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: 10256128
• 负责人: Floyd L. Wormley
• 金额: $ 17.02万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256128
• 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/antagonist; 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）是最常见的播散性真菌病， 艾滋病患者和负责全球艾滋病相关死亡的15%。的并发症 与HIV阳性CM患者开始抗逆转录病毒治疗（ART）相关的是 免疫重建炎症综合征（IRIS）的发展，可导致严重的 神经系统后遗症、发病率和显著死亡率。IRIS折磨高达30%的HIV阳性患者 既往诊断为隐球菌病并开始ART治疗的患者。 隐球菌相关的IRIS（C-IRIS）包括延迟ART的开始，直到无菌免疫。 和/或使用皮质类固醇和/或非甾体抗炎药（NSAID）作为 抗炎药，以防止C-IRIS。这些努力的重大缺点是， 延迟艾滋病毒阳性患者的抗逆转录病毒治疗会使病毒不受控制地传播， 炎性药物可以抑制宿主的免疫反应，并可能降低抗隐球菌 毒品活动因此，允许在诊断开始时开始ART的疗法不会抑制 抗真菌药物的疗效或保护性抗隐球菌宿主反应，并预防 有害的炎症反应将对降低发病率有显著影响 与C-IRIS有关。我们实验室的初步研究表明， 脂氧合酶（5-LO）活性导致神经恶化的显著减少， 与CM相关的发病率和死亡率。具体来说，使用实验小鼠的研究 隐球菌病模型显示，与野生型（WT）小鼠相比， 没有表现出与CM相关的典型神经系统后遗症或死亡率。此外，委员会认为， 骨髓细胞浸润和与C- 人的IRIS（即，CCL 2和CCL 3）在5-LO KO的脑组织中显著降低 与WT小鼠相比。综上所述，这些结果使我们假设， 5-LO信号传导减少了神经炎性后遗症， C-IRIS的发展。为了验证我们的假设，我们建议：1）确定5- LO阻断对C-IRIS发展的影响; 2）证明5-LO的治疗作用 抑制剂作为抗真菌治疗的辅助，使用C-IRIS的鼠模型。