Vibrio vulnificus toxin-receptor interactions

创伤弧菌毒素受体相互作用

• 批准号: 10198737
• 负责人: Karla J F Satchell
• 金额: $ 19.94万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-19 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198737
• 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; 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

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.

抽象的 Vibrio vulnificus是一种革兰氏阴性细菌病原体，会引起严重威胁生命的感染 人类吃贝类或在温暖的海水中游泳后。在美国，每年大约有200例 死亡率和发病率高。与其他食物相比，案件数量很少 病原体，患者的高死亡率给人类生活和经济带来了重大负担。 由于气候危机，V菌感染的发病率正在增加，预计这将增加。最多 V. vulnificus的突出毒力因子是5208 AA MARTX家族毒素，可将细胞毒性效应子传递到 细胞和这些效应子对于小鼠模型中的毒力至关重要。虽然已知广泛的信息 关于效应子的机制，关于剩余的2800 aa蛋白质的剩余AA知之甚少 毒素。这些区域既需要从细菌中分泌毒素，既是必需的，也足以分泌 毒素与真核细胞表面的相互作用，以及效应子跨等离子体的易位 膜。该项目建议识别宿主细胞受体和使用 一种遗传筛选和突变细胞的选择，可在毒素的细胞溶解作用中生存。我们还将使用 基于结构功能的方法来识别MARTX毒素的区域I型毒素至关重要 细菌，毒素与推定表面受体的结合，质膜中孔的形成， 和效应子转向真核细胞细胞质。这项研究将促进我们对 MARTX毒素重复区域的功能详细介绍，并有望影响我们对 V. vulnificus感染期间的病理生理。