5-Lipoxygenase Inhibition as a Therapy to Prevent Cryptococcus-related IRIS

5-脂氧合酶抑制作为预防隐球菌相关 IRIS 的疗法

• 批准号: 10358634
• 负责人: Floyd L. Wormley
• 金额: $ 14.58万
• 依托单位: TEXAS CHRISTIAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-22 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358634
• 关键词: Acquired Immunodeficiency Syndrome; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antifungal Agents; Antifungal Therapy; Arachidonate 5-Lipoxygenase; CCL2 gene; CCL3 gene; Cessation of life; Complication; Cryptococcosis; Cryptococcus; Data; Deterioration; Development; Diagnosis; Disease; Encephalitis; Exhibits; HIV; HIV Seropositivity; Human; Immune response; Immunity; Individual; Infection; Infiltration; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Laboratories; Lead; Leukocyte Trafficking; Lung; Lymphocyte; Meningoencephalitis; Modeling; Morbidity - disease rate; Myeloid Cells; Neurologic; Non-Steroidal Anti-Inflammatory Agents; Patients; Pharmaceutical Preparations; Placebos; Production; Rag1 Mouse; Signal Transduction; Sterility; Structure of parenchyma of lung; Syndrome; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Virus; Wild Type Mouse; antiretroviral therapy; brain tissue; chemokine; clinically relevant; cytokine; immune reconstitution; inhibitor; mortality; mouse model; pathogen; prevent; prophylactic

Cryptococcal meningoencephalitis (CM) is the most common disseminated fungal disease in AIDS patients and is responsible for 15% of AIDS-related deaths globally. A complication associated with the initiation of antiretroviral therapy (ART) in HIV positive patients with CM is the development of immune reconstitution inflammatory syndrome (IRIS) which can lead to severe neurological sequela, morbidity, and significant mortality. IRIS afflicts up to 30% of HIV positive patients with a prior diagnosis of cryptococcosis who begin ART. Current efforts to mitigate Cryptococcus-related IRIS (C-IRIS) include delaying initiation of ART until sterile immunity is achieved, and/or using corticosteroid and/or non-steroidal anti-inflammatory drugs (NSAIDs) as anti-inflammatory agents to prevent C-IRIS. Significant drawbacks to these efforts are that delaying ART therapy in HIV positive patients allows the virus to propagate unchecked and anti- inflammatory drugs can inhibit host immune responses and potentially reduce anti-cryptococcal drug activity. Thus, therapies that allow for ART initiation at the onset of diagnosis, do not inhibit the efficacy of antifungal drugs or protective anti-cryptococcal host responses, and prevent deleterious inflammatory responses will have a significant impact towards reducing morbidity associated with C-IRIS. Preliminary studies in our laboratory show that inhibition of 5- lipoxygenase (5-LO) activity results in a significant reduction in the neurological deterioration, morbidity and mortality associated with CM. Specifically, studies using an experimental mouse model of cryptococcosis show that 5-LO knockout (KO) mice, in contrast to wild-type (WT) mice, do not exhibit the classic neurological sequela or mortality associated with CM. Moreover, myeloid cell infiltration and the production of chemokines associated with the development of C- IRIS in humans (i.e., CCL2 and CCL3) were significantly reduced in brain tissues of 5-LO KO mice compared to WT mice. Taken together, these results lead us to hypothesize that inhibition of 5-LO signaling reduces the neurological inflammatory sequelae leading to the development of C-IRIS. To test our hypothesis, we propose to: 1) determine the impact of 5- LO blockade on the development of C-IRIS and 2) demonstrate the therapeutic impact of 5-LO inhibitors as an adjunct to antifungal therapy using a murine model of C-IRIS.

隐球菌脑膜脑炎（CM）是最常见的传播真菌疾病 AIDS患者，全球造成与AIDS相关的15％的死亡。一个并发症 与HIV阳性患者的抗逆转录病毒疗法（ART）有关的是 免疫重建炎症综合征（IRIS）的发展，这可能导致严重 神经后遗症，发病率和重大死亡率。虹膜遭受高达30％的艾滋病毒阳性 先前诊断出开始艺术的隐球菌病的患者。目前减轻的努力 与加密相关的虹膜（C-IRI）包括延迟艺术的启动，直到无菌免疫力为 实现和/或使用皮质类固醇和/或非甾体类抗炎药（NSAID）作为 防止C-IRIS的抗炎剂。这些努力的重要缺点是 在HIV阳性患者中延迟艺术疗法允许病毒传播未检查和抗 炎性药物可以抑制宿主免疫反应并有可能减少抗癌症 药物活性。因此，允许在诊断开始时进行艺术启动的疗法，不要抑制 抗真菌药物的功效或保护性抗晶状体宿主反应，并防止 有害的炎症反应将对降低发病率产生重大影响 与c-iris相关。我们实验室的初步研究表明，抑制5- 脂氧合酶（5-lo）活性导致神经系统恶化显着降低， 与CM相关的发病率和死亡率。具体而言，使用实验鼠标的研究 隐球菌病模型表明，与野生型（WT）小鼠相反，5-LO基因敲除（KO）小鼠 请勿表现出与CM相关的经典神经后遗症或死亡率。而且， 髓样细胞浸润以及与C-发展相关的趋化因子的产生 在5-lo KO的脑组织中，人类的虹膜（即CCL2和CCL3）显着降低 小鼠与WT小鼠相比。综上所述，这些结果使我们假设抑制作用 5-LO信号传导的神经系统炎症后遗症导致神经系统炎症性后遗症 C-IRIS的发展。为了检验我们的假设，我们建议：1）确定5-的影响 关于C-IRIS的发展和2）证明了5-lo的治疗影响 使用C-IRIS的鼠模型，抑制剂作为抗真菌治疗的辅助。