IL-27-mediated immunoregulation in HSV-1-induced stromal keratitis

HSV-1 诱导的基质性角膜炎中 IL-27 介导的免疫调节

基本信息

批准号：
10737119
负责人：
Amol Suryawanshi
金额：
$ 39.59万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737119
关键词：
Adrenal Cortex Hormones Affect Anti-Inflammatory Agents Antiviral Agents Antiviral Response Attenuated Blindness Chronic Citrates Citric Acid Cycle Clinical Complement Cornea Cyclic GMP Data Dendritic Cells Down-Regulation Enzymes Eye Infections GATA1 gene Genes Glycolysis Herpes stromal keratitis Herpesvirus 1 Herpetic Keratitis ISG15 gene Immune Immune Evasion Immune response Immunity Immunosuppression Immunotherapy Impairment Infection Inflammation Inflammatory Inflammatory Response Injury Interferon Type I Interferon alpha Interferon-beta Interferons Keratitis Knock-out Knockout Mice Knowledge Macrophage Mediating Metabolic Metabolism Mitochondria Molecular Multi-Drug Resistance Mus Outcome Study Pain Pathogenesis Pathway interactions Patients Phagolysosome Pilot Projects Play Predisposition Production Recurrence Regulation Resistance Risk Role Severities Stimulator of Interferon Genes Testing Treatment Efficacy Tricarboxylic Acids United States Viral Virus Virus Diseases Virus Replication Vision Visual impairment antiviral immunity cytokine ds-DNA immune cell infiltrate immunoregulation inhibitor interest metabolic phenotype mouse model novel novel therapeutics nuclear factor-erythroid 2 pathogen pharmacologic primary outcome programs receptor response side effect

项目摘要

Project Summary Among ocular infections, recurrent herpes simplex virus-1 (HSV-1) infection causes immune cell infiltration and opacity in the cornea and triggers a severe immuno-inflammatory condition called herpetic stromal keratitis (HSK). HSK is a painful condition and one of the leading causes of infectious blindness in the United States and worldwide. Current HSK treatments, such as anti-virals combined with corticosteroids, are partially effective, and prolonged use causes severe local and systemic side effects. Further, the emergence of multi- drug-resistant HSV-1 strains in HSK patients is a major clinical challenge. Therefore, there is an unmet clinical need to develop safe and effective immunotherapies to treat HSK. The selective induction of a potent anti- viral state with minimal activation of inflammatory immune responses embodies a powerful means to treat patients with recurrent HSK. In this application, we propose one such approach targeting IL-27, an immunoregulatory cytokine, to induce endogenous anti-viral and anti-inflammatory responses after corneal HSV-1 infection to suppress HSK progression. Macrophages (Mϕs) play a central role in initiating and resolving inflammation during HSK progression. Intracellular dsDNA from HSV-1 is recognized by cyclic- GMP-AMP (cGAMP) synthase (cGAS) and activates the stimulator of interferon genes (STING) pathway to promote anti-viral immunity. HSV-1 infected Mϕs promote glycolysis with compensatory downregulation of the tricarboxylic acid (TCA) cycle. We observed that the TCA cycle in activated Mϕs is disrupted with increased immune-responsive gene 1 (Irg1) expression, an enzyme that converts citrate to itaconate. Itaconate is an immunoregulatory mitochondrial metabolite that can play both pro- and anti-viral roles. Our preliminary data suggest that ocular HSV-1 infection promotes Irg1 expression in the cornea and Mϕs to suppress anti-viral immunity through negative regulation of the cGAS-STING pathway. Apart from pathogens, cytokines regulate metabolism in Mϕs to modulate their effector functions. We show that HSV-1 induces IL- 27 expression in the cornea, and mice lacking the IL-27 receptor are highly susceptible to ocular HSV-1 infection with increased viral titers and HSK severity. We show that IL-27 attenuates HSV-1-induced glycolytic metabolism in Mϕs and suppresses Irg1 expression to stimulate IFN-β and limit inflammatory cytokine production. Based on these observations, we hypothesize that HSV-1 reprograms Mϕs to promote the Irg1 to evade cGAS-STING-mediated anti-HSV-1 responses (Aim 1) and IL-27 attenuates HSV-1-induced glycolytic metabolism in Mϕs to suppress inflammation and promote anti-viral immunity through inhibition of Irg1 to activate cGAS-STING pathway (Aim 2). The primary outcome of this study will be to uncover how HSV-1 regulates Mϕ metabolism to evade anti-viral responses during HSK progression. Our proposed IL-27-based approach will complement the current anti-viral and immunosuppressive HSK therapies to increase their efficacy, thus lowering the risk of side effects.

项目摘要在眼部感染中，复发性疱疹单纯疱疹病毒-1（HSV-1）感染引起免疫细胞浸润角膜中的不透明度，并触发严重的免疫炎症状态，称为疱疹性基质角膜炎（HSK）。 HSK是一种痛苦的疾病，是统一感染失明的主要原因之一国家和全球。当前的HSK治疗，例如抗病毒与皮质类固醇相结合，部分是有效和长时间使用会导致严重的局部和全身副作用。此外，多数的出现 HSK患者中耐药的HSV-1菌株是主要的临床挑战。因此，有一个未修饰的临床需要开发安全有效的免疫疗法来治疗HSK。选择性诱导潜在的抗炎症免疫反应最少激活的病毒状态体现了一种强大的治疗方法复发性HSK的患者。在此应用中，我们提出了一种针对IL-27的方法免疫调节细胞因子，诱导角膜后内源性抗病毒和抗炎反应 HSV-1感染以抑制HSK的进展。巨噬细胞（Mϕ）在启动和解决HSK进展过程中的炎症。来自HSV-1的细胞内DSDNA通过环状识别 GMP-AMP（CGAMP）合酶（CGAS），并激活干扰素基因（STING）途径的刺激剂促进抗病毒免疫。 HSV-1感染的M ϕ促进糖酵解，补偿性下调三核酸（TCA）周期。我们观察到激活的M ϕ中的TCA周期被破坏了免疫反应性基因1（IRG1）表达增加，一种将柠檬酸盐转化为伊龙酸盐的酶。 Itaconate是一种免疫调节的线粒体代谢产物，可以扮演促病毒和抗病毒作用。我们的初步数据表明，眼HSV-1感染促进了角膜中的IRG1表达和M ϕs的表达通过CGAS刺激途径的负调节来抑制抗病毒免疫。除病原体外，细胞因子调节M ϕ中的代谢以调节其效应子功能。我们表明HSV-1诱导IL- 27在角膜中的表达，缺乏IL-27受体的小鼠非常容易受到眼部HSV-1的影响病毒滴度和HSK严重程度增加的感染。我们表明IL-27减弱了HSV-1诱导的糖酵解 M ϕs的代谢并抑制IRG1表达以刺激IFN-β并限制炎症细胞因子生产。基于这些观察结果，我们假设HSV-1重编程M ϕs以将IRG1提升为 EVADE CGAS插入介导的抗HSV-1反应（AIM 1）和IL-27减弱HSV-1诱导的糖酵解 M ϕ的代谢以抑制IRG1的抑制注射和促进抗病毒免疫力激活CGAS丁字道（AIM 2）。这项研究的主要结果是发现HSV-1如何调节M ϕ代谢，以逃避HSK进展过程中的抗病毒反应。我们提出的基于IL-27的方法将完成当前的抗病毒和免疫抑制性HSK疗法，以增加其有效性，从而降低了副作用的风险。