Stephen M. Beverley, PhD

Washington University in St. Louis (WU)

Our laboratory is interested in tropical infectious diseases, focusing on the protozoan parasite Leishmania which afflicts more than 10 million people world wide. It is a common opportunistic AIDS disease around the Mediterranean and several thousand cases are emerging in US soldiers returning from the Mideast. We have developed a wide array of molecular genetic, genomic, cell biological and biochemical tools of the genome, and are applying these towards dissecting how the parasites carry out their infectious cycle in both mammals and the sand fly vector which transmits them. We are interested in parasite molecules which play key roles in antigenic variation, macrophage survival, and disease progression, many of which constitute the surface glycocalyx. As our work is carried directly in a serious pathogen, it is perhaps unsurprising that many findings have potential clinical applications. Several of the ‘virulence’ pathways above as well as other metabolic pathways show great promise for development of selective chemotherapies. Our ability to modify the parasite genome easily permits us to generate attenuated candidate vaccine lines. One early line lacking the key metabolic enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) is slated to be tested shortly in one of the first such tests with Leishmania in humans in the Mideast. Recent studies yielded a remarkable parasite (lpg2-) able to indefinitely ‘persist without pathology’, while simultaneously showing great promise for long term and effective immunization in mouse models. Now we are studying how they accomplish this feat mechanistically, and how to extend these results to human vaccines.