The Debler Lab investigates mechanisms of gene regulation in protozoan parasites of medical importance, with an emphasis on Trypanosoma brucei, the causative agent of sleeping sickness. Using an interdisciplinary approach including structural biology, biochemistry, and cell biology, we focus on gene-regulatory mechanisms underlying life-cycle stage control (differentiation) and immune evasion in protozoan parasites. Investigation of trypanosome biology offers both the potential for important global health impact and an opportunity to explore fascinating eukaryotic biology.
Overview of research in the Debler Lab
Protozoan parasites cause tremendous mortality and morbidity worldwide with more than a billion people affected by their infections and represent masters of differentiation, as they seamlessly proceed through morphologically and physiologically distinct stages during their life cycles in different host organisms. Our research aims at dissecting the molecular machineries and mechanisms underlying gene expression, differentiation, and immune evasion in Trypanosoma brucei at atomic resolution. We seek to apply this knowledge in order to develop novel effective therapies for protozoan parasitic diseases.
Structure and function of chromatin regulators in protozoan parasites
It is well established that trypanosomes utilize a host of posttranscriptional mechanisms to regulate gene expression. However, we recently discovered that a class of chromatin regulators termed bromodomains is involved in life-cycle stage control, pointing towards an important, but thus far underappreciated role of transcriptional gene regulation in T. brucei. Specifically, we found that bromodomain inhibition in virulent bloodstream-form parasites in mammals leads to biochemical and physiological changes that are consistent with differentiation to the procyclic stage in the tsetse insect vector. Our goal is to decipher the molecular mechanisms that regulate gene expression and other processes on the chromatin level in protozoan parasites.
Life-cycle stage reprogramming as a new strategy to combat protozoan parasitic diseases
African trypanosomiasis is a fatal parasitic disease that causes sleeping sickness in humans and nagana in livestock. There is a significant unmet need for the development of efficacious anti-trypanosomal drugs, as the few drugs available have severe side effects, resistance is on the rise, and the pharmaceutical industry is generally less likely to invest in neglected tropical diseases. Based on our proof-of-principle discovery that a small molecule termed I-BET151 targeting Trypanosoma brucei chromatin proteins reprograms the life-cycle stage of the parasite from the virulent bloodstream form to a much less virulent insect-stage form that can be cleared by the immune system, we propose to develop this transformative approach into an effective chemotherapy for trypanosomiasis.
Immune evasion by monoallelelic expression of variant surface glycoprotein (VSG)
In the mammal, the African trypanosome resides extracellularly in its bloodstream form where it is densely covered with highly immunogenic Variant Surface Glycoprotein (VSG). By periodically switching this VSG from a repertoire of ~2500 distinct VSG genes by means of monoallelic expression, trypanosomes are masters of camouflage and successfully evade the immune system. This work will tackle the fundamental, long-standing question in eukaryotic biology of how allelic exclusion within a multi-gene family of alleles is achieved and will have profound implications for other fields, such as neuroscience (monoallelic expression of odorant receptors) and immunology (monoallelic expression of B-cell receptors).