The Role of Direct Pathogen Detection by Sensory Neurons in Combating Bacterial I

描述(由申请人提供)： 感觉神经系统支配着与病原体高度接触的粘膜组织。疼痛是传染病患者的主要症状。在组织炎症期间，伤害性感受器，即对强烈/破坏性刺激做出反应的神经元，被兴奋，导致痛觉过敏状态。痛觉纤维在宿主-病原体防御中的作用尚未阐明。在这项研究中，我们认为神经系统在检测和防御细菌感染方面起着积极的作用。我们发现伤害性感受器神经元可以直接识别和响应两种主要的细菌配体，N-甲酰-甲硫氨酸-亮氨酸-苯丙氨酸(FMLF)和脂多糖(LPS)。伤害性感受神经元表达内毒素、CD14和Toll样受体4(TLR4)的共同受体。因此，感觉神经元可能与先天免疫系统具有相似的病原体识别途径。在特定的目标1和目标2中，我将研究介导痛觉神经元识别FMLF和内毒素的受体信号通路。当受到刺激时，外周伤害性感受器纤维释放包括CGRP和P物质在内的神经肽，这些神经肽作用于内皮细胞和平滑肌细胞，诱导血管扩张。这会导致炎症介质的涌入和先天免疫细胞的招募。这种“神经源性炎症”的作用尚未在感染的背景下进行分析。我们认为，疼痛介导的炎症在限制病原体的入侵和传播方面发挥了重要作用。在具体目标3中，我将研究神经源性炎症与抵御细菌感染的相关性。我们将产生C纤维伤害性感受器神经元缺陷小鼠，它缺乏产生神经肽的能力，以及MyD88的神经元条件基因敲除小鼠，MyD88是所有Toll样受体的下游信号适配器。这些小鼠将在两种临床相关的内毒素血症和肺炎链球菌细菌感染模型中进行测试。感觉神经元直接检测病原体的机制表明，先天免疫和伤害性感受之间有着显著的相似之处。痛觉神经元的激活可能直接影响宿主对病原体的炎症反应。阐明介导这一过程的分子途径将有助于未来疼痛和传染病的治疗。 公共卫生相关性： 检测伤害性刺激，(伤害性感受器)感觉神经元支配高度暴露于病原体的组织。在这项研究中，我们建议神经系统在直接检测细菌配体和调节宿主保护性神经源性炎症的诱导中发挥作用。伤害性感受器感觉神经元在检测和防御病原体方面的作用对未来疼痛和传染病的治疗具有重要意义。

DESCRIPTION (provided by applicant): The sensory nervous system innervates mucosal tissues that are highly exposed to pathogenic organisms. Pain is a major symptom of patients suffering from infectious diseases. During tissue inflammation, nociceptors, the neurons which react to intense/damaging stimuli, are excited, leading to a state of hyper-algesia. The role of pain-sensing fibers in host-pathogen defense has not been elucidated. In this study, we propose that the nervous system plays an active role in the detection and defense against bacterial infection. We find that nociceptor neurons can directly recognize and respond to two major bacterial ligands, N-formyl-Met-Leu-Phe (fMLF) and Lipopolysaccharide (LPS). Nociceptor neurons express the co-receptors for LPS, CD14 and Toll-like Receptor 4 (TLR4). Therefore, sensory neurons may share similar pathogen recognition pathways as the innate immune system. In Specific Aim 1 and Aim 2, I will investigate the receptor signaling pathways that mediate the recognition of fMLF and LPS by pain-sensing neurons. Upon stimulation, peripheral nociceptor fibers release neuro-peptides including CGRP and substance P, which act on endothelial and smooth muscle cells to induce vaso-dilation. This leads to the influx of inflammatory mediators and recruitment of innate immune cells. The role of this "neurogenic inflammation" has not ben analyzed in the context of infection. We propose that pain mediated inflammation plays an important role in limiting the invasion and spread of pathogens. In Specific Aim 3, I will investigate the relevance of neurogenic inflammation in the defense against bacterial infection. We will generate C- fiber nociceptor neuron deficient mice, which lack the ability to produce neuropeptides, and neuronal conditional knockout mice for MyD88, the downstream signaling adaptor for all Toll-like Receptors. These mice will be tested in two clinically relevant models of LPS induced endotoxemia and Streptococcus Pneumoniae bacterial infection. A direct pathogen detection mechanism by sensory neurons indicates remarkable similarities between innate immunity and nociception. Activation of pain neurons may directly efectuate the host inflammatory response to pathogens. Elucidating the molecular pathways that mediate this process will benefit the future treatment of pain and infectious disease. PUBLIC HEALTH RELEVANCE: Noxious stimuli detecting, (nociceptor) sensory neurons innervate tissues that are highly exposed to pathogenic organisms. In this study, we propose a role for the nervous system in directly detecting bacterial ligands and modulating the induction of host protective neurogenic inflammation. A role for nociceptor sensory neurons in the detection and defense against pathogens holds implications for the future treatment of pain and infectious diseases.