The adaptive host response to latent cryptococcosis

宿主对潜伏隐球菌病的适应性反应

• 批准号: 10257692
• 负责人: Minna Ding
• 金额: $ 3.98万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10257692
• 关键词: AIDS-Related Opportunistic Infections; AIDS/HIV problem; Acute; Address; Autopsy; Biopsy; CD4 Positive T Lymphocytes; Caring; Cell Count; Cells; Cellular Immunology; Central Nervous System Infections; Clinical; Communicable Diseases; Containment; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Defect; Development; Disease; Disease Progression; Disease model; Doctor of Philosophy; Exposure to; Fostering; Goals; Granuloma; Granulomatous; Growth; HIV; Histologic; Human; Immune; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Immunology; Immunosuppression; Individual; Infection; Inflammatory; Inhalation; Interferon Type II; Interferons; Kinetics; Lead; Life; Link; Lung; Lung infections; Macrophage Activation; Mediating; Meningitis; Modeling; Mus; Patients; Phenotype; Physicians; Population; Production; RNA analysis; Rattus; Regimen; Reproduction spores; Research Personnel; Research Training; Risk; Scientist; Signal Transduction; Structure; Structure of parenchyma of lung; Supplementation; Symptoms; Syndrome; T cell response; T cell therapy; T-Cell Depletion; T-Lymphocyte Subsets; Techniques; Testing; Th1 Cells; Therapeutic; Time; Tissue-Specific Gene Expression; Training; Translational Research; Yeasts; adaptive immune response; design; early childhood; experimental study; immune function; immune reconstitution; immunomodulatory strategy; improved; insight; laser capture microdissection; latent infection; logarithm; mortality; mouse model; new therapeutic target; novel; opportunistic pathogen; pathogenic fungus; prevent; programs; pulmonary granuloma; reactivation from latency; response; targeted treatment; therapy development; transcription factor; transcriptome sequencing

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.

项目摘要 由机会性真菌病原体新形型引起的隐球菌脑膜炎（CM） （CN）是全球与HIV相关死亡率的主要原因。在健康的个体中，早期接触CN 儿童期导致无症状的肺潜伏感染，但导致肺的形成 颗粒。在免疫系统的HIV相关妥协之后，控制潜在CN感染 肺肉芽肿丢失，真菌病原体传播会引起脑膜炎。宿主免疫 细胞和效应子对于建立和维持对潜在CN感染的控制至关重要 确定。在高级艾滋病毒护理的背景下，有必要清除潜在感染。了解如何 健康免疫反应控制潜在的CN感染：1）定义关键免疫功能 预防疾病，2）确定为什么健康的免疫系统无法放射性潜在感染，而3） 开发靶向疗法，以减轻CM HIV患者的疾病进展。使用新颖的鼠标 在我们的实验室中开发的潜在隐球菌的吸入模型，我将测试我的中心假设，即Th1 CD4 T细胞反应是必要的，足以控制潜在的肺CN感染，但无法 清除因持续的CN存活而引起的干扰素-γ（IFNγ）信号传导中固有缺陷引起的感染 在颗粒中。在AIM 1中，我将将激光捕获微分辨率与RNA测序相结合以确定 细胞和效应子功能负责含有颗粒中的CN。在AIM 2中，我将使用 模仿HIV引起的CD4部署和验尸后肉芽肿组织活检的小鼠模型 来自CM的HIV患者，研究HIV诱导的CD4 T细胞损失如何破坏对潜在CN的控制 在AIM 3中，我将使用自适应T细胞转移和外源性IFNγ补充 阐明负责控制潜在CN感染的CD4 T细胞子集和效应子功能。这 这些研究的长期目标是发展免疫调节的HIV治疗策略 相关CM。这些策略包括在高风险的HIV免疫抑制之前清除潜在的CN感染 通过替换必需的CN特异性CD4来替换艾滋病毒/艾滋病患者的疾病进展 控制CN感染所需的T细胞子集。该提议将为 开发专门针对CN感染的疗法，但避免引起免疫重建 艾滋病毒/艾滋病商业患者的炎症综合征。 拟议的研究和培训计划为成功完成MD-提供了严格的计划 博士学位，将进一步发展成为成功的学术传染病医师 驾驶前沿的科学家翻译了艾滋病毒/艾滋病和艾滋病毒相关的机会主义研究 病原体。