Pathogenesis of Polymicrobial Cerebritis-Related Dementia

点击翻译按钮获取中文摘要

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.