Role for the Microbiota in Development of Herpes Stromal Keratitis

项目总结： 在全球范围内，工业化国家的大多数人(80%)携带潜伏的1型单纯疱疹病毒 (HSV1)感染感觉神经元，三叉神经节支配口面部是常见的 牵涉其中。各种应激源可以重新激活病毒，导致无症状的病毒脱落或在 口腔面部区域，包括角膜、眼皮和眼周皮肤。奇怪的是，当许多人流下HSV1的眼泪或 发生角膜上皮损伤，通常是自我修复的，一些人的复发性疾病涉及病毒复制 以及基质中剧烈的炎症反应，导致角膜瘢痕形成和视力障碍--称为 疱疹基质角膜炎(HSK)。反复的HSK会导致严重的疤痕和角膜损伤，这可能 失明的进步。 我们推测，反复发作的HSK患者存在肠道微生物区系失调，从而改变宿主免疫。 从而有利于HSK的发展。此外，可以想象，在这些人中，HSV1也可能 肠道神经元重新激活，导致肠道屏障功能障碍和炎症，这可能导致/加剧 微生物区系失调。我们推测，作为免疫调节因子，微生物区系是HSV1的重要决定因素 由于口服抗生素耗尽肠道而导致的包括HSK和脑炎(HSE)在内的炎症性疾病 眼部HSV1感染前的微生物区系显著减少血管生成和HSK(4)和我们的初步研究 表明改变肠道微生物区系可以调节HSK和HSE的发育。 我们提出了两个具体的目标来检验这一假设。在特定目标1中，目标是鉴定肠道细菌， 肠道细菌基因/基因产物/途径，以及与不同易感性相关的宿主免疫过程 HSV1感染后HSK和HSE的严重程度在特定的目标2中，我们将因果地测试细菌的能力 改变HSV1感染后HSK和HSE的易感性和严重性，并确定相关的变化 宿主豁免权。 通过证明肠道微生物区系的操纵可以调节HSK和HSE的严重性，我们预计 这个项目将改变我们对HSK和HSE的病理生理学的理解。我们还设想，通过验证， 根据我们的假设，这个项目将促进识别和表征细菌组合(或单个细菌)的研究 有潜力作为有效的益生菌发挥作用，为复发提供替代的天然预防疗法 HSK和HSE

Project Summary: Globally, the majority of people (>80%) in industrialized countries harbor latent Herpes simplex virus type 1 (HSV1) infections in sensory neurons with trigeminal ganglia that innervate the orofacial region being commonly involved. A variety of stressors can reactivate the virus resulting in asymptomatic shedding of virus or in lesions in the orofacial region including the cornea, eyelids and periocular skin. Curiously, while many people shed HSV1 in tears or develop corneal epithelial lesions that are usually self-healing, recurrent disease in some people involves virus replication and vigorous inflammatory responses in the stroma that cause corneal scarring and impairment of vision – referred to as herpes stromal keratitis (HSK). Repeated bouts of HSK result in severe scarring and damage to the cornea that can progress to blindness. We speculate that people who suffer from recurrent HSK have gut microbiota dysbiosis that alters host immunity and thereby predisposes to development of HSK. Furthermore, it is conceivable that in these people HSV1 might also reactivate in enteric neurons, resulting in gut barrier malfunction and inflammation, which could cause/exacerbate microbiota dysbiosis. We postulate that as regulators of immunity, the microbiota are important determinants of HSV1 induced inflammatory diseases including HSK and encephalitis (HSE) because oral antibiotic depletion of the gut microbiota prior to ocular HSV1 infection significantly reduced angiogenesis and HSK (4) and our preliminary studies showed that altering the gut microbiota can modulate HSK and HSE development. We propose two specific aims to test this hypothesis. In Specific Aim 1, the objective is to identify gut bacteria, gut bacterial genes/gene products/pathways, and host immune processes that correlate with varying susceptibilities to and severity of HSK and HSE following HSV1 infection. In Specific Aim 2, we will causally test bacteria for their abilities to alter the susceptibilities to and severity of HSK and HSE following HSV1 infection, and identify the associated changes in host immunity. By demonstrating that manipulation of the gut microbiota can modulate HSK and HSE severity, we anticipate that this project will change our understanding of the pathophysiology of HSK and HSE. We also envision that by validation of our hypothesis this project will spur research to identify and characterize consortia of bacteria (or individual bacteria) with the potential to function as effective probiotics, providing alternative natural prophylactic therapies for recurrent HSK and HSE