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.

项目概要： 单纯疱疹病毒1型（HSV-1）角膜感染是世界范围内致盲的主要传染性原因。 众所周知，HSV-1感染的致盲形式称为疱疹性角膜基质炎（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。疾病 由于病毒侵入并在感觉器官中建立静止（潜伏）感染， 最初（原发性）感染期间的神经。HSV-1周期性地从潜伏状态重新激活， 刺激角膜神经，引发HSK复发。HSK的一个特点是角膜敏感性丧失 这与角膜感觉神经末梢的丧失有关。然而， 感染角膜中的神经元变化和HSK的发病机制尚未得到很好的研究。我们 对小鼠的初步研究表明，当感觉神经被破坏时，交感神经侵入角膜。 交感神经在免疫细胞的激活及其对HSK的贡献中起着关键作用。 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，扩大我们的 初步发现，当CD 4 + T淋巴细胞或 巨噬细胞从宿主动物中耗尽。我们的第二个目标将决定 交感神经在受感染的角膜中诱导严重的炎症，通过扩展当前的知识， 由交感神经（但不是由感觉神经）产生的儿茶酚胺可以刺激巨噬细胞 CD 4 T淋巴细胞产生HSK炎症介质。在人类中，似乎角膜的丧失 感觉神经和角膜感觉是一个渐进的过程，随着HSK反复发作而进展， 与日益严重的HSK有关。我们的第三个目标将首次尝试诱导HSK系列 复发，并确定感觉神经损失和交感神经支配是否随着 连续递归我们预测随着复发，交感神经和儿茶酚胺的作用会越来越大 HSK小鼠模型。我们的研究将定义一个全新的HSK神经免疫成分，从而为HSK提供 新的途径来干预这种致盲性疾病。