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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.

项目总结/文摘