Role of sensory neurons in host resistance to enteric bacterial pathogens

感觉神经元在宿主抵抗肠道细菌病原体中的作用

基本信息

批准号：
10207404
负责人：
Colin Reardon
金额：
$ 19.63万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207404
关键词：
Ablation Address Affect Afferent Neurons American Bacterial Infections Bone Marrow CD3 Antigens CD4 Positive T Lymphocytes Cations Cell Adhesion Molecules Cells Chemotactic Factors Chimera organism Citrobacter rodentium Colon Communication Coupled Data Enteral Enterocytes Epithelial Cells Escherichia coli EHEC Escherichia coli Infections Exposure to Gastrointestinal tract structure Goals Health Hospitalization Host Defense Host Defense Mechanism Host resistance Human Immune Immune response Immunity In Vitro Infection Infectious Skin Diseases Injury Interleukin-17 Intestines Knockout Mice Knowledge Lamina Propria Lung Lung infections Lymphoid Cell Mechanics Mediating Modeling Morbidity - disease rate Mucosal Immune Responses Mucosal Immunity Mucous Membrane Mus Nervous system structure Neurogenic Inflammation Neuroimmune Neurons Neuropeptides Neurotransmitters Nociception Organism Outcome Pathogenesis Pathogenicity Island Peptides Physiological Population Role Sensory Site Skin Source Stimulus Substance P T cell response T cell therapy T-Lymphocyte TRPV1 gene Tissues Type III Secretion System Pathway United States adaptive immune response afferent nerve chemokine enteric infection enteric pathogen enteropathogenic Escherichia coli expectation experimental study host-microbe interactions human pathogen in vitro Assay in vivo inflammatory disease of the intestine innovation interleukin-22 intestinal epithelium member mortality nerve supply novel pathogen pathogenic bacteria prevent receptor recruit relating to nervous system response therapeutic target

项目摘要

Project Summary Host-microbial interactions are a critical determinant of health. In the gastrointestinal tract, there are several overlapping mechanisms of host defense that function together to prevent entry of pathogens into the body. These protective mechanisms are provided through the coordinated efforts of intestinal epithelial cells and immune cells in the lamina propria. Although sensory neurons and neurotransmitters are known to exacerbate intestinal inflammation, it has only recently been established that sensory neurons can suppress host response to pathogenic bacteria in the skin and lung. Unlike these other sites, our preliminary data indicates that sensory neurons are key to host- protective immunity to enteric bacterial pathogens. The overall goals of this project are to determine precisely define the role of the neuro-immune communication in response to enteric bacterial pathogens such as Citrobacter rodentium. This will be achieved by selective ablation of sensory neurons, and use of knockout mice with targeted deficiency in the polymodal nociceptive receptor TRPV1 (SA1.1). To determine if enteric pathogens can directly activate these neurons, an in vitro approach will be used with primary cultures of sensory neurons (SA1.2). The role of the predominant sensory neurotransmitter, Substance P (Tac1), during enteric infection will be assessed using bone marrow chimera approach with WT or Tac1 KO mice as donors and recipients (SA2.1). As Substance P is a potent chemoattractant that can induce chemokine and adhesion molecule expression, the role of this molecule in mediating T- cell recruitment will be assessed (SA2.2). Together, these proposed studies will decipher the contribution of the sensory nervous system and a unique immune cell population to mucosal host defense.

项目概要宿主与微生物的相互作用是健康的关键决定因素。在胃肠道中，有是几种重叠的宿主防御机制，它们共同作用以防止病毒进入病原体进入体内。这些保护机制是通过协调一致来提供的肠上皮细胞和固有层免疫细胞的努力。虽然是感官上的已知神经元和神经递质会加剧肠道炎症，但它只最近发现感觉神经元可以抑制宿主对病原体的反应皮肤和肺部的细菌。与这些其他位点不同，我们的初步数据表明感觉神经元是宿主的关键对肠道细菌病原体的保护性免疫力。该项目的总体目标是确定精确定义神经免疫通讯在肠反应中的作用细菌病原体，例如啮齿类柠檬酸杆菌。这将通过选择性消融来实现感觉神经元，以及使用具有多模式靶向缺陷的敲除小鼠伤害感受器 TRPV1 (SA1.1)。确定肠道病原体是否可以直接激活这些神经元，体外方法将用于感觉神经元的原代培养（SA1.2）。主要感觉神经递质 P 物质 (Tac1) 在将使用 WT 或 Tac1 KO 的骨髓嵌合方法评估肠道感染小鼠作为供体和受体（SA2.1）。由于 P 物质是一种有效的化学引诱剂，可以诱导趋化因子和粘附分子表达，该分子在介导 T- 将评估细胞募集（SA2.2）。这些拟议的研究将共同破译感觉神经系统和独特的免疫细胞群对粘膜的贡献主机防御。