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

基本信息

批准号：
10626786
负责人：
Makoto Inoue
金额：
$ 38万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-03 至 2025-05-31
项目状态：
未结题

项目摘要

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.

项目摘要/摘要加密赛相关的免疫重构炎症综合征（C-IRI）在在恢复免疫功能之前，先前先感染了隐孢子虫的免疫功能低下的患者。已知C-IRI发生在接受抗逆转录病毒疗法的HIV患者中，可恢复免疫 CD4+ T细胞等组件。在接受A的免疫功能低下的患者中，还报告了C-IRI 固体器官移植，多发性硬化症患者，停止纳塔尔珠单抗治疗和产后女性。这表明与免疫状态快速变化有关的任何临床状况是有利于c-iris。 C-IRI的患者通常出现肺部功能障碍，脑水肿和脑病变。 C-iris可能是致命的。目前，免疫系统重建引起的机制对潜在的隐孢子菌感染患者的有害信号传导知之甚少。解决这项重大的临床挑战，我们使用加密赛建立了第一个可靠的小鼠模型 Neoformans（CN）血清型A菌株H99。 CN H99是最常见的CN血清型环境和临床样品。我们预感染了CN的免疫功能低下的小鼠的模型 H99并接受CD4+ T细胞转移的表现，表现出使人联想到C-IRIS人类患者的表型。我们的 c-iris小鼠在大脑，脑水肿，脑干神经元中显示出大量的CN H99和CD4+ T细胞损伤和肺部功能障碍，没有肺组织学损害。因此，我们假设1）CN 脑中的H99触发CD4+ T迁移到该器官，2）脑浸润CD4+ T和先天免疫细胞损害脑干神经元，该神经元直接和/或间接通过水肿控制呼吸功能，并且 3）脑干神经元损害会导致肺部功能障碍和最终死亡。我们的目标是确定这些关键症状的基础机制，以铺平目标发展的道路 C-IRIS的临床治疗学。在AIM 1中，我们将确定CD4+ T细胞亚型和先天免疫的作用大脑中的细胞进行C-IRIS发育。此外，我们将通过靶向CD4+ T细胞和CN H99向大脑迁移并上调共刺激分子。在AIM 2中，我们将确定脑干中的肺部神经元的损害是否导致肺 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虹膜小鼠通过靶向四个候选途径（脑水肿，脑CD4+ T细胞神经毒性，脑率先免疫细胞神经毒性和脑CN H99）。提议的实验的完成将解开如何免疫系统重建会引起C-IRIS的有害信号传导，并扩大目标治疗性途径对于C-iris。此外，这项研究将提供有关适应性免疫的机械见解反应调节大脑神经元功能。这项研究的结果还将为新的研究领域开放研究自身免疫性和神经退行性疾病的潜在感染成分。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

T cell infiltration into the brain triggers pulmonary dysfunction in murine Cryptococcus-associated IRIS.

DOI：
10.1038/s41467-023-39518-x
发表时间：
2023-06-28
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Kawano, Tasuku;Zhou, Jinyan;Anwar, Shehata;Salah, Haneen;Dayal, Andrea H.;Ishikawa, Yuzuki;Boetel, Katelyn;Takahashi, Tomoko;Sharma, Kamal;Inoue, Makoto
通讯作者：
Inoue, Makoto

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