The adaptive host response to latent cryptococcosis

项目摘要 由条件致病菌新生隐球菌引起的隐球菌性脑膜炎(CM) (CN)是全球艾滋病毒相关死亡的主要原因。在健康个体中，早期接触CN 儿童时期的肺部潜伏感染是无症状的，但会导致肺的形成。 肉芽肿。在艾滋病毒相关的免疫系统受损后，将潜在的CN感染控制在 肺部肉芽肿消失，真菌传播导致脑膜炎。宿主免疫 对建立和维持对隐匿性CN感染的控制至关重要的细胞和效应器功能尚未得到 已确认身份。在高级艾滋病毒护理的背景下，清除潜在感染是必要的。了解如何 健康的免疫反应控制潜在的CN感染是需要的：1)定义关键的免疫功能， 预防疾病，2)确定为什么健康的免疫系统无法根除潜伏的感染，以及3) 开发有针对性的治疗方法，以减缓患有CM的艾滋病毒患者的疾病进展。使用一种新的鼠标 在我们实验室建立的潜伏隐球菌病吸入模型中，我将测试我的中心假设 CD4T细胞反应是控制潜伏性肺部CN感染的必要条件和充分条件，但不能 清除持续CN存活引起的干扰素-γ(干扰素γ)信号的内在缺陷所致的感染 肉芽肿内。在目标1中，我将结合激光捕获显微切割和RNA测序来确定 负责控制肉芽肿内CN的细胞和效应器功能。在目标2中，我将使用 模拟HIV诱导的CD4耗竭和死后肉芽肿肺组织活检的小鼠模型 从患有CM的HIV患者中研究HIV诱导的CD4T细胞丢失如何破坏潜伏CN的控制 肉芽肿内感染。在目标3中，我将使用过继T细胞转移和外源性干扰素γ补充 阐明CD4T细胞亚群和效应器功能在控制隐匿性CN感染中的作用。这个 这些研究的长期目标是开发免疫调节的艾滋病毒治疗策略。 关联的CM。这些策略包括在高危人群中在艾滋病毒免疫抑制之前清除潜在的CN感染 通过替换基本的CN特异性CD4来缓解HIV/AIDS患者的个体和疾病进展 控制CN感染所需的T细胞亚群。这项提议将为以下工作奠定必要的基础 开发针对CN感染的治疗方法，但避免引发免疫重建 合并CM的HIV/AIDS患者的炎症综合征。 拟议的研究和培训计划为顺利完成医学硕士课程提供了严格的计划。 博士学位，并将进一步发展成为一名成功的学术传染病医生 推动艾滋病毒/艾滋病和艾滋病毒相关机会主义前沿转化研究的科学家 病原体。

Project Summary Cryptococcal meningitis (CM), caused by the opportunistic fungal pathogen Cryptococcus neoformans (Cn), is a leading cause of HIV-related mortality worldwide. In healthy individuals, exposure to Cn in early childhood results in a pulmonary latent infection that is asymptomatic, but leads to the formation of lung granulomas. Following HIV-associated compromise of the immune system, control of latent Cn infection within pulmonary granulomas is lost and the fungal pathogen disseminates to cause meningitis. The host immune cells and effector functions critical for establishing and maintaining control of latent Cn infections have not been identified. Clearance of latent infections is warranted in the context of advanced HIV care. Understanding how the healthy immune response controls latent Cn infection is needed to: 1) define critical immune functions that prevent disease, 2) determine why a healthy immune system is unable to eradicate latent infections, and 3) develop targeted therapies that mitigate disease progression in HIV patients with CM. Using a novel mouse inhalation model of latent cryptococcosis developed in our lab, I will test my central hypothesis that a Th1 CD4 T-cell response is necessary and sufficient to control the latent pulmonary Cn infection, but is unable to clear the infection due to intrinsic deficiencies in interferon-γ (IFNγ) signaling caused by persistent Cn survival within granulomas. In Aim 1, I will combine laser capture microdissection with RNA sequencing to determine the cellular and effector functions responsible for containing Cn within granulomas. In Aim 2, I will use a mouse model that mimics HIV-induced CD4 depletion and post-mortem granulomatous lung tissue biopsies from HIV patients with CM to investigate how HIV-induced loss of CD4 T-cells disrupts control of latent Cn infection within granulomas. In Aim 3, I will use adoptive T-cell transfers and exogenous IFNγ supplementation to elucidate the CD4 T-cell subset and effector functions responsible for controlling latent Cn infection. The long-term goal of these studies is the development of immune-regulated therapeutic strategies for HIV- associated CM. These strategies include clearing latent Cn infection prior to HIV-immunosuppression in at-risk individuals and mitigating disease progression in HIV/AIDS patients by replacing the essential Cn-specific CD4 T-cell subset required for control of Cn infections. This proposal will lay the necessary groundwork for developing therapies that specifically target Cn infection, but avoids eliciting immune reconstitution inflammatory syndrome in HIV/AIDS patients with CM. The proposed research and training plans provide a rigorous program for successful completion of MD- PhD degrees, and will further my development into a successful academic infectious disease physician scientist who drives cutting-edge translational research in HIV/AIDS and HIV-associated opportunistic pathogens.