Typhoid Toxin and Salmonella Typhi pathogenesis

伤寒毒素和伤寒沙门氏菌发病机制

• 批准号: 10461034
• 负责人: Jorge E Galan
• 金额: $ 57.7万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461034
• 关键词: ADP Ribose Transferases; Acute; Animal Model; Animals; Applications Grants; Bacteria; Bacterial Proteins; Biology; Cell model; Cells; Cessation of life; Clinical; DNA Damage; Deoxyribonucleases; Developing Countries; Development; Disease; Disease Outbreaks; Engineering; Exhibits; Extracellular Space; Family member; Food Poisoning; Foundations; Funding; Gastroenteritis; Grant; Health; Human; Infection; Intoxication; Knowledge; Label; Laboratories; Lethargies; Life; Link; Membrane Glycoproteins; Metabolic; Mus; Neuraxis; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Predisposition; Prevention strategy; Protein Secretion; Proteins; Proteomics; Public Health; Recording of previous events; Salmonella; Salmonella enterica; Salmonella paratyphi; Salmonella typhi; Salmonella typhimurium; Savings; Stupor; Symptoms; Therapeutic; Tissues; Toxin; Transferase; Typhoid Fever; United States; Vaccines; Vacuole; base; combat; fascinate; genetic makeup; human pathogen; improved; insight; novel; novel therapeutics; pathogen; prevent; public health relevance; receptor; vesicle transport

PROJECT DESCRIPTION Salmonella enterica serovar Typhi (S. Typhi) and the related serovar S. Paratyphi cause typhoid fever in humans, a devastating disease that results in ~200,000 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, S. Typhi is an exclusive human pathogen and causes systemic, often lethal, disease. Despite its Public Health importance, the mechanisms of pathogenesis of typhoidal Salmonellae remain poorly understood. Our laboratory has been exploring the unique aspects of S. Typhi pathogenesis and devoted a substantial amount of effort to the study of typhoid toxin, an A2B5 toxin that is highly conserved in typhoidal Salmonella serovars (i. e. S. Typhi and S. Paratyphi), but that it is largely absent from non-typhoidal Salmonellae. Typhoid toxin is an atypical AB toxin in that, unlike all known AB5 toxin family members, it has two enzymatically active subunits: an ADP ribosyl transferase (PltA) with an as of yet unidentified host target, and a deoxyribonuclease (CdtB), which inflicts DNA damage on intoxicated cells. These two subunits are covalently linked to one another and are associated to a homopentameric B subunit composed of PltB. Typhoid toxin is uniquely adapted to humans as it recognizes Neu5Ac-terminated sialoglycans on surface glycoproteins. Administration of typhoid toxin to experimental animals can reproduce many of the acute pathognomonic symptoms of typhoid fever, including stupor and lethargy, which most likely involve the central nervous system (CNS). Typhoid toxin exhibits a remarkable biology in that it is only produced by intracellular bacteria, and after its synthesis and assembly, it is released into the Salmonella-containing vacuole and subsequently transported to the extracellular space by specific vesicle transport carriers. During the past funding period we have unraveled many mechanistic aspects of the biology of typhoid toxin, including the description of its unique mechanism of intracellular expression, the characterization of all the steps of its remarkable transport pathways, the discovery of novel bacterial protein secretion mechanism, the description of its unique evolutionary history, and the discovery of an alternative form of typhoid toxin. Finally, these studies have led to the discovery of a novel cell-intrinsic pathogen restriction mechanism that prevents the replication of S. Typhi in mouse tissues and that it is antagonized by the mouse pathogen S. Typhimurium through the activity of specific type III protein secretion effectors absent from S. Typhi. These studies have raised very important questions related to pathogenesis of typhoid fever that we intend to pursue during the next funding period.

项目描述 沙门氏菌肠血清Typhi（S。Typhi）和相关的血清链球菌引起伤寒。 人类是一种毁灭性的疾病，每年导致约20万人死亡。虽然大多数情况发生 在发展中国家，爆发偶尔在美国发生。与其他沙门氏菌不同 血清可感染各种宿主并可能导致有限的胃肠炎，鼠伤口 人类病原体并引起全身性，通常是致命的疾病。尽管公共健康的重要性，但 伤寒沙门氏菌的发病机理的理解还不足。我们的实验室已经 探索S. typhi发病机理的独特方面，并为研究大量努力 伤寒毒素，一种在伤寒沙门氏菌血清中高度保守的A2B5毒素（即 副氏菌），但在很大程度上不存在非细类藻类。伤寒毒素是一种非典型的AB毒素 这与所有已知的AB5毒素家族成员不同，它具有两个酶促的活性亚基：ADP核糖基 具有尚未确定的宿主靶标的转移酶（PLTA）和脱氧核糖核酸酶（CDTB），该酶会造成DNA 陶醉细胞的损害。这两个亚基是共价链接的，并与 同型B亚基由PLTB组成。伤寒毒素在识别时独特地适应了人类 在表面糖蛋白上，NEU5AC终止的唾液聚糖。伤寒毒素对实验 动物可以重现伤寒的许多急性疾病症状，包括昏昏欲睡和 嗜睡，很可能涉及中枢神经系统（CNS）。伤寒毒素表现出非凡的 生物学仅是由细胞内细菌产生的，在其合成和组装后，它被释放 进入含沙门氏菌的液泡，然后通过特定运输到细胞外空间 囊泡运输载体。在过去的资金期间，我们揭示了许多机械方面 伤寒毒素的生物学，包括描述其独特的细胞内表达机制， 表征其非凡的传输途径的所有步骤，即新型细菌蛋白的发现 分泌机制，对其独特进化史的描述以及替代的发现 伤寒毒素的形式。最后，这些研究导致发现了一种新型的细胞内部病原体 防止小鼠组织中鼠伤寒链球菌复制的限制机制，并且它被拮抗 小鼠病原体鼠伤寒S. typhimurium通过特异性III型蛋白分泌效应子的活性不存在 来自S. Typhi。这些研究提出了与伤寒发烧有关的非常重要的问题， 我们打算在下一个资金期间追求。