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.

项目概要 隐球菌性脑膜炎 (CM)，由机会性真菌病原体新生隐球菌引起 (Cn) 是全球健康个体中与艾滋病毒相关的死亡的主要原因。 儿童时期导致无症状的肺部潜伏感染，但导致肺部形成 与 HIV 相关的免疫系统受损后，控制体内潜伏的 Cn 感染。 肺部肉芽肿消失，真菌病原体播散，引起宿主免疫。 对于建立和维持潜在 Cn 感染控制至关重要的细胞和效应器功能尚未得到研究 在高级艾滋病毒护理的背景下，有必要清除潜伏感染。 健康的免疫反应控制潜在的 Cn 感染需要：1）定义关键的免疫功能， 预防疾病，2) 确定健康的免疫系统为何无法根除潜伏感染，以及 3) 使用新型小鼠开发靶向疗法，以减轻患有 CM 的 HIV 患者的疾病进展。 我们实验室开发了潜伏性隐球菌病吸入模型，我将测试我的中心假设，即 Th1 CD4 T 细胞反应对于控制潜伏性肺部 Cn 感染是必要且充分的，但无法 清除因 Cn 持续存活而导致的干扰素-γ (IFNγ) 信号传导内在缺陷引起的感染 在目标 1 中，我将结合激光捕获显微切割和 RNA 测序来确定。 负责在肉芽肿中包含 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 耗竭和死后肉芽肿性肺组织活检的小鼠模型 来自患有 CM 的 HIV 患者的研究，旨在研究 HIV 诱导的 CD4 T 细胞丢失如何破坏潜在 CN 的控制 在目标 3 中，我将使用过继性 T 细胞移植和外源性 IFNγ 补充剂。 阐明负责控制潜在 Cn 感染的 CD4 T 细胞亚群和效应器功能。 这些研究的长期目标是开发针对艾滋病毒的免疫调节治疗策略 这些策略包括在高危人群中进行 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 来减轻 HIV/AIDS 患者的疾病进展 该提案将为控制 Cn 感染奠定必要的基础。 开发专门针对 Cn 感染但避免引发免疫重建的疗法 患有 CM 的 HIV/AIDS 患者的炎症综合征。 拟议的研究和培训计划为成功完成医学博士提供了严格的计划 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尖端转化研究的科学家 病原体。