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: 10404508
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404508
• 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; Persons; Play; Polysaccharides; Prevalence; Process; Proteins; Publishing; Recording of previous events; Reporting; Research; Role; Salmonella; Salmonella typhi; Southeastern Asia; 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.

项目总结/摘要 伤寒，由伤寒沙门氏菌引起。伤寒），是最成功的传染病之一， 疾病，仍然是一个主要的全球健康威胁，在发展中国家持续爆发， 国家伤寒每年造成20万人死亡，2100万人患病。多重耐药菌株 S.伤寒正在迅速蔓延。抗生素最有效的替代措施之一是 针对伤寒的基本毒力机制。然而，对致病性 S.伤寒其中一个重要的毒力因子是S.伤寒是最近发现的 伤寒毒素。伤寒毒素具有许多独特的结构和功能特征。这种毒素由三种成分组成 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）， 导致其独特的A2 B5化学计量。当给实验室动物注射伤寒毒素时， 伤寒的许多特征性症状，如嗜睡、不适、昏迷、白细胞减少， 神经系统并发症预期伤寒毒素在人类感染期间起类似作用， 临床报告表明，在患者血清中存在大量的抗伤寒毒素抗体， 恢复期伤寒患者，以及我们最近的研究表明，表达的特定聚糖 细胞上伤寒毒素的受体导致伤寒症状。然而，我们仍然没有一个好的 了解伤寒毒素的每个亚单位如何影响其毒力。为了填补我们知识上的空白， 在这里，我们的目标是确定伤寒毒素的亚单位在毒力中的确切作用，重点是 PltA和PltB。拟议的研究是重要的，因为这项工作将提供重要的见解 发展针对S.伤寒和减毒型 S.伤寒毒力。