Chronic Murine Cerebral Mycosis: Pathogenesis, Neuroimmune Response, and Relevance to Alzheimer's Disease

慢性鼠脑真菌病：发病机制、神经免疫反应以及与阿尔茨海默病的相关性

• 批准号: 10723848
• 负责人: Lynn Bimler
• 金额: $ 12.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723848
• 关键词: 16S ribosomal RNA sequencing; Affect; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antifungal Agents; Anxiety; Aspartic Endopeptidases; Bacteria; Bacterial Adhesins; Behavior; Biological Response Modifiers; Blocking Antibodies; Blood - brain barrier anatomy; Blood Circulation; Brain; C57BL/6 Mouse; Candida albicans; Cause of Death; Cells; Cerebrum; Characteristics; Chronic; Complement; Data; Dementia; Deposition; Development; Diagnosis; Disease; Disease Progression; Dose; Enterobacteriaceae; Enzyme-Linked Immunosorbent Assay; Filament; Fright; Gastritis; Gastrointestinal tract structure; Genes; Genotype; Genus staphylococcus; Granuloma; Harvest; Histologic; Histology; Human; Immune; Immune Evasion; Immune response; Infection; Inflammatory; Interferons; Intestines; Intravenous; Invaded; Link; Lytic; Memory Loss; Memory impairment; Modeling; Monitor; Morphology; Mus; Neoplasm Metastasis; Neurofibrillary Tangles; Neuroimmune; Neuroimmunomodulation; Neurologic Dysfunctions; Oral; Pathogenesis; Pathogenicity; Pathologic; Peptides; Physiological; Proteolysis; Proteome; Public Health; Publishing; Recurrence; Research; Role; Sampling; Senile Plaques; Site; Structure; Surface; Tauopathies; Testing; Tissues; Toxin; Transgenic Mice; United States; Virulence Factors; Western Blotting; Yeasts; apolipoprotein E-4; behavior test; blood-brain barrier penetration; brain size; candidemia; cognitive function; cytokine; disease phenotype; enteritis; fungus; gut bacteria; gut colonization; gut inflammation; intravenous administration; migration; mouse model; mutant; novel; prevent; response; success; synthetic polymer Bioplex; tau-1; translational model; transmission process; yeast infection

Alzheimer’s Disease (AD) is the sixth leading cause of death in the United States and the only cause of death in the top ten that cannot be effectively prevented, treated, or cured. Recent evidence suggests that AD may be linked to fungal brain infections. To rigorously study this possibility, we established a model of cerebral mycosis by intravenously (IV) injecting the pathogenic yeast Candida albicans, which transits the blood brain barrier to establish a parenchymal brain infection. The resulting cerebral mycosis induces mild memory deficits and fungal induced glial granulomas (FIGGs) consisting of microglial aggregates, amyloid β (aβ) deposits, and amyloid precursor protein (APP) surrounding yeast aggregates. This structure essentially duplicates AD’s characteristic senile plaques, but the cerebral mycosis and memory loss are transient, not persisting beyond 10 days after a single intravenous infection. In contrast, AD involves numerous senile plaques and tauopathy that presumably accrue over many years in the setting of chronic cerebral mycosis that is linked to progressive, irreversible dementia. This raises the key possibility that C. albicans might persist in a remote tissue site, such as the intestines, from which it might periodically mobilize to chronically re-infect the brain. As both C. albicans colonization of the GI tract and low-level candidemia deriving from the GI tract have been documented in humans, we hypothesize that chronic C. albicans enteritis leads to low-level transmission of fungal cells into the bloodstream and persistent cerebral mycosis. To test this hypothesis and establish a more translationally relevant chronic model, we administered yeast from C. albicans to wildtype C57BL/6 mice via oral gavage. We found that live yeast are recoverable from the brain as soon as 2 days post gavage and out to at least day 58 and this persistence is altered in human APOE4 transgene mice, which express the human allele of APOE that is linked to two-thirds of AD cases. Additionally, these colonies were polymicrobial, consisting of both yeast and bacteria, an observation that is consistent with recent published analysis and our own cultures of AD brains that demonstrate polymicrobial brain infections involving both fungi and bacteria. Consistent with our previous IV model, chronically infected WT mice present with elevated brain aβ 1-40 and 1-42 and both genotypes present with abnormal behavior. To further determine the potential of this model as a translational model for AD, we propose the following aims: (1) to determine the histopathological and physiological brain response to polymicrobial infection, (2) To determine the mechanism of metastasis of gut fungi and bacteria to the brain, (3) to determine effect of gastric inflammation on metastasis of gut fungi and bacteria to the brain. Through this study we will establish if this infection produces an AD phenotype, how this infection invades the brain and persists in the host, and the immune mechanisms involved in fungal clearance. This research is groundbreaking for the AD field, suggesting the use antifungals as treatment and prevention for AD, elucidating novel neuroimmune mechanisms, and producing an unprecedented model for AD therapeutic and mechanistic studies.

阿尔茨海默病（AD）是美国第六大死因，也是美国唯一的死因 无法有效预防、治疗或治愈的十大疾病。最近的证据表明 AD 可能是 与大脑真菌感染有关。为了严格研究这种可能性，我们建立了脑真菌病模型 通过静脉内 (IV) 注射致病性酵母白色念珠菌，该酵母可穿过血脑屏障 建立脑实质感染。由此产生的脑真菌病会导致轻度记忆缺陷和真菌感染 诱导性神经胶质肉芽肿 (FIGG)，由小胶质细胞聚集体、β 淀粉样蛋白 (aβ) 沉积物和淀粉样蛋白组成 酵母聚集体周围的前体蛋白（APP）。这种结构本质上复制了AD的特征 老年斑，但脑霉菌病和记忆力减退是暂时的，术后不会持续超过 10 天。 单次静脉感染。相比之下，AD 涉及大量老年斑和 tau 蛋白病，可能 在慢性脑真菌病的情况下多年积累，与进行性、不可逆转有关 失智。这提出了白色念珠菌可能持续存在于远程组织部位的关键可能性，例如 它可能会定期从肠道中动员起来，长期地重新感染大脑。由于两种白色念珠菌 胃肠道定植和源自胃肠道的低水平念珠菌血症已在 在人类中，我们假设慢性白色念珠菌肠炎导致真菌细胞低水平传播到肠道 血流和持续性脑真菌病。为了测试这个假设并建立一个更平移的 相关的慢性模型中，我们通过口服管饲法向野生型 C57BL/6 小鼠施用来自白色念珠菌的酵母。我们 发现灌胃后 2 天即可从大脑中回收活酵母，并且至少持续到第 58 天 这种持久性在人类 APOE4 转基因小鼠中发生了改变，这些小鼠表达了 APOE 的人类等位基因 与三分之二的 AD 病例有关。此外，这些菌落是多种微生物，由酵母和 细菌，这一观察结果与最近发表的分析和我们自己的 AD 大脑培养物一致 证明涉及真菌和细菌的多种微生物脑部感染。和我们之前的IV一致 模型中，慢性感染的 WT 小鼠大脑 aβ 1-40 和 1-42 升高，并且两种基因型均存在 具有异常行为。为了进一步确定该模型作为 AD 转化模型的潜力，我们 提出以下目标：（1）确定大脑的组织病理学和生理学反应 多种微生物感染，(2) 确定肠道真菌和细菌向大脑转移的机制，(3) 确定胃炎症对肠道真菌和细菌向大脑转移的影响。通过这个 我们将进行研究以确定这种感染是否会产生 AD 表型、这种感染如何侵入大脑以及 持续存在于宿主体内，免疫机制参与真菌清除。这项研究具有开创性 对于 AD 领域，建议使用抗真菌药物作为 AD 的治疗和预防，阐明新的 神经免疫机制，并为 AD 治疗和机制研究提供了前所未有的模型。