General Interests
Our laboratory seeks to understand how gene are
expressed and regulated in the organisms that
cause the major tropical diseases of the world, such as trypanosomiasis, leishmaniasis and malaria. These parasitic organisms evade the human
immune system using sophisticated molecular mechanisms that are based on the appearance of unique surface proteins at
the appropriate times during infection. Our goal is to determine, at the DNA and RNA level, how these parasites developmentally
regulate the production of these proteins in anticipation that this information will help to eliminate or better
control these diseases.
Variant Surface Glycoprotein (VSG)
One project in the lab involves the characterization of gene rearrangements that occur in African trypanosomes. These protozoan
parasites are transmitted by tsetse flies to the bloodstream of humans and animals
in sub-Saharan Africa where they cause the disease
trypanosomiasis (sleeping sickness). African trypanosomes avoid their host's immune system by periodically switching their major surface
protein, a process called antigenic variation. A given trypanosome can sequentially express several hundred of these
different variant surface glycoproteins (VSGs) as it continually escapes the
host's antibodies directed against it. We have
isolated the genes for several VSGs and demonstrated that gene duplications often govern the selection of a specific VSG
gene to be transcribed, while excluding all of the other VSG genes from expression. The expressed, duplicated gene is
always located near a chromosomal telomere. We are currently studying the promoters that
regulate transcription of these
telomere-linked VSG expression sites, and we are examining the possible mechanisms that might be responsible for the high rate
of mutation that we detect within the duplicated, expressed VSG gene.
GP63
Another project in our lab focuses on the genes that encode a protease known as glycoprotein 63
(gp63). Gp63 is located on the surface of leishmania
parasites which cause visceral leishmaniasis in many tropical regions worldwide
and homologues of GP63 have now been identified in T. brucei and T.
cruzi. Leishmania avoid their host's
immune response by invading macrophages - the very cells of the immune system designed to destroy foreign pathogens.
Gp63 participates in the macrophage invasion process and contributes to the
parasite's survival within the macrophage. We
have found leishmania actually has three different forms of gp63 that are expressed at different stages in its life cycle
and probably serve different functions. The different gp63 forms are encoded by related genes that are regulated
post-transcriptionally, i.e., after the initial precursor RNA is synthesized. We are now using DNA transfection procedures
to examine the molecular mechanisms of this post-transcriptional and translational control of the different gp63 genes.