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.

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.

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.