High-resolution, high-throughput systems for decoding parasite sequestration

African trypanosome infections (Trypanosoma congolense, T. vivax, T. brucei) cause animal African trypanosomiasis and result in high animal mortality ( 70%/herd) and great economic loss (~US$4.5 billion/year in Africa). Besides its impact in socio-economic development in Africa, South America and Asia, trypanosomiasis also poses a significant zoonotic risk for Human sleeping sickness. Resolving trypanosomiasis is an enormous challenge, proven by the absence of an effective vaccine and rapid increase in drug resistance.
One of the greatest difficulties in trypanosomiasis control is the complexity of the trypanosome interaction with mammalian host. Trypanosomes have evolved sophisticated mechanisms to survive in varied mammalian hosts and tissue microenvironments, and to sustain infection at low parasite numbers. To study such multifaceted interactions, we require innovative, cross-disciplinary approaches. I have discovered that parasite adhesion to the vasculature, or sequestration, is a virulence factor that affects trypanosomiasis progression and clinical outcome. However, we are still uncertain how sequestration is mediated and how parasites adapt to become sequestered. Currently, we lack appropriate systems to address it. In this research plan, I propose to build a Trypanosome Sequestration Atlas, which will allow me to uncover the biological and biomechanical aspects of trypanosome sequestration and how they have evolved. I will:
1) Reveal the sequestration molecular machinery of trypanosomes by targeted transcriptomics
and in vivo high-throughput phenotyping.
2) Understand how sequestration has evolved in trypanosomes by molecular evolution analyses
of sequestration-associated genes in the context of remaining trypanosomatids.
3) Identify biophysical determinants of sequestration, using a 3D bovine brain microvessels system.
With this project, I will shed light on the mechanistic and evolutionary basis of sequestration, a key trypanosome survival strategy; provide the research community with an innovative tool for the study of trypanosome-host interactions; and pioneer the application of in vitro 3D vascular systems in trypanosomiasis. Collectively, the scientific and technological knowledge arising from this project will open novel avenues for drug design, offer a versatile platform to investigate host-parasite interactions and to test drugs without using animals.