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.

项目概要在眼部感染中，复发性单纯疱疹病毒 1 (HSV-1) 感染会导致免疫细胞浸润角膜混浊，引发严重的免疫炎症，称为疱疹性基质病角膜炎 (HSK) 是一种痛苦的疾病，也是美国感染性失明的主要原因之一。目前的 HSK 治疗，例如抗病毒药物联合皮质类固醇，是部分有效的。有效且长期使用会导致严重的局部和全身副作用。 HSK患者中的耐药HSV-1菌株是一个重大的临床挑战，因此，存在未解决的临床挑战。需要开发安全有效的免疫疗法来治疗HSK，选择性诱导有效的抗-HSK。炎症免疫反应激活程度最低的病毒状态体现了一种强大的治疗手段在本申请中，我们提出了一种针对 IL-27（一种免疫调节细胞因子，在角膜后诱导内源性抗病毒和抗炎反应 HSV-1 感染抑制 HSK 进展。解决 HSK 进展过程中的炎症 HSV-1 的细胞内 dsDNA 被循环识别。 GMP-AMP (cGAMP) 合酶 (cGAS) 并激活干扰素基因刺激剂 (STING) 通路促进抗病毒免疫，HSV-1 感染的 Mphis 会通过补偿性下调促进糖酵解。我们观察到激活的 Mphis 中的 TCA 循环被破坏。免疫反应基因 1 (Irg1) 表达增加，Irg1 是一种将柠檬酸转化为衣康酸的酶。衣康酸是一种免疫调节线粒体代谢物，可以发挥促病毒和抗病毒作用。初步数据表明，眼部 HSV-1 感染可促进角膜中 Irg1 的表达，并促进 Mφs 的表达。通过负调节 cGAS-STING 途径抑制抗病毒免疫除了病原体之外，细胞因子调节 Mphis 中的代谢以调节其效应器功能我们表明 HSV-1 诱导 IL-。 27在角膜中表达，缺乏IL-27受体的小鼠对眼部HSV-1高度敏感我们发现 IL-27 可以减弱 HSV-1 诱导的糖酵解。 Mphis 中的代谢并抑制 Irg1 表达以刺激 IFN-β 并限制炎症细胞因子基于这些观察，我们勇敢地承认 HSV-1 会重新编程 Mφs 以促进 Irg1 的产生。逃避 cGAS-STING 介导的抗 HSV-1 反应（目标 1），IL-27 减弱 HSV-1 诱导的糖酵解 Mphis 中的代谢通过抑制 Irg1 来抑制炎症并促进抗病毒免疫激活 cGAS-STING 通路（目标 2）。本研究的主要结果是揭示 HSV-1 是如何激活的。我们提出的基于 IL-27 的方案可调节 MΦ 代谢以逃避 HSK 进展期间的抗病毒反应。该方法将补充当前的抗病毒和免疫抑制 HSK 疗法，以提高其疗效功效，从而降低副作用的风险。