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Typhoid Toxin and Salmonella Typhi pathogenesis

伤寒毒素和伤寒沙门氏菌发病机制

基本信息

批准号：
10686399
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
项目类别：
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/10686399
关键词：
ADP Ribose Transferases Acute Animal Experiments Animal Model Applications Grants Bacteria Bacterial Proteins Biology Cell model Cells Central Nervous System 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 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 Stupor Symptoms Therapeutic Tissues Toxin Transferase Typhoid Fever United States Vaccines Vacuole base combat fascinate genetic makeup human pathogen human tissue improved insight novel novel therapeutics pathogen prevent public health relevance receptor vesicle transport

项目摘要

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

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure and function of the Salmonella Typhi chimaeric A(2)B(5) typhoid toxin.

DOI：
10.1038/nature12377
发表时间：
2013-07-18
期刊：
Nature
影响因子：
64.8
作者：
通讯作者：

Receptor-Mediated Sorting of Typhoid Toxin during Its Export from Salmonella Typhi-Infected Cells.

受体介导的伤寒毒素从伤寒沙门氏菌感染的细胞中出口期间。

DOI：
10.1016/j.chom.2016.10.005
发表时间：
2016-11-09
期刊：
Cell host & microbe
影响因子：
30.3
作者：
Chang SJ;Song J;Galán JE
通讯作者：
Galán JE

Evolution of host adaptation in the Salmonella typhoid toxin.

DOI：
10.1038/s41564-017-0033-2
发表时间：
2017-12
期刊：
Nature microbiology
影响因子：
28.3
作者：
Gao X;Deng L;Stack G;Yu H;Chen X;Naito-Matsui Y;Varki A;Galán JE
通讯作者：
Galán JE

Decoding a Salmonella Typhi Regulatory Network that Controls Typhoid Toxin Expression within Human Cells.

DOI：
10.1016/j.chom.2017.12.001
发表时间：
2018-01-10
期刊：
Cell host & microbe
影响因子：
30.3
作者：
Fowler CC;Galán JE
通讯作者：
Galán JE

Typhoid toxin sorting and exocytic transport from Salmonella Typhi-infected cells.

DOI：
10.7554/elife.78561
发表时间：
2022-05-17
期刊：
ELIFE
影响因子：
7.7
作者：
Chang, Shu-Jung;Hsu, Yu-Ting;Chen, Yun;Lin, Yen-Yi;Lara-Tejero, Maria;Galan, Jorge E.
通讯作者：
Galan, Jorge E.