[
International Worm Meeting,
2005]
In recent years, the use of C. elegans as an alternative host for a variety of human pathogens has driven rapid advances in our understanding of virulence mechanisms. In addition to numerous bacterial pathogens, the work of Mylonakis et al (1) has shown that the yeast Cryptococcus neoformans is capable of killing C. elegans. C. neoformans is the causative agent of cryptococcosis, a life-threatening disease of humans. An improved understanding of the biological mechanism that underlies pathogenicity in this organism is thus of great importance. We now demonstrate that C. neoformans killing of C. elegans is toxin-mediated. The active molecule is a polysaccharide that also plays a critical role as an immunosuppressant during infection of the human host. Thus a single molecule can act as a virulence factor in two highly divergent hosts via two unrelated mechanisms. Using a genetic approach, we are now investigating the role of detoxification mechanisms in host resistance to C. neoformans. In addition, we have identified a number of natural nematode strains that show enhanced survival on C. neoformans, indicative of the intense selective pressure that pathogens have had on the evolution of nematode species. By combining knockout analysis with gene expression profiling, we hope to determine the molecular basis of this resistance mechanism.1. Mylonakis, E., F. M. Ausubel, J. R. Perfect, J. Heitman, and S. B. Calderwood. 2002. Killing of Caenorhabditis elegans by Cryptococcus neoformans as a model of yeast pathogenesis. Proc Natl Acad Sci U S A 99:15675-80.