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

破解伤寒沙门菌密码：了解伤寒沙门菌毒素的致病机制

• 批准号: 10164712
• 负责人: Jeongmin Song
• 金额: $ 53.86万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-04 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164712
• 关键词: ADP Ribose Transferases; Acute; Address; Africa South of the Sahara; Antibiotic Therapy; Antibiotics; Antibodies; Antimicrobial Resistance; Area; Attenuated; Binding; Biology; Category B pathogen; Cell Nucleus; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Child; Clinical; Code; Communicable Diseases; Cytoplasm; Developing Countries; Development; Disease; Disease Outbreaks; Endocytosis; Environment; Goals; Homologous Gene; Human; Infection; Intoxication; Knowledge; Laboratory Animals; Lethargies; Leukopenia; Malaise; Mediating; Molecular; Mono(ADP-Ribose) Transferases; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Neurologic; Pathogenicity; Patients; Play; Polysaccharides; Prevalence; Process; Proteins; Publishing; Recording of previous events; Reporting; Research; Role; Salmonella; Salmonella typhi; Southeastern Asia; Structure; Stupor; Symptoms; Testing; Tissues; Toxin; Typhoid Fever; Vacuole; Vesicle; Virulence; Virulence Factors; Work; base; combat; epidemiology study; extracellular; global health; holotoxins; in vivo; insight; novel; novel strategies; nuclease; priority pathogen; receptor; receptor binding; resistant strain; small molecule therapeutics; stoichiometry; therapeutic protein; therapeutic target; trafficking

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.

项目概要/摘要 伤寒由肠伤寒沙门氏菌（S. Typhi）引起，是最成功的传染病之一 人类历史上的疾病，仍然是全球主要健康威胁，发展中国家持续爆发 国家。伤寒每年导致 20 万人死亡，2100 万人患病。多重耐药菌株 伤寒沙门氏菌正在迅速传播。抗生素最有效的替代对策之一是 针对伤寒的基本毒力机制。然而，人们对致病菌知之甚少 伤寒沙门氏菌特有的机制。最近发现的一种针对伤寒沙门氏菌的重要毒力因子 毒素：伤寒毒素。伤寒毒素具有许多独特的结构和功能特征。这种毒素由三部分组成 亚基、CdtB（核酸酶）、PltA（单 ADP 核糖基转移酶）和 PltB 的同五聚体（受体结合）， 从而产生其独特的 A2B5 化学计量。当给实验动物施用时，伤寒毒素重现 伤寒的许多特征性症状，如嗜睡、不适、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着类似的作用，因为 临床报告表明，患者血清中存在丰富的抗伤寒毒素抗体。 恢复期伤寒患者，以及我们最近的研究证明了特定聚糖的表达 细胞上的伤寒毒素受体导致伤寒症状。然而，我们仍然没有一个好的办法 了解伤寒毒素的每个亚基如何增强其毒力。为了填补我们知识上的空白， 在这里，我们的目标是定义伤寒毒素亚基在毒力中的精确作用，重点是 PltA 和 PltB。拟议的研究意义重大，因为这项工作将为我们提供重要的见解 制定针对伤寒沙门氏菌特异性致病机制并减弱的有效策略 伤寒沙门氏菌毒力。