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，但疼痛感测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、稳态和组织炎症中起着重要作用。伤害感受器神经元专门用于检测有害/有害刺激，并在激活时消除疼痛感。伤害感受器神经元密集地支配外周组织，包括皮肤、肺和胃肠道，这些组织经常暴露于病原体感染。细菌感染常常会引起严重的疼痛。我们以前的工作表明，S。金黄色葡萄球菌通过释放N-甲酰肽和成孔毒素-溶血素直接激活伤害感受器神经元，从而产生疼痛。在激活时，这些伤害感受器神经元释放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和响应病原体。我们推测，伤害感受器神经元可能发挥重要的和以前未被重视的作用，在主机防御病原体。本研究的目的是确定伤害感受器神经元及其神经肽在细菌宿主防御过程中调节先天性和适应性免疫细胞功能的贡献。我们将利用特定的遗传和药理学工具沉默或激活伤害感受器神经元的活动，微生物学和免疫学分析，以确定神经免疫通讯在宿主防御S。金黄色葡萄球菌感染。这些实验将测试伤害感受器神经元在以下调节中的作用：1）神经元和单核细胞介导的S.金黄色葡萄球菌和树突状细胞活化过程中感染。2)T细胞对S.包括在淋巴结中的引发和在感染部位的效应器功能。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.