Central role for skin sensory neurons in anti-helminth immunity

皮肤感觉神经元在抗蠕虫免疫中的核心作用

• 批准号: 10665391
• 负责人: De'Broski R Herbert
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-17 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10665391
• 关键词: Address; Affect; Afferent Neurons; Agonist; Analgesics; Anemia; Anti-Inflammatory Agents; Automobile Driving; Awareness; Bathing; Biological; Biological Models; Bone Marrow; Brain; Bypass; Calcium; Capsaicin; Case Study; Cations; Cell Communication; Cell physiology; Cells; Chimera organism; Chronic; Data; Dermal; Development; Disease; Dose; Epithelial Cells; Epithelium; Equation; Exposure to; Goals; Helminths; Host resistance; Human; Immune; Immune response; Immunity; Impairment; Infection; Inflammation; Inflammatory; Injections; Invaded; Knowledge; Larva; Lasers; Light; Mass Spectrum Analysis; Mediating; Methods; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Needles; Nematoda; Nerve; Neuroimmune; Neuromedin U; Neurons; Neuropeptides; Nociceptors; Pain; Parasites; Parasitic infection; Penetration; Perception; Persons; Population; Process; Proteins; Pruritus; Resistance development; Rhodopsin; Role; Saline; Sensory; Skin; Soil; Stimulus; Strongyloides ratti; Strongyloides stercoralis; System; TRPV channel; TRPV1 gene; Techniques; Testing; Therapeutic; Tissues; Transgenic Mice; Vanilloid; Wild Type Mouse; Withdrawal; Work; behavioral outcome; behavioral response; cytokine; experimental study; fast protein liquid chromatography; foot; gastrointestinal epithelium; gastrointestinal symptom; helminth infection; immunoregulation; insight; keratinocyte; multidisciplinary; neuroimmunology; neurotransmitter release; novel; optogenetics; pain inhibition; pain perception; pain sensation; pain signal; parasitism; pathogenic fungus; pathogenic microbe; prevent; recruit; release of sequestered calcium ion into cytoplasm; response; secondary infection; sensory neuroscience; skin damage; skin disorder; transmission process

Most soil transmitted helminth (STH) species have skin-penetrating larval stages that facilitate chronic human infections causing significant morbidity worldwide. Although these infectious larvae (iL3) are known to release a wide array of excretory-secretory products (ES) that damage skin and mucous membranes human hosts have very little awareness of this process. Rare case reports indicate itch, but otherwise most people do not know they are infected until there are gastrointestinal symptoms or anemia. This suggests that the pain-sensing neurons in the skin may be actively silenced by worm ES. While the activity of transient receptor potential channel vanilloid 1 (TRPV1)-expressing sensory neurons is known to contribute to host protective immunity against microbial and fungal pathogens, it is entirely unknown whether these skin neurons influence immunity against STH infection. This major gap in knowledge is likely because current experimental methods use needle injection to deliver iL3, which bypasses neurons that innervate the epidermal and dermal layers of skin. To address this issue, we have developed a natural model of STH infection where the foot of a mouse is transiently exposed to a saline bath of iL3, allowing natural penetration. Our preliminary studies show that significantly fewer iL3 penetrate the skin of wild-type mice in a second exposure to iL3, indicating that resistance develops. Optogenetics uses blue light to activate the cation channel rhodopsin (CHR2) that is expressed by specific cell populations expressing the cre protein in transgenic mice. When we used this technique to activate TRPV1+ cells, we found a significant reduction in iL3 skin penetration suggesting that sensory neuron activity may contribute to host protective mechanisms. Further, iL3 ES seem to reduce the ability of neurons to respond to the TRPV1 agonist capsaicin. Thus, our overarching goal is to combine this parasite infection model system with sensory neuroscience methods that non-invasively activate specific populations of pain or itch-sensing neurons to investigate how neurons control the ability of iL3 to penetrate the skin. Aim 1 tests whether optogenetic activation of nociceptors or other TRPV1+ cells augments host resistance against STH through induction of skin neuropeptides, inflammatory cells and/or Type 2 and Type 17 cytokines. Also, based on our data showing that treatment with ES products impairs sensory neuron activation, experiments in Aim 2 seek to identify the molecules in ES products that suppress sensory neuron activation and determine whether this equates with blunted behavioral responses to itchy or painful stimuli. Taken together, this R21 stands to break new ground in understanding the neuroimmunology of host protection against parasitic helminths and may reveal novel bioactive molecules with multidisciplinary therapeutic potential.

大多数土壤传播蠕虫（STH）物种都具有穿透皮肤的幼虫阶段，这有助于人类慢性感染 在世界范围内造成严重发病率的感染。尽管已知这些感染性幼虫（iL 3）释放 一系列破坏皮肤和粘膜的排泄分泌产物（ES） 对这个过程的认识很少。罕见的病例报告表明瘙痒，但除此之外，大多数人不知道 他们被感染，直到出现胃肠道症状或贫血。这表明疼痛感 皮肤中的神经元可能被蠕虫ES主动沉默。而瞬时受体电位的活性 已知表达香草酸1通道（TRPV 1）的感觉神经元有助于宿主保护性免疫 对于微生物和真菌病原体，这些皮肤神经元是否影响免疫力是完全未知的 抵抗STH感染。这一知识上的主要差距可能是因为目前的实验方法使用针 注射以递送iL 3，iL 3绕过神经支配皮肤的表皮和真皮层的神经元。到 为了解决这个问题，我们已经开发了一种STH感染的自然模型，其中小鼠的脚短暂地 暴露于iL 3的盐水浴，允许自然渗透。我们的初步研究表明， 在第二次暴露于iL 3时，iL 3穿透野生型小鼠的皮肤，表明产生了抗性。 光遗传学利用蓝光激活特定细胞表达的阳离子通道视紫红质（CHR 2） 在转基因小鼠中表达cre蛋白的群体。当我们用这种技术激活TRPV 1+时， 细胞，我们发现iL 3皮肤渗透的显着减少，表明感觉神经元活动可能 有助于宿主的保护机制。此外，iL 3 ES似乎降低了神经元对神经元刺激的反应能力。 TRPV 1激动剂辣椒素。因此，我们的首要目标是将联合收割机这个寄生虫感染模型系统 用感觉神经科学的方法，非侵入性地激活特定群体的疼痛或痒感， 研究神经元如何控制iL 3穿透皮肤的能力。目标1测试是否 伤害感受器或其他TRPV 1+细胞的光遗传学激活增强了宿主对STH的抗性 通过诱导皮肤神经肽、炎性细胞和/或2型和17型细胞因子。还有， 基于我们的数据显示用ES产品处理损害感觉神经元激活， 目的2寻求鉴定ES产物中抑制感觉神经元激活的分子， 确定这是否等同于对瘙痒或疼痛刺激的迟钝行为反应。采取 总之，这种R21代表着在理解宿主保护的神经免疫学方面开辟新的天地， 寄生蠕虫，并可能揭示新的生物活性分子与多学科的治疗潜力。