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Vibrio vulnificus toxin-receptor interactions

创伤弧菌毒素受体相互作用

基本信息

批准号：
10056473
负责人：
Karla J F Satchell
金额：
$ 23.7万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-19 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056473
关键词：
Address Bacteria Binding Blood Circulation C-terminal CRISPR screen Calcium Caspase Cell membrane Cell surface Cells Cessation of life Chromosomes Climate Clinical Consumption Cytoskeleton Cytosol Cytotoxin Death Rate Disease Eating Economic Burden Epithelial Epithelium Eukaryotic Cell Family Fishes Food Food Contamination Functional disorder Future Gene Expression Regulation Genes Genetic Screening Glycolipids Golgi Apparatus Grant Growth Harvest Human Incidence Infection Inflammatory Insecta Integration Host Factors Intestines Intoxication Ions Knowledge Lead Lethal Dose 50 Life Mexico Morbidity - disease rate Mus Mutation N-terminal Nature Operon Patients Phytic Acid Policies Polysaccharides Protease Domain Proteins Receptor Cell Resistance Route Seafood Seawater Sepsis Septicemia Shellfish Structure Surface Swimming Terminal Repeat Sequences Testing Toxin Variant Vibrio Vibrio cholerae Vibrio vulnificus Virulence Virulence Factors alpha Toxin arm base beta-Lactamase cytokine cytotoxic foodborne pathogen genetic selection human pathogen inhibition of autophagy intestinal epithelium mortality mouse model mutant pathogenic bacteria receptor receptor function transmission process

项目摘要

ABSTRACT Vibrio vulnificus is a Gram-negative bacterial pathogen that causes severe life-threatening infections in humans after eating shellfish or swimming in warm seawater. In the US, there are about 200 cases annually with high rates of mortality and morbidity. While the number of cases is low compared to other food-borne pathogens, the high rates of death among patients exerts a significant burden on human life and the economy. This is expected to increase as incidence of V. vulnificus infections is rising due to the climate crisis. The most prominent virulence factor of V. vulnificus is a 5208 aa MARTX family toxin that delivers cytotoxic effectors to cells and these effectors are essential for virulence in a mouse model. While extensive information is known about the mechanisms of the effectors, very little is known about the remaining over 2800 aa of the protein toxin. These regions are known to be both necessary and sufficient for secretion of the toxin from the bacteria, interaction of the toxin with the eukaryotic cell surface, and translocation of the effectors across the plasma membrane. The project proposes to identify host cell receptors and host factors essential for intoxication using a genetic screen and selection for mutant cells that survive the cytolytic action of the toxin. We will also use a structure-function based approach to identify regions of the MARTX toxin essential for Type I secretion from the bacterium, binding of the toxin to a putative surface receptor, formation of a pore in the plasma membrane, and translocation of effectors to the eukaryotic cell cytosol. This study will advance our understanding of the function of the MARTX toxin repeat regions in detail and is expected to impact our understanding of pathophysiology during V. vulnificus infection.

摘要