Pathogenesis of Polymicrobial Cerebritis-Related Dementia

我的实验室的长期目标是了解猪瘟的免疫和环境基础。 炎症性肺部疾病，如哮喘和这些病因在人类疾病中的更广泛作用。 令人费解的是，阿尔茨海默病(AD)是导致痴呆症的最常见原因，也是导致痴呆的第五大原因 在美国老年人中死亡，在流行病学上与哮喘有关，这表明存在共同的 病因。AD是前十大死因中唯一一个无法预防、减缓或 治愈了。AD已经是美国最昂贵的医疗疾病，总成本估计为2000亿美元， 但如果医疗保健得不到改善，预计到2050年，这一数字将达到惊人的1万亿美元。 尽管有这些令人震惊的统计数据和数十年的研究，阿尔茨海默病和相关疾病的根本原因 痴呆症仍不清楚。正如我们之前所展示的，哮喘在许多情况下是由于呼吸道真菌病， 呼吸道粘膜的一种浅表感染，涉及各种真菌。这一发现是对 我们的父应用程序AI135803。此外，阿尔茨海默病与多菌脑感染有关，基于 发现真菌，尤其是白色念珠菌的酵母菌，并在这些人的大脑中发现各种细菌 患有阿尔茨海默病。因此，这种应用的前提是低度多菌脑感染 涉及白色念珠菌和可能来自胃肠道的细菌可能是根本原因 阿尔茨海默病和其他可能的慢性神经退行性疾病。我们的初步研究表明，C. 白念珠菌诱导AD的典型特征，在体内支持真菌感染可能 在某些学科中，AD是基础。我们的进一步研究表明，当白色念珠菌注射到小鼠身上时 通过口服途径逃离胃肠道，与许多细菌一起进入小鼠的大脑， 产生一种以真菌为中心的多菌脑炎。尽管如此，真菌感染的确凿证据 阿尔茨海默病的病因学缺乏。因此，我们假设胃肠道白色念珠菌感染是传播的 血源性脑部与肠道细菌一起建立脑部多菌感染。为了测试 这一假说，我们提出了以下目标：目标1.确定细菌的起源和身份 与多菌脑真菌病(白色念珠菌+细菌)有关。目的2.确定作用机制 白念珠菌和细菌通过这种方式建立多菌脑感染。总之，这些目标将阐明 环境真菌和细菌在多菌脑发病机制中的可能作用 以前与AD有关的感染。

The broad, long-term objectives of my laboratory are to understand the immune and environmental basis of inflammatory lung diseases such as asthma and the broader role of these etiologic factors in human disease. Inexplicably, Alzheimer's disease (AD), the most common cause of dementia and the 5th leading cause of death among elderly Americans, is epidemiologically linked to asthma, suggesting the existence of a shared etiologic factor. AD is the only one among the top 10 causes of death that cannot be prevented, slowed, or cured. AD is already the most expensive medical condition in the US, with total costs estimated at $200 billion, but this is expected to rise to an astonishing $1 trillion by 2050 if improvements in medical care are not found. Despite these alarming statistics and decades of research, the fundamental cause of AD and related dementias remains unknown. As we have previously shown, asthma in many cases is due to airway mycosis, a superficial infection of the airway mucosa involving diverse fungi. This discovery is the central observation in our parent application AI135803. Furthermore, AD has been linked to polymicrobial brain infections based on the discovery of fungi, especially the yeast Candida albicans, and a variety of bacteria in the brains of those suffering from AD. The premise of this application is therefore that low-grade polymicrobial brain infections involving C. albicans and bacteria potentially deriving from the gastrointestinal (GI) tract could be a root cause of AD and potentially other chronic neurodegenerative conditions. Our preliminary studies demonstrated that C. albicans induces canonical features of AD, providing in vivo support of the concept that fungal infection may underlie AD in some subjects. Our additional studies now show that C. albicans when administered to mice through the oral route escape the GI tract and enter the mouse brain together with numerous bacteria, producing a polymicrobial, fungus-centered cerebritis. Nonetheless, definitive evidence of a fungal infectious etiology in AD is lacking. We therefore hypothesize that GI tract infection with C. albicans spreads hematogenously to the brain together with enteric bacteria to establish polymicrobial brain infections. To test this hypothesis, we propose the following Aims: Aim 1. To determine the origin and identity of bacteria associated with polymicrobial cerebral mycosis (C. albicans + bacteria). Aim 2. To determine the mechanism by which C. albicans and bacteria establish polymicrobial brain infections. Together, these aims will elucidate the possible contribution of environmental fungi and bacteria to the pathogenesis of polymicrobial brain infections previously linked to AD.