Role of sensory neurons in host resistance to enteric bacterial pathogens

项目摘要 宿主-微生物相互作用是健康的一个关键决定因素。在胃肠道中， 是几种重叠的宿主防御机制，它们共同起作用，以防止入侵。 病原体进入体内。这些保护机制是通过协调的 肠上皮细胞和固有层中的免疫细胞的努力。虽然感官 已知神经元和神经递质会加剧肠道炎症， 最近已经确定，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 与其他部位不同，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。该项目的总体目标是 精确地确定神经免疫通讯在肠道免疫应答中的作用。 细菌病原体如啮齿柠檬酸杆菌。这将通过选择性消融 感觉神经元，以及多模态神经元靶向缺陷的敲除小鼠的用途 伤害感受性受体TRPV 1（SA1.1）。为了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物 （SA1.2）。主要的感觉神经递质P物质（Tac 1）在 肠道感染将使用骨髓嵌合体方法与WT或Tac 1 KO进行评估 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物， 诱导趋化因子和粘附分子的表达，这种分子在介导T- 将评估细胞募集（SA2.2）。总之，这些拟议的研究将破译 感觉神经系统和独特的免疫细胞群对粘膜免疫的贡献 宿主防御

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.