The molecular basis for the translocation of fungi from blood-to-brain.

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PROJECT ABSTRACT The blood-brain barrier (BBB) is a highly-restrictive and selective structure that protects the central nervous system (CNS). A few pathogens, such as Cryptococcus neoformans (Cn), have managed to overcome the BBB by mechanisms that are still largely unknown. Fungal spores are prevalent in our environment and we become infected following inhalation of aerosolized spores from soil, certain types of trees and pigeon droppings. Once inhaled, spores of Cn proliferate in lung tissue and due to their highly neurotropic nature, disseminate to the CNS. Although observations of fungal cells in the CNS have been reported in real-time and at autopsy, we still do not fully understand the molecular interactions at the brain endothelium or the pathways that mediate the movement of pathogens into the CNS. The proposed research project will address 2 specific aims that are fundamentally different from the parent project but importantly, they address the over-arching goal which is to resolve the molecular mechanisms that define the infiltration of Cn into the CNS and the subsequent effect on over-all brain health. While the parent grant focuses on the role of EphA2-RTK as a mediator of Cn infiltration into the CNS, the supplement study proposed here will examine how a transcellular-paracellular cross-talk in the BBB can favor the infiltration of fungal pathogens across the BBB. The aims will test the hypothesis that a paracellular pathway across the BBB contributes to the infiltration of Cn into the CNS as a consequence of cytoskeleton remodeling induced by Cn. Specific aim 1 will examine whether transcytosis and the opening of a paracellular path are normally linked or co-regulated in healthy brains or if pathogens can selectively activate both pathways. Specific aim 2 will involve ex-vivo studies to determine whether pathogens can destabilize tight junctions and induce a concomitant paracellular opening. The proposed studies will have a direct impact on developing new therapeutics that could prevent neuroinfections and on designing novel strategies for technologies geared toward crossing the BBB to deliver cargo to the brain. The proposed project is intended as a supplement to promote diversity in the biomedical sciences. The supplement candidate, Amelia Bennett, has a strong interest in neuroscience specifically, neuroinfections, and was motivated to join my lab so that she could study the molecular mechanisms that drive a human fungal pathogen, Cn, into the central nervous system (CNS). This area of research is understudied despite the significant morbidity and mortality that is associated with fungal meningoencephalitis. Through this project Amelia will acquire expertise in neuroinfections and use this to establish a niche that will allow her to be competitive in her research career. The project has been specifically designed to enhance Amelia’s participation in biomedical research, to provide Amelia with the research skills needed for a successful career as an independent scientist and to provide Amelia with the professional career training that will allow her to thrive as a researcher, educator and mentor in biomedical sciences in academia.