The role of nociceptor neurons in bacterial host defense and inflammation

描述（由申请人提供）：疼痛是炎症的主要组成部分，但痛觉伤害感受器神经元在调节炎症过程中的作用尚不清楚。越来越清楚的是，神经系统和免疫系统之间的分子和细胞相互作用在发育、体内平衡和组织炎症中起着重要作用。痛觉感受器神经元专门用于检测有害刺激，并在激活后转导疼痛的感觉。痛觉感受器神经元密集地支配周围组织，包括皮肤、肺和胃肠道，这些组织经常暴露于致病性感染。细菌感染通常会产生明显的疼痛。我们之前的研究表明，金黄色葡萄球菌通过释放n -甲酰基肽和成孔毒素溶血素直接激活伤害感受器神经元，从而产生疼痛。一旦被激活，这些伤害感受器神经元就会释放出能够直接作用于免疫系统的神经肽。因此，像免疫系统一样，神经系统能够直接检测病原体并对其作出反应。我们假设伤害感受器神经元可能在宿主防御病原体的过程中发挥了重要的作用。本研究的目的是确定在细菌宿主防御过程中，伤害感受器神经元及其神经肽在调节先天和适应性免疫细胞功能中的作用。我们将利用特定的遗传和药理学工具，通过微生物和免疫学分析来沉默或激活伤害感受器神经元的活动，以确定神经免疫通讯在宿主防御金黄色葡萄球菌感染中的意义。这些实验将测试伤害感受器神经元在以下方面的作用：1)感染期间中性粒细胞和单核细胞介导的金黄色葡萄球菌清除和树突状细胞活化。2) T细胞对金黄色葡萄球菌的反应，包括淋巴结的启动和感染部位的效应功能。这些分析将确定伤害感受器神经元在调节免疫和炎症中的作用，这是一个相对未被探索和潜在重要的研究领域。这些研究有可能改变我们对宿主-病原体相互作用和细菌宿主防御中的神经免疫机制的理解。

DESCRIPTION (provided by applicant): Pain is a major component of inflammation, but the role of pain-sensing nociceptor neurons in the regulating the inflammatory process is not well understood. It is increasingly clear that molecular and cellular interactions between the nervous system and immune system play important roles in development, homeostasis, and tissue inflammation. Nociceptor neurons are specialized to detect noxious/harmful stimuli and upon activation, transduce the sensation of pain. Nociceptor neurons densely innervate peripheral tissues including the skin, lungs, and gastrointestinal tract, tissues that are often exposed to pathogenic infection. Bacterial infection often produces significant pain. Our previous work demonstrated that S. aureus directly activates nociceptor neurons through release of N-formyl peptides and the pore-forming toxin �emolysin, thereby producing pain. Upon activation, these nociceptor neurons release neuropeptides that are able to directly act on the immune system. Thus, like the immune system, the nervous system is able to directly detect and respond to pathogens. We hypothesize that nociceptor neurons may play an important and previously unappreciated role in host defense against pathogens. The goal of this study is to determine the contribution of nociceptor neurons and their neuropeptides in modulating the function of both innate and adaptive immune cells during bacterial host defense. We will utilize specific genetic and pharmacological tools to silence or activate nociceptor neuron activity with microbiological and immunological analyses to ascertain the significance of neuro-immune communication in host defense against S. aureus infection. These experiments will test the role of nociceptor neurons in the regulation of: 1) Neutrophil and monocyte mediated clearance of S. aureus and dendritic cell activation during infection. 2) T cell responses to S. aureus including priming in lymph nodes and effector function at the site of infection. These analyses will determine the role of nociceptor neurons in regulating immunity and inflammation, a relatively unexplored and potentially significant area of research. These studies have the potential to transform our understanding of host-pathogen interactions and of neuro-immune mechanisms in bacterial host defense.