toxin: typhoid toxin. Typhoid toxin has many unique structural and functional features. This toxin consists of three subunits, CdtB (nuclease), PltA (mono ADP ribosyltransferase), and a homopentamer of PltB (receptor binding), resulting in its unique A2B5 stoichiometry. When administered to laboratory animals, typhoid toxin recapitulated many of the characteristic symptoms of typhoid fever, such as lethargy, malaise, stupor, leukopenia, and neurological complications. It is expected that typhoid toxin plays a similar role during human infection, as supported by clinical reports indicating the abundant presence of anti-typhoid toxin antibodies in the sera of convalescent typhoid patients, as well as our recent studies demonstrating the expression of the specific glycan receptor for typhoid toxin on cells resulting in typhoid symptoms. However, we still do not have a good understanding of how each subunit of typhoid toxin contributes to its virulence. To fill this gap in our knowledge, here we aim to define the precise role(s) of typhoid toxin’s subunits in virulence, with an emphasis on roles of PltA and PltB. The proposed research is significant because this work will offer important insights into the development of effective strategies for targeting the pathogenic mechanisms specific to S. Typhi and attenuating S. Typhi virulence.