PATHOGENESIS OF CRYPTOCOCCAL MENINGOENCEPHALITIS

描述：（改编自申请人摘要）隐球菌 脑膜脑炎由新型隐球菌引起， 在城市环境中普遍存在的包囊真菌。感染 被认为是通过呼吸系统发生后吸入 C.新人类呼吸道感染通常是短暂的， 不明显，但随后的系统性隐球菌病往往导致 隐球菌性脑膜脑炎， 隐球菌病隐球菌性脑膜炎是无法治愈的患者， 艾滋病，尽管抗真菌治疗。在这个实验中要检验的假设 有观点认为小胶质细胞和星形胶质细胞可以作为效应细胞发挥作用 在隐球菌性脑膜脑炎中， 细胞因子和调理素的效应子功能可以改变病程， 隐球菌感染的结果。第一个具体目标将研究 小胶质细胞与C.新形式，以及 细胞因子和capturele特异性抗体在修饰相互作用中的作用。 将特别强调在这方面开发的mAb的作用。 已被证明在小鼠中提供保护性免疫的机构 感染在第二篇《特定目的》中，C.新形式- 感染的小胶质细胞将被确定，因为有证据表明吞噬细胞 杀死是C.新人类 待检验的假设包括吞噬细胞死亡的方式可以 决定了生物体的命运。通过定义宿主细胞参数 成功地杀死了C。申请人希望， to be able能够to optimize优化the therapy治疗.在第三个具体目标中， C的相互作用。将确定小胶质细胞中的新生儿和HIV-1。 由于大多数隐球菌脑膜炎患者也携带HIV-1病毒， 在中枢神经系统中，审查以下方面的作用至关重要： HIV-1修饰小胶质细胞产生的抗真菌效应机制。 在第四个具体目标中，他们将检验假设C。 新生儿改变CNS中的细胞因子和趋化因子环境， 转，调节小胶质细胞的抗真菌和抗病毒活性， 星形胶质细胞最后一个具体目标将定义一氧化氮的作用 合成酶在人CNS和培养物中抗隐球菌活性。 具体地说，他们将确定精氨酸激活的星形胶质细胞是否可以 与小胶质细胞协同作用，通过提供 一氧化氮这些实验将使用人类脑细胞， 允许观察到的结果与潜在的 对人类的治疗干预。

DESCRIPTION: (Adapted from Applicant's Abstract) Cryptococcal meningoencephalitis is caused by Cryptococcus neoformans, an encapsulated fungus which is ubiquitous in urban environments. Infection is thought to occur via the respiratory system following inhalation of C. neoformans. The respiratory infection is often transient or inapparent, but subsequent systemic cryptococcoses often result in cryptococcal meningoencephalitis, the classical presentation of cryptococcoses. Cryptococcal meningitis is incurable in patients with AIDS, despite antifungal treatments. The hypothesis to be tested in this proposal is that microglia and astrocytes can function as effector cells in cryptococcal meningoencephalitis and that modulation of their effector function by cytokines and opsonins may modify the course and the outcome of cryptococcal infection. The first Specific Aim will study the interaction of microglia with C. neoformans, and the role of cytokines and capspule-specific antibodies in modifying the interaction. Particular emphasis will be placed on the role of mAbs developed in this Institution that have been shown to offer protective immunity in murine infection. In the second Specific Aim, the fate of C. neoformans- infected microglia will be determined, since evidence suggests phagocyte killing as a novel mechanism of host injury induced by C. neoformans. The hypotheses to be tested include that the mode of phagocyte death can determine the fate of organisms. By defining the host cell parameters that successfully lead to killing of C. neoformans, the applicants hope to be able to optimize the therapy. In the third Specific Aim, interactions of C. neoformans and HIV-1 in microglia will be determined. Since most patients with cryptococcal meningitis also harbor HIV-1 virus in the CNS, it will be of paramount importance to examine the role of HIV-1 in modifying antifungal effector mechanisms exerted by microglia. In the fourth Specific Aim, they will test the hypothesis that C. neoformans alter the cytokine and chemokine milieu in the CNS which, in turn, modulates antifungal and antiviral activity of microglia and astrocytes. The last Specific Aim will define the role of nitric oxide synthase in anticryptococcal activity in human CNS and in culture. Specifically, they will determine if cytokine-activated astrocytes can synergize with microglia to promote intracellular killing by providing nitric oxide. These experiments will use human brain cells thus permitting the direct correlation of the observed results to potential therapeutic intervention in man.