Research Abstract:
We study the protozoan parasite Leishmania, infecting more than 10 million people in tropical regions. We want to understand how the parasite carries out its infectious cycle, which comprises an intracellular phagolysosomal stage within vertebrate macrophages and an extracellular stage within the gut of a sand fly vector.
We have developed powerful methods such as functional genetic rescue, gene knockouts, transposon mutagenesis and DNA microarrays. We have identified many genes with ‘interesting’ functions, expression patterns and/or database relationships and assessed their role in virulence using a variety of genetic and biochemical methods. Parasites can be grown readily in culture under conditions where they differentiate well, and there are excellent mouse models enabling dissection of host defenses.
One fruitful genetic screen involves a surface glycoconjugate, lipophosphoglycan (LPG), an essential virulence determinant involved in adhesion and survival. LPG genes encode proteins involved in biosynthesis, compartmentalization of LPG intermediates within the eukaryotic secretory pathway, and regulation. We are especially interested in understanding the role of LPG in manipulating host cell signal transduction, which is radically altered in Leishmania infections, and in sand fly transmission and co-evolution.
Another focus involves novel biochemical pathways implicated in chemotherapy and drug resistance. Leishmania are auxotrophic for folates and pteridines, and we are characterizing this pathway genetically, biochemically and structurally. Remarkably, biopterin metabolism was recently implicated in the control of Leishmaniavirulence.
Other interests of the lab include parasite chromosome structure and organization, gene regulation, molecular evolution of parasitism and virulence, and the use of modified parasites as vaccines.
Selected Publications:
Akopyants NS, Clifton SW, Martin J, et al. A survey of the Leishmania major Friedlin strain VI genome by shotgun sequencing: A resource for DNA microarrays and expression profiling. Mol Biochem Parasitol 2001 113:337-340.
Cunningham ML, Titus R, Turco SJ, Beverley SM. Regulation of differentiation to the infective stage of the protozoan parasite Leishmania by tetrahydrobiopterin. Science 2001 292:285-287.
Späth GF, Epstein L, Leader B, et al. Lipophosphoglycan (LPG) is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania majo. Proc Natl Acad Sci USA 2000 97:9258-9263.
Gueiros-Filho FJ, Beverley SM. Trans-kingdom transposition: Mobilization of the Drosophila element mariner in the protozoan Leishmania. Science 1997 276:1716-1719.
Beverley SM. Hijacking the cell: Parasites in the driver’s seat. Cell 1996 78:787-789.
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