Fungal pathogen-host interactions: Resolving mechanisms of fungal dissemination to the central nervous system.

We study the pathogenesis of human fungal pathogens with a particular focus on fungi that disseminate to the central nervous system (CNS). Among the pathogens we study is Cryptococcus neoformans (Cn) – the leading cause of fungal meningoencephalitis. Our studies are aimed at resolving the molecular mechanisms mediating the interplay between fungi and the CNS. This interest was spearheaded in part by our study of the extracellular proteome of Cn, where we identified a key fungal secreted metalloprotease, Mpr1, that promotes fungal disease in the CNS. In parallel studies, we identified EphA2, a tyrosine kinase receptor in brain microvascular endothelial cells (a.k.a. the blood-brain barrier) and demonstrated that Cn engages EphA2 in order to access CNS.

Translational Studies.

Current studies include translation of our basic research to develop novel antifungals via drug screens aimed at blocking Mpr1 protease activity,  and developing a platform technology that will deliver therapeutic drugs across the blood-brain barrier by conjugating the Mpr1 to drug-loaded nanocarriers.

Resolving mechanisms of Coccidioides pathogenesis.

Our  research efforts include collaborative studies aimed at the  characterization of a similar protease in the pulmonary-to-CNS dissemination of Coccidioides, the cause of Valley Fever through out the southwestern United States, and a novel diagnostic tool that would differentiate a pulmonary cancer nodule from a fungal nodule.

 

How endothelial cell senescence impacts the integrity of the blood-brain barrier.

Our interest in the blood-brain barrier during pathological conditions has resulted in a collaborative study aimed at understanding how endothelial cell senescence during aging alters blood-brain barrier function and how that impacts the onset of dementia.

 

(Contact: Angie Gelli, acgelli@ucdavis.edu, University of California, Davis)