Role of corneal neuropeptides in the pathogenesis of herpetic stromal keratitis

描述（由申请人提供）：单纯疱疹病毒 1 (HSV-1) 复发可引起许多眼部病变，包括角膜基质中免疫细胞介导的慢性炎症。如果不及时治疗，角膜基质中的慢性免疫炎症反应可引起疱疹性基质角膜炎（HSK）；一种导致角膜永久性疤痕的疾病，是美国感染引起角膜失明的主要原因。目前治疗 HSK 病变的疗法有显着的缺点。因此，迫切需要研究控制 HSK 病变严重程度的新方法。在本研究中，我们将探讨角膜神经肽、P 物质 (SP) 和血管活性肠肽 (VIP) 在小鼠模型 HSK 病变的进展和严重程度中的作用。我们的长期目标是了解神经肽在调节 HSV-1 感染免疫力中的作用。据报道，神经肽 SP 和 VIP 在促进或抑制炎症方面具有不同的作用。我们的初步研究表明，与轻度 HSK 损伤的小鼠相比，重度 HSK 损伤的小鼠角膜中 SP 含量较高，但 VIP 水平较低。因此，我们假设发炎角膜中的神经肽 SP 和 VIP 调节 HSK 病变的进展和严重程度。 HSK 病变的发展是免疫介导的，涉及促炎细胞因子（IL-1、IL-6、IL-2、IFN-3 和 TNF-1）、趋化因子（MIP-1 和 MIP-2）以及中性粒细胞和 CD4 T 细胞等免疫细胞类型。因此，我们将通过证明角膜神经肽 SP 和 VIP 调节 HSV-1 感染的角膜中促炎和抗炎细胞因子以及趋化因子的量来检验我们的假设。我们还将证明 SP 和 VIP 调节病毒感染角膜中中性粒细胞和 CD4 T 细胞的流入、存活和效应功能。我们预计我们的研究结果将提供一种新的方法来阐明 HSK 的发病机制，并可能对这种疾病的治疗产生重大影响。 公共卫生相关性：角膜的复发性单纯疱疹病毒 1 型 (HSV-1) 感染会导致疱疹性基质角膜炎 (HSK)，这种疾病会导致永久性疤痕和视力丧失。目前控制 HSK 的疗法有明显的缺点。在这项研究中，我们将通过了解角膜神经肽在 HSK 进展和严重程度中的作用，研究一种在小鼠模型中管理 HSK 的新方法。

DESCRIPTION (provided by applicant): Herpes simplex virus-1 (HSV-1) recurrences can cause many ocular pathologies including, immune cell mediated chronic inflammation in the corneal stroma. If left untreated, the chronic immunoinflammatory reactions in the corneal stroma can give rise to herpetic stromal keratitis (HSK); a disease that results in permanent scarring of the cornea and is a leading cause of infection induced corneal blindness in the United States. The current therapies to manage the HSK lesions have significant downsides. Therefore, investigating novel approaches to control the severity of HSK lesions are urgently needed. In this study, we will explore the role of corneal neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), in the progression and severity of HSK lesions in a mouse model. Our long-term goal is to understand the role of neuropeptides in regulating the immunity to HSV-1 infection. Neuropeptides SP and VIP are reported to have differential roles in promoting or inhibiting the inflammation. Our pilot studies demonstrated higher amounts of SP but lower levels of VIP in the mice corneas with severe HSK lesions in comparison to those with mild HSK lesions. Therefore, we hypothesize that neuropeptides SP and VIP in the inflamed cornea regulate the progression and severity of HSK lesions. The development of HSK lesions is immune-mediated, with the involvement of pro-inflammatory cytokines (IL-1, IL-6, IL-2, IFN-3 and TNF-1), chemokines (MIP-1 and MIP-2), and immune cell types such as neutrophils and CD4 T cells. Therefore, we will test our hypothesis by demonstrating that corneal neuropeptides SP and VIP regulate the amounts of pro- and anti-inflammatory cytokines, and chemokines in HSV-1 infected corneas. We will also demonstrate that SP and VIP regulate the influx, survival and effector function of neutrophils and CD4 T cells in virus infected corneas. We anticipate that our findings will provide a novel approach to elucidate the pathogenesis of HSK and may significantly impact the management of this condition. PUBLIC HEALTH RELEVANCE: Recurrent herpes simplex virus type-1 (HSV-1) infection of the cornea results in the development of herpetic stromal keratitis (HSK), a disease that can cause permanent scarring and loss of vision. The current therapies to control HSK have significant drawbacks. In this study, we will investigate a novel approach to manage HSK in a mouse model by understanding the role of corneal neuropeptides in the progression and severity of HSK.