Faculty and Research
J. Andrew Alspaugh, MD
Department of Medicine, Division of Infectious Diseases
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.