Contribution of sympathetic nerves to herpes stromal keratitis

交感神经对疱疹性基质角膜炎的影响

• 批准号: 9308061
• 负责人: ANTHONY J ST LEGER
• 金额: $ 62.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308061
• 关键词: Adrenergic Antagonists; Adrenergic beta-Agonists; Animals; Axon; Back; Biological Assay; Blindness; CD4 Positive T Lymphocytes; Catecholamines; Cells; Cornea; Corneal Stroma; Diffuse; Disease; Dose; Enzyme-Linked Immunosorbent Assay; Epinephrine; Esthesia; Excision; Exhibits; Flow Cytometry; Future; Herpesvirus 1; Human; Immune Cell Activation; Immune response; Immunohistochemistry; Individual; Infection; Inflammation; Inflammation Mediators; Interleukin-17; Interleukin-6; Intervention; Invaded; Keratitis; Knowledge; Laboratories; Lead; Measures; Modeling; Mus; Nerve; Nerve Growth Factors; Nerve Regeneration; Neuroimmune; Neuroimmunomodulation; Neurons; Norepinephrine; Numbness; Pathogenesis; Patients; Pharmacology; Play; Primary Infection; Process; Proteins; RNA; Recurrence; Research; Role; Sensory Nerve Endings; Severities; Source; Steroids; Structure of superior cervical ganglion; Testing; Time; Travel; UV induced; Vascular Endothelial Growth Factors; Virus; afferent nerve; base; beta-adrenergic receptor; chemokine; cytokine; experience; in vivo; latent infection; macrophage; nano-string; nerve supply; neurotrophic factor; prevent

Project Summary: Herpes simplex virus type 1 (HSV-1) corneal infections are a leading infectious cause of blindness world-wide. It is well established that the blinding form of HSV-1 infection called herpes stromal keratitis (HSK) is caused by the immune response to the virus rather than by a direct effect of the virus on corneal cells. The disease tends to recur in people because the virus invades and establishes a quiescent (latent) infection in sensory nerves during initial (primary) infection. HSV-1 periodically reactivates from the latent state, travels back down the nerves to the cornea, and triggers recurrent bouts of HSK. A hallmark of HSK is loss of corneal sensitivity that has been associated with loss of corneal sensory nerve endings. However, the relationship between neuronal changes in infected corneas and the pathogenesis of HSK has not been well studied. Our preliminary studies in mice demonstrated that sympathetic nerves invade the cornea when sensory nerves are lost, and sympathetic nerves play a key role in the activation of immune cells and their contribution to HSK. Our proposed studies will explore the mechanisms of this neuro-immune interaction. Our first aim will determine the mechanisms responsible for sympathetic nerve invasion of the cornea, expanding on our preliminary finding that these nerves fail to invade infected corneas when CD4+ T lymphocytes or macrophages are depleted from the host animal. Our second aim will determine the mechanism by which sympathetic nerves induce severe inflammation in infected corneas, by expanding on current knowledge that the catecholamines produced by sympathetic nerves (but not by sensory nerves) can stimulate macrophages and CD4 T lymphocytes to produce inflammatory mediators of HSK. In people it appears that loss of corneal sensory nerves and corneal sensation is a gradual process that progresses with serial HSK recurrences and is associated with increasingly severe HSK. Our third aim will attempt for the first time to induce serial HSK recurrences in mice and determine if sensory nerve loss and sympathetic nerve innervation progress with serial recurrences. We predict an increasing role for sympathetic nerves and catecholamines with recurrences of HSK in mice. Our studies will define a whole new neuro-immune component of HSK and in so doing provide new avenues of intervention in this blinding disease.

项目总结： 单纯疱疹病毒1型(HSV-1)角膜感染是世界范围内导致失明的主要感染性原因。 众所周知，单纯疱疹病毒1型致盲感染称为单纯疱疹间质角膜炎(HSK)。 通过对病毒的免疫反应，而不是通过病毒对角膜细胞的直接影响。这种病 倾向于在人身上复发，因为病毒入侵并在感觉上建立了静止(潜伏)的感染 最初(原发)感染时的神经。HSV-1周期性地从潜伏状态重新激活，并向下传播 神经传导到角膜，引发HSK反复发作。HSK的一个特点是角膜敏感度的丧失 这与角膜感觉神经末梢的丢失有关。然而，两国之间的关系 单纯疱疹病毒性角膜炎(HSK)感染后角膜神经元的变化及发病机制尚未得到很好的研究。我们的 对小鼠的初步研究表明，当感觉神经侵入角膜时，交感神经 失神经和交感神经在免疫细胞的激活及其在HSK中的作用起着关键作用。 我们提出的研究将探索这种神经免疫相互作用的机制。我们的首要目标是 确定交感神经侵入角膜的机制，在我们的 初步发现这些神经不能侵入感染的角膜当CD4+T淋巴细胞或 宿主动物体内的巨噬细胞被耗尽。我们的第二个目标将决定 交感神经在感染的角膜中引起严重的炎症，这是根据目前的知识扩展的 交感神经(但不是感觉神经)产生的儿茶酚胺可以刺激巨噬细胞。 和CD4T淋巴细胞产生HSK的炎症介质。在人类中，角膜的丢失似乎 感觉神经和角膜知觉是一个循序渐进的过程，随着HSK的一系列复发而进展，并 伴随着日益严重的HSK。我们的第三个目标将首次尝试诱导连续HSK 并确定感觉神经丢失和交感神经支配是否随着 连续重现。我们预测交感神经和儿茶酚胺的作用会随着复发而增加。 对小鼠单纯疱疹病毒感染的影响。我们的研究将定义HSK的一种全新的神经免疫成分，并通过这样做提供 干预这一致盲疾病的新途径。