Mechanisms of balancing the immune response during cryptococcal meningoencephalitis

项目摘要 隐球菌病是一种机会性真菌感染，由新生隐球菌和 通常发生在免疫功能受损的人，包括艾滋病毒/艾滋病患者。尽管感染始于 通过吸入肺部的致病真菌，隐球菌病最常见的表现是 脑膜脑炎，这是艾滋病毒/艾滋病患者死亡的主要原因，占 全球每年有181,000人死亡。艾滋病毒/艾滋病患者对新生弧菌感染的高度易感性是 归因于它们的细胞免疫功能受损。因此，新生葡萄球菌在大脑中繁殖，而不是 控制，导致微生物介导的脑损伤。抗逆转录病毒治疗(Art)是治疗的重大进展。 通过恢复艾滋病毒/艾滋病患者的细胞免疫反应。然而，在启动ART后，高达30%的 患有隐球菌病的艾滋病毒/艾滋病患者出现免疫重建炎症综合征(IRIS)，并 异常过度的免疫反应导致宿主介导的脑损伤。此外，感染后 炎性反应综合征(PIIRS)在HIV阴性的隐球菌患者中频繁发生 脑膜脑炎。因此，控制真菌生长需要强大的免疫反应； 然而，必须严格控制免疫反应，以避免宿主在 隐球菌性脑膜脑炎。我们在理解上的一个关键差距仍然存在： 隐球菌病中保护性免疫反应与免疫病理的平衡 脑膜脑炎相关虹膜？IL-10是一种重要的抗炎细胞因子及其作用机制 在隐球菌IRIS期间，艾滋病毒/艾滋病患者的脑脊液中的产量增加。基于 临床数据和我们的初步小鼠研究，我们假设IL-10在平衡 隐球菌性脑膜脑炎相关性虹膜病变期间的免疫反应。我们将在一个 模拟HIV/AIDS患者的隐球菌IRIS的小鼠模型，通过解决以下目的：(1) IL-10调节隐球菌免疫应答的机制(S) 脑膜脑炎相关性虹膜损伤；(2)探讨IL-10在大鼠脑内的诱导机制(S)。 在隐球菌性脑膜脑炎相关虹膜期间的大脑。如果成功，这项研究的发现 将是理解隐球菌免疫平衡调节的基础 并为该细胞因子靶向治疗提供科学依据。 控制隐球菌IRIS/AIDS患者大脑中的有害炎症。

Project Summary Cryptococcosis is an opportunistic fungal infection that is caused by Cryptococcus neoformans and often occurs in immunocompromised individuals including HIV/AIDS patients. Although the infection starts in the lung via inhalation of the pathogenic fungus, the most common manifestation of cryptococcosis is meningoencephalitis, which is a leading cause of mortality of HIV/AIDS patients and accounts for proximately 181,000 deaths worldwide annually. The high susceptibility of HIV/AIDS patients to C. neoformans infection is attributed to their impaired cellular immunity. Consequently, C. neoformans proliferates in the brain without control, leading to microbe-mediated brain damage. Antiretroviral therapy (ART) is a major advance in treating HIV/AIDS patients by restoring cellular immune responses. However, after initiation of ART, up to 30% of HIV/AIDS patients with cryptococcosis develop immune reconstitution inflammatory syndrome (IRIS), an aberrant excessive immune response leading to host-mediated brain damage. Furthermore, post-infectious inflammatory response syndrome (PIIRS) occurs frequently in HIV-negative patients with cryptococcal meningoencephalitis. Therefore, a robust immune response is required for controlling the fungal growth; however, the immune response must be tightly controlled to avoid host-mediated brain damage during cryptococcal meningoencephalitis. A critical gap in our understanding remains: what are the mechanisms of maintaining the balance between protective immune responses and immunopathology during cryptococcal meningoencephalitis-associated IRIS? IL-10 is an important cytokine with anti-inflammatory properties and its production was enhanced in the cerebrospinal fluid of HIV/AIDS patients during cryptococcal IRIS. Based on clinical data and our preliminary murine studies, we hypothesize that IL-10 is critically involved in balancing the immune responses during cryptococcal meningoencephalitis-associated IRIS. We will test the hypothesis in a murine model that closely mimics cryptococcal IRIS of HIV/AIDS patients, by addressing the following aims: (1) To determine the mechanism(s) involved in regulation of the immune responses by IL-10 during cryptococcal meningoencephalitis-associated IRIS; (2) To determine the mechanism(s) involved in induction of IL-10 in the brain during cryptococcal meningoencephalitis-associated IRIS. If successful, the findings from this study would be fundamental for understanding regulation of immune balance during cryptococcal meningoencephalitis-associated IRIS and provide scientific basis for targeting this cytokine aiming at controlling deleterious inflammation in the brain of cryptococcal IRIS/AIDS patients.