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

隐球菌性脑膜脑炎(CM)是我国最常见的播散性真菌病 艾滋病患者，占全球艾滋病相关死亡人数的15%。复杂的问题 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 神经后遗症、发病率和显著死亡率。高达30%的HIV阳性患者患有虹膜 曾被诊断为隐球菌病的患者开始接受抗逆转录病毒治疗。目前正在努力缓解 与隐球菌相关的IRIS(C-IRIS)包括推迟ART的启动，直到无菌免疫 达到和/或使用皮质类固醇和/或非类固醇抗炎药(NSAIDs)作为 用于预防C-IRIS的抗炎药。这些努力的重大缺陷是 推迟对HIV阳性患者的ART治疗使病毒肆无忌惮地传播和抗病毒 炎症性药物可抑制宿主免疫反应，并有可能降低抗隐球菌 毒品活动。因此，允许在诊断开始时启动ART的治疗不会抑制 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，对5-羟色胺的抑制 脂氧合酶(5-LO)活性导致神经恶化显著减轻， 与CM相关的发病率和死亡率。具体地说，使用实验小鼠进行的研究 隐球菌病模型显示，与野生型(WT)小鼠相比，5-LO基因敲除(KO)小鼠， 不要表现出与CM相关的典型的神经后遗症或死亡率。此外， 髓系细胞的浸润和趋化因子的产生与C-C细胞的发展 人的虹膜(即CCL2和CCL3)在5-LO-KO的脑组织中显著减少 小鼠与WT小鼠进行比较。综上所述，这些结果让我们假设抑制 5-LO信号转导减少导致神经炎性后遗症 C-IRIS的发展。为了检验我们的假设，我们建议：1)确定5- LO对C-IRIS发展的阻断作用和2)5-LO的治疗作用 使用C-IRIS小鼠模型将抑制剂作为抗真菌治疗的辅助药物。

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.