Filtering of disseminating Cryptococcus neoformans out of vasculature

项目摘要 隐球菌病是一种机会性感染，发生在免疫功能低下的个体中。 包括艾滋病患者，器官移植接受者，癌症患者和接受治疗的人 免疫抑制疗法。据估计，有100万例隐球菌病和 全球每年约有60万人死亡。感染开始于肺部，通过吸入 被包裹的真菌新生隐球菌。然而，最主要和最致命的并发症是 隐球菌病是脑膜脑炎。要引起脑膜脑炎，新生梭菌必须传播 从肺部进入血液。因此，在艾滋病患者中经常发现真菌血症 隐球菌病，被认为是发展和持续的最关键的步骤之一 隐球菌性脑膜脑炎。然而，对血管内清除知之甚少。 由于活体研究的技术挑战，传播新生葡萄球菌。特别是，在以下方面存在一个严重差距 我们的理解仍然是：是否存在积极消除传播新生葡萄球菌的机制 血管系统外，其机制是什么？肝脏位于动脉和静脉的交汇处。 血。库普弗细胞(KC)占全身组织巨噬细胞的90%，占 约占肝细胞总数的15%。CRIG是一种独特的补体受体，最近被发现 在人类和动物的KC上。尽管肝脏不是隐球菌病的靶器官，但我们假设， 根据我们的初步数据，KCs在过滤传播新生葡萄球菌方面起着关键作用 通过一种涉及补体受体CRIG的机制促进循环。我们将通过以下方式验证该假设 使用活体显微镜和其他先进方法实现以下目标：(1) 描述KCs在滤除血管系统中新生葡萄球菌的作用；(2)剖析其机制(S) 参与了KCs捕获传播新生葡萄球菌的工作。这项研究的结果将表明 一种旨在增强肝脏巨噬细胞募集和活性的治疗策略可能会有所帮助 降低艾滋病患者患隐球菌性脑膜炎的风险。

Project Summary Cryptococcosis is an opportunistic infection that occurs in immunocompromised individuals including AIDS patients, organ transplant recipients, cancer patients, and those treated with immunosuppressive therapies. It is estimated there are one million cases of cryptococcosis and proximately 600,000 deaths worldwide annually. The infection starts in the lung via inhalation of the encapsulated fungus Cryptococcus neoformans. However, the major and most lethal complication of cryptococcosis is meningoencephalitis. To cause meningoencephalitis, C. neoformans must disseminate from the lung and enter the bloodstream. As such, fungemia, detected frequently in AIDS patients during cryptococcosis, is believed to be one of the most critical steps in the development and persistence of cryptococcal meningoencephalitis. However, little is known about intravascular clearance of the disseminating C. neoformans due to technical challenge for in vivo studies. In particular, a critical gap in our understanding remains: Does a mechanism exist to actively eliminate disseminating C. neoformans out of vasculature, and what is the mechanism? Liver is situated at a confluence of arterial and venous blood. Kupffer cells (KCs) constitute ~90% of the tissue macrophages in the whole body and account for ~15% of the total liver cell population. CRIg, a unique complement receptor, has been recently identified on KCs of humans and animals. Although the liver is not a target organ of cryptococcosis, we hypothesize, based on our preliminary data, that KCs play a critical role in filtering of disseminating C. neoformans out of circulation via a mechanism involving complement receptor CRIg. We will test the hypothesis by addressing the following aims using intravital microscopy and other advanced approaches: (1) To characterize the role of KCs in filtering C. neoformans out of vasculature; (2) To dissect the mechanism(s) involved in capture of disseminating C. neoformans by KCs. The findings from this study will suggest that a therapeutic strategy aimed at enhancing macrophage recruitment and activity in the liver could help reducing the risk of cryptococcal meningocephalitis in AIDS patients.