Brain neuron damage-mediated respiratory failure and mortality during Cryptococcus-associated immune reconstitution inflammatory syndrome in mice

隐球菌相关免疫重建炎症综合征期间脑神经元损伤介导的呼吸衰竭和死亡率

• 批准号: 10406338
• 负责人: Makoto Inoue
• 金额: $ 38.05万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-03 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406338
• 关键词: Address; Adrenal Cortex Hormones; Animal Model; Appearance; Area; Autoimmune Diseases; B-Lymphocytes; Brain; Brain Edema; Brain Injuries; Brain Stem; CCR5 gene; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cessation of life; Clinical; Clinical Management; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Development; Diphtheria Toxin; Disease; Edema; Environment; Ephrin-B3; FDA approved; Functional disorder; Goals; HIV; Histologic; Human; Immune; Immune system; Immunocompromised Host; Immunosuppression; Infection; Infiltration; Inflammation; Inflammatory; Injections; Integrin alpha4; Intravenous; Label; Lead; Lesion; Life; Location; Lung; Mediating; Microglia; Modeling; Mus; Mycoses; Natural Immunity; Neurites; Neurodegenerative Disorders; Neurons; Non-Steroidal Anti-Inflammatory Agents; Organ; Organ Transplantation; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Postpartum Women; Predisposition; Rag1 Mouse; Reactive Oxygen Species; Recovery; Regulatory T-Lymphocyte; Reporting; Research; Respiration; Respiratory Failure; Respiratory physiology; Rho-associated kinase; Risk; Role; Sampling; Semaphorins; Serotyping; Signal Transduction; Solid; Symptoms; Syndrome; System; T cell reconstitution; T-Lymphocyte; TNFSF5 gene; Techniques; Th1 Cells; Therapeutic; Therapeutic Human Experimentation; Therapeutic Intervention; Tissues; Translational Research; Tumor-infiltrating immune cells; adaptive immune response; adaptive immunity; antiretroviral therapy; aquaporin 4; base; cell injury; cell motility; clinically relevant; cytokine; disease mechanisms study; experience; experimental study; immune function; immune reconstitution; immunological status; insight; lung injury; macrophage; migration; mortality; mouse model; multiple sclerosis patient; natalizumab; neuron loss; neurotoxic; neurotoxicity; neutrophil; novel; pathogen; reconstitution; targeted treatment; therapeutic target; therapeutically effective

PROJECT SUMMARY/ABSTRACT Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is induced in immunocompromised patients who were pre-infected with Cryptococcus before recovering immune function. C-IRIS is known to occur in HIV patients who received antiretroviral therapy, which restores immune components such as CD4+ T cells. C-IRIS is also reported in immunocompromised patients who received a solid-organ transplant, multiple sclerosis patients who discontinue Natalizumab treatment, and postpartum women. This suggests that any clinical condition associated with a rapid change in immune status is conducive to C-IRIS. Patients with C-IRIS typically present with pulmonary dysfunction, brain edema, and brain lesions. C-IRIS can be fatal. Currently, the mechanism by which immune system reconstitution induces detrimental signaling in patients with an underlying Cryptococcus infection is poorly understood. To resolve this significant clinical challenge, we established the first reliable mouse model using the Cryptococcus neoformans (Cn) serotype A strain H99. Cn H99 is the most common Cn serotype to be isolated from the environment and from clinical samples. Our model of immunocompromised mice that are pre-infected with Cn H99 and received CD4+ T cell transfer show phenotypes reminiscent of those in C-IRIS human patients. Our C-IRIS mice show an abundance of Cn H99 and CD4+ T cells in the brain, brain edema, brainstem neuronal damage, and pulmonary dysfunction without lung histological damage. Therefore, we hypothesize that 1) Cn H99 in the brain trigger CD4+ T migration to this organ, 2) brain-infiltrating CD4+ T and innate immune cells damage brainstem neurons, which control respiratory function, directly and/or indirectly through edema, and that 3) brainstem neuronal damage leads pulmonary dysfunction and eventual death. Our objective is to identify the mechanisms underlying these key symptoms to pave the way toward the development of targeted clinical therapeutics for C-IRIS. In Aim 1, we will identify the role of CD4+ T cell subtypes and innate immune cells in the brain for C-IRIS development. In addition, we will identify the potential therapeutic strategies by targeting CD4+ T cell and Cn H99 migration to the brain and upregulated co-stimulatory molecules. In Aim 2, we will determine whether damage of lung-innervating neurons in the brainstem leads to pulmonary dysfunction and death in C-IRIS mice. We will also identify the mechanism of brain neuronal damage in C- IRIS mice by targeting four candidate pathways (brain edema, brain CD4+ T cell neurotoxicity, brain innate immune cell neurotoxicity, and brain Cn H99). Completion of the proposed experiments will unravel how immune system reconstitution induces detrimental signaling in C-IRIS and expand targeted therapeutic avenues for C-IRIS. Furthermore, this study will provide mechanistic insights into how adaptive immune responses modulate brain neuronal function. Findings from this study will also open a new area of research to investigate the potential infective component in autoimmune and neurodegenerative diseases.

项目概要/摘要 隐球菌相关免疫重建炎症综合征 (C-IRIS) 是在 在免疫功能恢复之前预先感染隐球菌的免疫功能低下患者。 已知 C-IRIS 发生在接受抗逆转录病毒治疗的 HIV 患者中，该治疗可恢复免疫功能 CD4+ T 细胞等成分。在接受过治疗的免疫功能低下患者中也有报道出现 C-IRIS 实体器官移植、停止那他珠单抗治疗的多发性硬化症患者以及产后 女性。这表明任何与免疫状态快速变化相关的临床病症都是 有利于C-IRIS。 C-IRIS 患者通常表现为肺功能障碍、脑水肿和 脑部病变。 C-IRIS 可能是致命的。目前，免疫系统重建诱导的机制 对于潜在隐球菌感染患者的有害信号传导知之甚少。解决 为了应对这一重大临床挑战，我们使用隐球菌建立了第一个可靠的小鼠模型 新型隐球菌 (Cn) 血清型 A 菌株 H99。 Cn H99 是从 Cn 中分离出的最常见的 Cn 血清型 环境和临床样本。我们预先感染 Cn 的免疫受损小鼠模型 H99 和接受 CD4+ T 细胞转移的表型与 C-IRIS 人类患者的表型相似。我们的 C-IRIS小鼠大脑中显示大量Cn H99和CD4+T细胞，脑水肿，脑干神经元 损伤和肺功能障碍而无肺组织学损伤。因此，我们假设 1) Cn 大脑中的 H99 触发 CD4+ T 迁移到该器官，2) 大脑浸润 CD4+ T 和先天免疫细胞 损害直接和/或通过水肿间接控制呼吸功能的脑干神经元，以及 3）脑干神经元损伤导致肺功能障碍并最终死亡。我们的目标是 确定这些关键症状背后的机制，为开发有针对性的药物铺平道路 C-IRIS 的临床治疗。在目标 1 中，我们将确定 CD4+ T 细胞亚型和先天免疫的作用 大脑中用于 C-IRIS 发育的细胞。此外，我们将通过以下方式确定潜在的治疗策略： 靶向 CD4+ T 细胞和 Cn H99 迁移至大脑并上调共刺激分子。在目标 2 中， 我们将确定脑干中支配肺的神经元的损伤是否会导致肺损伤 C-IRIS 小鼠的功能障碍和死亡。我们还将确定 C-中脑神经元损伤的机制 IRIS 小鼠通过靶向四种候选途径（脑水肿、脑 CD4+ T 细胞神经毒性、脑先天性 免疫细胞神经毒性和大脑 Cn H99)。完成所提出的实验将揭示如何 免疫系统重建会在 C-IRIS 中诱导有害信号传导并扩大靶向范围 治疗性的 大道 对于 C-IRIS。此外，这项研究将为适应性免疫如何发挥作用提供机制见解。 反应调节大脑神经元功能。这项研究的结果也将开辟一个新的研究领域 研究自身免疫性疾病和神经退行性疾病中潜在的感染成分。