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Contribution of sympathetic nerves to herpes stromal keratitis

交感神经对疱疹性基质角膜炎的影响

基本信息

批准号：
10528224
负责人：
ANTHONY J ST LEGER
金额：
$ 41万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10528224
关键词：
Affect Alzheimer&apos s Disease Antiviral Agents Architecture Axon Back Blindness Bone Marrow CD4 Positive T Lymphocytes Cell Maturation Cell physiology Cells Chimera organism Cornea Corneal Opacity Data Desiccation Development Diabetic Neuropathies Disease Exposure to Flow Cytometry Ganglia Generations Genes Goals Growth Health Herpesvirus 1 Herpetic Keratitis Human Immune Immune response Immunity In Vitro Infection Infiltration Inflammation Inflammatory Inflammatory Response Integration Host Factors Invaded Keratitis Lead Life Link Measures Metabolism Modality Modeling Monitor Mus Myelogenous Myeloid Cells Nature Nerve Nerve Degeneration Neuroimmune Neurons Parkinson Disease Pathogenesis Pathology Persons Play Population Primary Infection Process Production Publishing Recurrence Role Sensory Sensory Nerve Endings Simplexvirus Sterility Steroids Stress Structure of trigeminal ganglion T-Lymphocyte Testing Therapeutic Time Traumatic Brain Injury Travel VEGFA gene Vaccines Vascular Endothelial Growth Factors Viral Virion Virus Virus Diseases Work adeno-associated viral vector afferent nerve axon growth blink reflexes cytokine effective therapy in vivo latent infection migration monocyte novel preclinical study prevent response symptom treatment targeted treatment

项目摘要

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.

项目概要/摘要 1 型单纯疱疹病毒 (HSV-1) 角膜感染是全球范围内导致失明的主要原因。众所周知，HSV-1 感染导致致盲，称为疱疹性基质角膜炎 (HSK) 通过对病毒的免疫反应，而不是病毒对角膜细胞的直接影响。疾病由于病毒侵入感觉器官并建立静止（潜伏）感染，因此往往会在人类中复发最初（原发性）感染期间的神经。 HSV-1 定期从潜伏状态重新激活，向下传播角膜神经，并引发 HSK 反复发作。 HSK 的一个标志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尚不完全清楚。我们对小鼠的初步研究表明，宿主因素，含有 1 (SARM1) 的无菌 alpha 和 TIR 基序，可在 SARM1 缺陷小鼠发育时预防 HSK 与 WT 对照相比，HSK 更严格。虽然 SARM1 通常与神经元细胞相关，但它也可以在各种免疫细胞群中发挥作用。因此，我们计划评估功能后果 HSK 期间神经和免疫细胞中的 SARM1。具体来说，我们的第一个目标是研究 SARM1 如何随着时间的推移，缺乏可能会影响病毒控制和抗病毒免疫反应的产生。我们的第二个目标将重点通过比较免疫细胞功能来定义 SARM1 的免疫细胞内在机制， SARM1 缺陷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 SARM1 缺陷如何影响感觉神经和交感神经生长稳定状态和神经营养性病毒感染的背景下。我们假设一个角色，SARM1限制激活炎症单核细胞的同时也限制了交感神经的生长，我们发现交感神经可以有助于眼部 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 SARM1 作为宿主因素，在预防 HSK 中发挥着不可或缺的作用。