RUI: genetic mechanisms that regulate surface protein remodeling during life cycle transitions in the african trypanosome parasite

The National Science Foundation Division of Molecular and Cellular Biosciences awarded Harvey Mudd College $573,378 on August 1, 2026, under the Biological Sciences program (CFDA 47.074) to investigate genetic mechanisms that regulate surface protein remodeling in Trypanosoma brucei, the African trypanosome parasite, during its transition between mammalian and insect hosts.

The research examines how the parasite switches from expressing a variable surface glycoprotein coat in the mammalian bloodstream to an invariant procyclin coat in the tsetse fly midgut. Understanding this molecular mechanism will advance knowledge of parasite adaptation and may inform therapeutic strategies for African trypanosomiasis, a fatal disease if untreated.

The project integrates research with undergraduate and high school education. Three high school students and 10 to 12 undergraduates will participate in cutting-edge research alongside career development activities including lectures, career panels, and networking events with biotechnology industry leaders. This educational component aims to prepare students for careers in academia and biotechnology.

Work is performed in Claremont, California, with a period of performance from August 1, 2026, through July 31, 2029. The award is classified as a Project Grant, an assistance type supporting discrete scientific investigations.

Abstract

African trypanosomes are parasites transmitted to the bloodstream of humans and cattle via the bite of the tsetse fly. Infected humans and animals develop african trypanosomiasis, a disease that is fatal if untreated. The parasites cover themselves with different surface proteins depending on whether they are in the mammal or the fly, and these surface proteins are key to the survival of the parasite in both organisms. The scientific goal of this project is to understand the molecular mechanism that allows the parasite to change its surface proteins when IT travels from the mammalian bloodstream to the GUT of the fly following a bloodmeal. Understanding this mechanism will help shed light on how parasites evolved to adapt to different environments and could inform strategies to generate alternate therapies for the disease. The educational goal of the project is to allow full participation of 3 high school students and 10-12 undergraduates in cutting-edge research to help prepare them for careers in academia and biotechnology industries. Undergraduates participating in the program will attend lectures, career panels, and networking events with leaders in the biotechnology industry to expose them to exciting applications of biotechnology and help prepare them for careers in these fields. Rigorous research training at the high school and undergraduate level will create the foundation for these students to become leaders in industries that improve the health of the american public. The african trypanosome, trypanosoma brucei, undergoes morphological and metabolic adaptation as IT switches hosts. During transition from the mammalian bloodstream to the fly midgut, parasites remodel their cell surface, switching from a thick protein coat of antigenically variable variant surface glycoprotein (VSG) to an invariant procyclin coat in the fly midgut. While the environmental cues that trigger surface protein remodeling have been identified, little is known about the genetic mechanism that regulates initiation of transcription for the gpeet and EP genes that code for the invariant insect-stage procyclin protein. Our lab has shown that the histone acetyl lysine binding bromodomain protein BDF3 localizes to the EP promoter after parasites are triggered to differentiate from the bloodstream to the insect stage. BDF3 is thought to bind the H4K10AC mark made by the histone acetyltransferase HAT2. We hypothesize that changes in histone acetylation at the EP locus by the histone acetyl transferase HAT2 drives recruitment of BDF3, which facilitates initiation of EP transcription and surface protein remodeling at differentiation. We will test this hypothesis by (1) using a DCAS9-BDF3 crispr activation system to ask whether BDF3 recruitment is sufficient to initiate EP transcription in the absence of environmental cues, and (2) characterizing the histone acetylation state and BDF3 occupancy at the EP locus in the presence or absence of HAT2. (3) we will also knock down 3 bromodomain protein complex members using rnai and test their importance in regulating the EP locus. These studies will shed light on the role for the ?primitive? Histone code in early branching eukaryotes and the regulation of transcription in biologically diverse systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the foundation's intellectual merit and broader impacts review criteria.- subawards are not planned for this award.