The focus of my research is to understand the mechanisms of microbial pathogenesis using the tools of fungal genetics. I am especially interested in the ways in which microorganisms sense and respond to changes in their environment. For example, as microbial pathogens enter the microenvironment of the infected host, dramatic genetic and phenotypic events occur that allow these organisms to survive in this harsh environment. We study the model fungal organism Cryptococcus neoformans to elucidate signal transduction pathways associated with fungal pathogenicity. This important human pathogen displays well-characterized and inducible virulence determinants. It also offers an excellent genetic system to study microbial pathogenesis. Importantly, the genome of this fungus is now being sequenced. Such attributes make it an ideal system for dissecting the signaling pathways associated with pathogenicity.

The main techniques used in our lab are those of molecular genetics. We are now able to readily clone C. neoformans genes and to disrupt them by homologous recombination. Mutant strains with disruptions in targeted genes are then evaluated in vitro for various mutant phenotypes including altered expression of virulence determinants such as polysaccharide capsule and melanin. The effects of gene disruption on pathogenicity are also evaluated in various animal models of systemic cryptococcal disease. Using these techniques, we have demonstrated that conserved signal transduction pathways have been co-opted by pathogens to enable parasitism of the host. For example, we recently identified a novel G-alpha protein/cAMP-dependent signaling pathway associated with mating and pathogenicity in C. neoformans. Additionally, we have also demonstrated that Ras signaling pathways control pathogenicity and development in this organism. Other components of these pathways are now been identified and their roles in pathogenesis are being evaluated.

This research is complemented by the work of other investigators in the Duke University Mycology Research Unit. The members of this research community are pursuing studies in fungal pathogenesis, identifying novel antifungal drug targets, and studying the ecology of several medically important fungi.