Molecular and Metabolic Mechanisms of Trypanosoma vivax Vascular Sequestration

Objective

Animal African trypanosomiasis (AAT) is a deadly vector-borne disease of livestock caused by Trypanosoma brucei, T. congolense, and T. vivax. T. vivax is the least studied but the most geographically widespread, driving epidemics across Africa and South America with major economic and social impacts. In the mammalian host, T. vivax exhibits unique vascular tropism through cytoadhesion to endothelial cells (i.e. sequestration), which promotes endothelial activation and tissue pathology. This host–parasite interaction requires both specific adhesion factors and energy to sustain binding under blood flow. Preliminary transcriptomic data from the host lab show that T. vivax undergoes marked transcriptional reprogramming during sequestration, with differential expression of adhesion factors, and upregulation of glycolytic genes, indicating that glucose metabolism supports vascular tropism. In VIVASEQ, I propose to elucidate the molecular and metabolic mechanisms underlying T. vivax sequestration, with the ultimate goal of functionally disrupting this process, therefore preventing disease. This will be achieved by: 1) identifying the candidate parasite molecules mediating sequestration, 2) characterizing the metabolic remodeling that sustains this interaction, and 3) functionally targeting adhesion factors to disrupt sequestration. I will apply cutting-edge approaches not yet implemented in T. vivax research, including targeted mass spectrometry, ultrastructural expansion microscopy, metabolomics, and a host-specific vessel-on-chip model. VIVASEQ will provide fundamental knowledge to support the implementation of sequestration-blocking strategies to control AAT, whilst potentially uncovering evolutionarily conserved mechanisms of parasite-endothelial cell interactions with broader relevance to vascular infections.