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，由新型隐球菌引起， 通常发生在免疫功能低下的个体，包括HIV/AIDS患者。虽然感染开始于 隐球菌病最常见的表现是 脑膜脑炎是艾滋病毒/艾滋病患者死亡的主要原因， 全球每年有18.1万人死亡。HIV/AIDS患者对C.新形式感染是 这是因为他们的细胞免疫力受损。因此，C.新生儿在大脑中增殖， 控制，导致微生物介导的脑损伤。抗逆转录病毒疗法（ART）是治疗艾滋病的一项重大进展。 艾滋病毒/艾滋病患者恢复细胞免疫反应。然而，在开始抗逆转录病毒疗法后， HIV/AIDS隐球菌病患者发生免疫重建炎症综合征（IRIS）， 异常的过度免疫反应导致宿主介导的脑损伤。此外，感染后 炎症反应综合征（PIIRS）经常发生在HIV阴性的隐球菌感染患者中， 脑膜脑炎因此，需要强有力的免疫应答来控制真菌生长; 然而，免疫反应必须严格控制，以避免宿主介导的脑损伤， 隐球菌脑膜脑炎在我们的理解中仍然存在一个关键的差距： 维持隐球菌感染期间保护性免疫应答和免疫病理学之间的平衡 脑膜脑炎相关IRIS？IL-10是一种重要的具有抗炎特性的细胞因子， 在隐球菌IRIS期间，HIV/AIDS患者的脑脊液中产生增强。基于 临床数据和我们的初步小鼠研究，我们假设IL-10是关键参与平衡， 隐球菌性脑膜脑炎相关IRIS期间的免疫应答。我们将在一个 通过解决以下目标，建立了密切模拟HIV/AIDS患者隐球菌IRIS的鼠模型：（1） 为了确定隐球菌感染期间IL-10调节免疫应答的机制， （2）探讨脑膜脑炎相关IRIS中IL-10的诱导机制。 隐球菌脑膜脑炎相关IRIS期间的大脑。如果成功，这项研究的结果 将是理解隐球菌感染过程中免疫平衡调节的基础。 并为靶向这种细胞因子提供科学依据， 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.