Contribution of sympathetic nerves to herpes stromal keratitis

项目概要/摘要 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，神经免疫的作用 病理学中的轴不完全理解。我们对小鼠的初步研究表明， 无菌α和TIR基序包含1（SARM 1），作为SARM 1缺陷小鼠发育，可预防HSK 与WT对照组相比，HSK更严重。虽然SARM 1通常与神经元细胞相连，但它也 可以在各种免疫细胞群中发挥作用。因此，我们计划评估 SARM 1在HSK期间在神经和免疫细胞中的表达。具体来说，我们的第一个目标将调查如何SARM 1 随着时间的推移，缺乏可能影响病毒控制和抗病毒免疫应答的产生。我们的第二 目标将集中于通过比较免疫细胞功能来定义SARM 1的免疫细胞内在机制， SARM 1缺陷型免疫细胞在体内和体外向WT免疫细胞的迁移和代谢。最后， 我们的第三个目标是研究SARM 1缺乏如何影响感觉和交感神经的生长， 稳定状态和神经营养病毒感染的背景下。我们认为SARM 1限制了 同时也限制了交感神经的生长，我们已经发现， 有助于眼部HSV-1感染的发病机制。总的来说，我们预计我们的研究将确定SARM 1 作为宿主因素，在预防HSK中起着不可或缺的作用。

PROJECT SUMMARY/ABSTRACT Herpes simplex virus type 1 (HSV-1) corneal infections are leading infectious causes 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 role of the neuroimmune axis in pathology is incompletely understood. Our preliminary studies in mice demonstrated that a host factor, Sterile alpha and TIR motif containing 1 (SARM1), acts to prevent HSK as SARM1 deficient mice develop more severe HSK compared to WT controls. While SARM1 is conventionally linked to neuronal cells, it also can function in various immune cell populations. Therefore, we plan to assess the functional consequences of SARM1 during HSK in nerve and immune cells. Specifically, our first aim will investigate how SARM1 deficiency may affect viral control and the generation of the anti-viral immune response over time. Our second aim will focus on defining immune cell intrinsic mechanisms of SARM1 by comparing immune cell functionality, migration, and metabolism of SARM1 deficient immune cells to WT immune cells in vivo and in vitro. Finally, our third aim will investigate how SARM1 deficiency affects sensory and sympathetic nerve growth during steady state and in the context of neurotrophic viral infection. We posit a role that SARM1 limits the activation of inflammatory monocytes while also limiting the outgrowth of sympathetic nerves, which we have found to contribute to pathogenesis in ocular HSV-1 infection. Overall, we anticipate that our studies will identify SARM1 as a host factor that plays an integral role in preventing HSK.