My laboratory broadly focuses on uncovering the biomolecular mechanisms that regulate mitochondrial dynamics, metabolism, and cell differentiation in kinetoplastid parasites. Kinetoplastid parasites infect millions of people worldwide, from the Americas to Africa and Asia, where they cause devastating consequences, ranging from permanent physical mutilations to chronic infections with a 30% mortality rate and no available treatment options. Thus, there is an urgent need to understand the biology of these ancient parasitic organisms. Our primary model organism is Trypanosoma brucei, the causative agent of African sleeping sickness in humans and nagana disease in domesticated livestock across sub-Saharan Africa. Our secondary model is Trypanosoma cruzi, a related parasite that causes American sleeping sickness (Chagas disease) in Central and South America.

All kinetoplastid parasites that infect humans have complex life cycles consisting of multiple stages that exist in different cell/tissue environments between their human host and respective insect vector. Trypanosoma brucei is transmitted by the bite of infected tsetse flies. T. brucei is a completely extracellular parasite that never invades host cells, but it does establish niche infections in various human host tissues, including the blood, lymphatic fluid, adipose tissue, and cerebrospinal fluid in late-stage infections. Trypanosoma cruzi is transmitted by the kissing bug and has both extracellular and intracellular life cycle stages. T. cruzi parasites can invade and multiply within a wide variety of host cells throughout the body. However, T. cruzi parasites have an affinity for heart, brain, liver, intestinal, and muscle cells. Both trypanosome species must make major adjustments as they encounter various environmental stressors while progressing through their respective life cycles. One major adjustment that all kinetoplastid parasites must achieve is the dramatic remodeling of their single, large mitochondrion. As the parasites differentiate from one life cycle stage to another, several mitochondrial features—including morphology, metabolic activity, mitochondrial mRNA U-indel editing, cytochrome expression, and redox homeostasis—drastically change. The timely and effective remodeling of the parasite mitochondrion is necessary for parasite survival and transmission from host to host. However, the signaling pathways that kinetoplastid parasites utilize to coordinate extracellular and intracellular cues with mitochondrial remodeling remain unexplored.

My lab uses a systems biology approach to study these two microscopic parasites, pursuing the long-term research goals of (1) deciphering how various environmental stimuli and intracellular cues regulate different functional aspects of the kinetoplastid mitochondrion, (2) investigating how the metabolic status of the mitochondrion dictates parasite differentiation, and (3) targeting regulatory mechanisms conserved between kinetoplastid parasite species to identify potential pan-kinetoplastid drug targets.

One major research focus of the lab is to understand how two regulatory kinases that are only expressed in kinetoplastid organisms, RDK1 and RDK2, govern separate signaling pathways that control mitochondrial attenuation in parasite life cycle stages optimized for survival and persistence in the human host. We are utilizing phosphoproteomics screening to identify direct in vivo phosphorylation targets for RDK1 and RDK2, and we perform a thorough arsenal of biochemical and cell biology assays to evaluate different aspects of mitochondrial function to determine the roles of RDK1 and RDK2 substrates.

Another focus of the lab is to determine the functions of several uncharacterized metabolite carrier proteins (MCPs) that facilitate the transport of membrane-impermeable metabolites across the mitochondrial inner membrane and how they contribute to parasite mitochondrial function. MCPs are indispensable for proper mitochondrial function, and kinetoplastid parasites express several MCP homologues that do not have human counterparts. Thus, we are using a functional genomics approach coupled with in vitro and in vivo metabolomics to understand the critical metabolites that kinetoplastid parasites require in each life cycle stage and during host transmission events.