权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Intestinal granuloma formation during Yersinia pseudotuberculosis infection

假结核耶尔森菌感染期间肠道肉芽肿的形成

基本信息

批准号：
10417032
负责人：
RINA MATSUDA
金额：
$ 4.68万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417032
关键词：
Ablation Acute Animal Genetics Bacteria Biological Models Cell physiology Cells Chronic Chronic Disease Communicable Diseases Crohn&apos s disease Cytosol Data Defect Diagnostic Disease Disease model Encapsulated Exhibits Future Gastroenteritis Gene Expression Granuloma Granulomatous disease Histologic Host Defense Human Immune Immune response Immunization Immunocompetent Immunologics Immunotherapy Infection Inflammatory Injections Integration Host Factors Intestinal Mucosa Intestines Invaded Knowledge Liver Lung Lymphadenitis Lymphoid Tissue Mediating Modeling Mus Mutation Needles Oral Organ Outcome Pasteurella pseudotuberculosis Pathologic Patients Peripheral Phagocytes Phagocytosis Plague Plasmids Play Proteins Receptor Signaling Reporter Rodent Role Sarcoidosis Side Signal Transduction Site Source Spleen Structure System TNF gene Testing Therapeutic Time Tissues Tumor Necrosis Factor Receptor Tumor-Derived Type III Secretion System Pathway Virulence Virulence Factors Work Yersinia Yersinia infections Yersinia pseudotuberculosis Infections acute infection base chronic infection cytokine enteric infection experimental study human pathogen immune function improved insight lymph nodes lymphoid organ microbicide monocyte mortality mouse model mutant neutrophil novel pathogen pathogenic bacteria prevent recruit response therapeutic target transmission process

项目摘要

Project Summary/Abstract In various infectious and non-infectious contexts, chronic immune stimulation induces the formation of granulomas: aggregations of recruited immune cells that are thought to encapsulate pathogens and prevent their dissemination. Despite being a prominent feature of numerous infections, key gaps in our knowledge are the mechanisms of granuloma formation and the functional role of these structures in controlling infectious disease. Yersinia are bacterial pathogens that block immune cell function and induce granuloma formation in lymphoid tissues. Yersinia pseudotuberculosis (Yptb) causes self-limiting gastroenteritis and lymphadenitis in immunocompetent hosts following fecal-oral transmission. Yptb subverts the immune response through the injection of Yersinia outer proteins (Yops) into nearby immune cells through a needle-like type III secretion system, blocking functions such as phagocytosis and pro-inflammatory gene expression. While granulomas are well-described during Yersinia infection of lymphatic tissue, relatively little is known about early intestinal infection. In this proposal, we describe, for the first time, a murine model of granuloma formation in the intestinal mucosa during acute Yptb infection. Importantly, live bacteria are abundant within granulomas but are largely absent from surrounding non-granuloma intestinal tissue, suggesting that granulomas play a previously uncharacterized role at the intestinal mucosa, an immunological barrier that bottlenecks Yersinia dissemination. Interestingly, Yptb lacking Yops does not induce intestinal granuloma formation, suggesting that these structures form in response to features of bacterial virulence. Further, intestinal granulomas are highly enriched in neutrophils and inflammatory monocytes. Strikingly, monocyte-deficient Ccr2- /- mice show defects in restriction of bacterial dissemination, succumbing to acute infection. Similarly, mice deficient in tumor necrosis factor (TNF) signaling, a cytokine that enhances phagocyte microbicidal function, exhibit defects in bacterial restriction. I therefore hypothesize that blockade of immune cell function by Yop effector proteins induces the formation of intestinal granulomas, which protect the host through bacterial restriction mediated by monocyte-derived TNF. In this proposal, I will investigate the formation and function of intestinal granulomas from both the bacterial and host sides. First, I will uncover how Yersinia virulence factors induce intestinal granuloma formation by testing a panel of Yop mutant strains, in addition to using an injection reporter strain (Aim 1). Second, I will dissect immune cell functions that are necessary for restriction of Yersinia by intestinal granulomas through complementary mechanistic studies using chimeric animals and genetic ablation systems (Aim 2). This work will mechanistically define a previously unappreciated facet of the host immune response to Yersinia infection. Findings from this novel model of intestinal granuloma formation will provide insight into future work on poorly-studied granulomatous disorders and underscore potential therapeutic targets for the treatment of chronic disease.

项目总结/文摘