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Genetic Analyses of bacteremia non-typhoidal Salmonella

非伤寒沙门氏菌菌血症的遗传分析

基本信息

批准号：
10580145
负责人：
MICAH WORLEY
金额：
$ 46.95万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580145
关键词：
Anti-Inflammatory Agents Antibiotics Apical Attenuated Bacteremia Biological Assay Blood Blood Circulation Cells Cessation of life Chemotaxis Circulation Clinical Dendritic Cells Disease Effectiveness Endothelium Fatality rate Gastrointestinal tract structure Genes Goals Health Homologous Gene Human Immunologist In Vitro Induction of Apoptosis Infection Inflammation Inflammatory Inflammatory Response Inhibition of Apoptosis Innate Immune System Integration Host Factors Intervention Intestines Invaded Lethal Genes Life Link Lyase Lymphatic Endothelium Lymphatic System MAPK8 gene Mentors Microbe Migration Assay Migration Inhibitory Factor Mitogen-Activated Protein Kinase Kinases Modeling Molecular Movement Multi-Drug Resistance Mus Operon Pathway interactions Persons Phagocytes Phosphothreonine Physiological Process Property Publications Reporting Role Route Salmonella Sepsis Signal Pathway Signal Transduction Site Students Systemic disease Talents Testing Vascular Endothelium Virulence Virulence Factors Work antimicrobial cost cytokine enteric pathogen experimental study genetic analysis in vitro Assay in vitro Model in vivo lymphatic vessel member microbial microbicide migration monolayer non-typhoidal Salmonella novel therapeutic intervention p38 Mitogen Activated Protein Kinase pathogen prevent resistant strain undergraduate student

项目摘要

Project Summary There are at least 3.4 million cases of bacteremia with invasive non-typhoidal Salmonella per year that result in 680,000 deaths1. Despite its significant cost on human health with a 20% fatality rate, bacteremia caused by this pathogen is poorly understood. One important class of virulence factors is ones that are anti-inflammatory. Traditionally, such genes were thought to promote virulence by attenuating anti-microbial mechanisms such as intracellular killing and the induction of apoptosis. My undergraduates surprisingly discovered that one of dozens of such effectors, SpvC, is instead required for extraintestinal dissemination by interdicting the host's ability to control the movement of infected phagocytes. They developed an in vitro cell c0-culture assay that models the traversal of the blood vascular endothelium by phagocytes in the basal to apical direction that before their work had only been observed with uninfected cells, a process that immunologists refer to as reverse transmigration. The long-term goal of this work is to develop new therapeutic intervention strategies for compartmentalizing infections, thereby greatly reducing their chance of lethality. The short-term objective of this work is to characterize how microbial and host factors regulate the extraintestinal dissemination of invasive non- typhoidal Salmonella. In the first aim, with two in vitro models we will test a detailed molecular mechanism that accounts for the ability of SpvC to promote movement. In the second aim, we quantify how much each of the known pathways of extraintestinal dissemination contribute to systemic disease and assess the role of SpvC in each. We hypothesize that the phosphothreonine lyase activity of SpvC deactivates three MAPK kinases, to down regulate the host cytokine MIF, which normally potently inhibits phagocyte movement. We will test if this prevents Salmonella from disseminating through both the lymphatic system and the reverse transmigration pathways.

项目总结