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.

项目摘要： 单纯疱疹病毒1型（HSV-1）角膜感染是全世界失明的主要感染原因。 众所周知，HSV-1感染的盲目形式称为疱疹基质角膜炎（HSK） 通过对病毒的免疫反应，而不是病毒对角膜细胞的直接作用。疾病 倾向于在人中复发，因为病毒侵入并在感觉中建立了静止（潜在）感染 初始感染期间的神经。 HSV-1定期从潜在状态重新激活，向下行驶 角膜的神经，并触发HSK的反复发作。 HSK的标志是失去角膜灵敏度 这与角膜感觉神经末端的丧失有关。但是， 感染角膜的神经元变化和HSK的发病机理尚未得到很好的研究。我们的 对小鼠的初步研究表明，当感觉到神经是同情的神经会侵入角膜 丢失，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讨这种神经免疫相互作用的机制。我们的第一个目标 确定负责角膜神经侵袭的机制，并在我们的身上扩展 初步发现，当CD4+ 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哪种机制 通过扩大当前的知识，促进感染角膜的紧张神经会引起受感染角膜的严重炎症 交感神经产生的儿茶酚胺（但不是通过感觉神经）可以刺激巨噬细胞 和CD4 T淋巴细胞可产生HSK的炎症介质。在人们看来，角膜损失 感觉神经和角膜感觉是一个逐步的过程，随着串行HSK的复发而进行，IS 与日益严重的HSK相关。我们的第三个目标将首次尝试诱导串行HSK 小鼠复发，并确定感觉神经丧失和交感神经神经神经神经神经神经支配是否随着 串行复发。我们预测，复发的交感神经和儿茶酚胺的作用越来越大 小鼠中的HSK。我们的研究将定义HSK的全新神经免疫成分，因此可以提供 干预这种盲目疾病的新途径。