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Dissection of Shigella pathogenesis in vivo using a new oral infection mouse model

使用新的口腔感染小鼠模型剖析志贺氏菌体内发病机制

基本信息

批准号：
10681402
负责人：
RUSSELL E VANCE
金额：
$ 43.83万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
2020-09-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681402
关键词：
Actins Animal Model Animal Testing Alternatives Back Bacteria Bacterial Proteins Body Weight decreased CASP4 gene Caspase Cavia Cells Cessation of life Data Development Disease Dissection Dose Eicosanoids Epithelial Cells Epithelium Exhibits Feces Fever Flagellin Foundations Hemorrhagic colitis Human Human Characteristics Immune Immune response Immunity Immunocompromised Host Immunologics Infant Infection Inflammasome Inflammatory Response Intestines Invaded Knowledge Lung Mediating Methodology Modeling Morbidity - disease rate Mus Muscle Cramp Natural Immunity Needles Neutrophil Infiltration Oral Oral Ingestion Organoids Oryctolagus cuniculus Pathogenesis Pathology Physiological Predisposition Primates Protein Secretion Reagent Research Research Personnel Resistance Rod Route Salmonella Salmonella infections Shigella Shigella Infections Tail Testing Time Type III Secretion System Pathway Vaccines Virulence Factors Work Zebrafish Zinc deficiency adaptive immune response cell motility cost cytokine gut colonization gut inflammation human disease human pathogen in vivo interest intestinal epithelium intraperitoneal mortality mouse genetics mouse model mutant neutrophil oral infection pathogen pathogenic bacteria response sensor success tool

项目摘要

Project Summary/Abstract Shigella species are highly infectious and important pathogens of humans. In 2016, there were an estimated 269 million cases and 212,000 deaths due to Shigella. Humans are typically infected with Shigella after oral ingestion of a minimal inoculum, consisting of as few as 10-100 bacteria. A major roadblock in Shigella research is the lack of an in vivo oral infection mouse model that recapitulates key aspects of human disease. Mice resist oral doses of Shigella as high as 100 million bacteria, but the reason for this resistance remains poorly understood. In our preliminary data, we describe our discovery that the reason mice are resistant to Shigella is because of a robust and mouse-specific innate immune inflammasome response in intestinal epithelial cells. Mice lacking inflammasomes are thus susceptible to oral Shigella infection and provide the first opportunity to use the full repertoire of mouse genetic and immunological tools and methodologies to dissect Shigella pathogenesis in a physiological infection model. Importantly, our data suggest that inflammasome-deficient mice are a highly relevant model because, in humans, we find Shigella inhibits or evades the NAIP/NLRC4 inflammasome. We propose three Specific Aims. In Aim 1, we will characterize innate immune and bacterial factors responsible for shigellosis in vivo. In Aim 2, we will characterize the adaptive immune responses of mice to wild-type and mutant Shigella. In, Aim 3, we will test the hypothesis that Shigella encodes effectors to inactivate the human NAIP/NLRC4 inflammasome. By exploiting the experimental tractability of our new model, we hope to identify the key factors mediating immunity and disease during Shigella infection, thereby providing a foundation of knowledge to inform the development of safer and more effective vaccines.

项目总结/文摘