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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：
10098247
负责人：
RUSSELL E VANCE
金额：
$ 45.04万
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/10098247
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 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 Primates Proteins 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 adaptive immune response base cell motility cost cytokine gut colonization human disease human pathogen in vivo inflammatory disease of the intestine 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/摘要志贺氏菌属是人类的重要病原体，具有高度传染性。2016年，有一个估计有2.69亿病例和21.2万人死于志贺氏菌。人类通常会感染志贺氏菌在口服摄入最小接种物后，由少至10-100个细菌组成。一个主要志贺氏菌研究的障碍是缺乏体内口腔感染小鼠模型，人类疾病的各个方面。小鼠抵抗口服剂量的志贺氏菌高达1亿个细菌，但原因是因为这种抵抗力仍然知之甚少。在我们的初步数据中，我们描述了我们的发现，小鼠对志贺氏菌具有抵抗力的原因是小鼠特异性的强大先天免疫肠上皮细胞的炎性小体反应。因此，缺乏炎性小体的小鼠容易受到口服志贺氏菌感染，并提供了第一次机会，使用小鼠遗传和免疫学工具和方法来剖析志贺氏菌在生理感染模型中的发病机制。重要的是，我们的数据表明，炎性小体缺陷小鼠是一个高度相关的模型，因为，在人类中，我们发现志贺氏菌抑制或逃避NAIP/NLRC 4炎性体。我们提出三个具体的目标。在目标1中，我们将描述先天免疫和细菌因素在体内志贺菌病。在目标2中，我们将描述小鼠对野生型和突变型志贺氏菌的适应性免疫应答。在中、目的3，我们将检验志贺氏菌编码效应子以抑制人NAIP/NLRC 4的假设炎性小体通过利用我们新模型的实验易处理性，我们希望找到关键志贺氏菌感染过程中免疫和疾病的调节因子，从而为志贺氏菌感染的免疫调节提供了基础。为开发更安全、更有效的疫苗提供信息。