Leah Cowen

Microbial pathogens cause a myriad of infectious diseases and are a leading cause of human mortality worldwide. Human health relies critically on maintaining effective drugs to combat infectious disease. This is a perpetual challenge, as the evolution of drug resistance is ubiquitous in nature. With the growing immunocompromised population due to organ transplant, chemotherapy, and AIDS, the frequency of life-threatening fungal infections has sharply increased. Clinically useful antifungal drugs are limited and resistance compromises the efficacy of all. Innovative approaches to understanding mechanisms of fungal evolution, drug resistance, and pathogenesis are crucial for maintaining effective therapeutic strategies. Since fungi are eukaryotes like their human hosts, they also afford a unique window into the molecular mechanisms driving eukaryotic evolution.

Research in my laboratory explores the role of global cellular regulators in fungal evolution, drug resistance, and pathogenesis. Much of our work focuses on the mechanisms by which changes in the molecular chaperone Hsp90 (heat shock protein 90) can drive adaptive evolution. Hsp90 is an essential molecular chaperone that regulates the form and function of diverse client proteins, many of which are key regulators of cellular signaling. Our research is motivated by the discovery that in fungi separated by ~ 800 million years of evolution, Hsp90 potentiates the evolution of drug resistance by enabling specific signal transduction networks. Hsp90 inhibitors abrogate drug resistance of diverse fungal pathogens, suggesting new therapeutic strategies. Hsp90 is a central modulator of phenotypic diversity in eukaryotes providing strong rationale for Hsp90 to mitigate the evolution of host-pathogen interactions. Our interdisciplinary approach incorporates state-of-the-art genomic and imaging technologies, experimental evolution, molecular genetics, and models of fungal pathogenesis. This work will reveal novel mechanisms enabling fungal evolution, drug resistance, and pathogenesis as well as new strategies for treating infectious disease.

1. Cowen, L.E., Carpenter, A.E., Matangkasombut, O., Fink, G.R. and Lindquist, S. 2006. Genetic Architecture of Hsp90-Dependent Drug Resistance. Eukaryot. Cell. 5:2184-8.

2. Cowen, L.E. and Lindquist, S. 2005. Hsp90 Potentiates the Rapid Evolution of New Traits: Drug Resistance in Diverse Fungi. Science. 309: 2185-89.

3. Anderson, J.B., Sirjusingh, C., Parsons, A., Boone, C., Wickens, C., Cowen, L.E., Kohn, L.M. 2003. Mode of Selection and Experimental Evolution of Antifungal Drug Resistance. Genetics 163: 1287-98.

4. Cowen, L.E., Nantel, A., Whiteway, M.S., Thomas, D.Y., Tessier, D.C., Kohn, L.M., Anderson, J.B. 2002. Population Genomics of Drug Resistance in Candida albicans. Proc. Natl. Acad. Sci. U.S.A. 99: 9284-89.

5. Cowen, L.E., Anderson, J.B., Kohn, L.M. 2002. Evolution of Drug Resistance in Candida albicans. Annu. Rev. Microbiol. 56: 139-65.

6. Cowen, L.E. 2001. Predicting the Emergence of Resistance to Antifungal Drugs. FEMS Microbiol. Lett. 204: 1-7.

7. Cowen, L.E., Kohn, L.M., Anderson, J.B. 2001. Divergence in Fitness and Evolution of Drug Resistance in Experimental Populations of Candida albicans. J. Bacteriol. 183: 2971-78.

8. Luu, L.N., Cowen, L.E., Sirjusingh, C., Kohn, L.M., Anderson, J.B. 2001. Multilocus Genotyping Indicates That the Ability to Invade the Bloodstream is Widespread Among Candida albicans Isolates. J. Clin. Microbiol. 39: 1657-60.

9. Anderson, J.B., Wickens, C., Khan M., Cowen, L.E., Federspiel, N., Jones, T., Kohn, L.M. 2001. Infrequent Genetic Exchange and Recombination in the Mitochondrial Genome of Candida albicans. J. Bacteriol. 183: 865-72.

10. Cowen, L.E., Sanglard, D., Calabrese, D., Sirjusingh, C., Anderson, J.B., Kohn, L.M. 2000. Evolution of Drug Resistance in Experimental Populations of Candida albicans. J. Bacteriol. 182: 1515-22.

11. Cowen, L.E., Sirjusingh, C., Summerbell, R.C., Walmsley, S., Richardson, S., Kohn, L.M., Anderson, J.B. 1999. Multilocus Genotypes and DNA Fingerprints do not Predict Variation in Azole Resistance Among Clinical Isolates of Candida albicans. Antimicrob. Agents Chemother. 43: 2930-38.

Leah E. Cowen, Ph.D.

Fungal Evolution, Drug Resistance, and Infectious Disease

Publications