Characterisation of Trypanosoma sequestration to endothelial cells

State of the art, preliminary data and relevance

African trypanosome infections (Trypanosoma congolense, T. vivax, T. brucei) cause animal trypanosomiasis or nagana and result in high animal mortality (up to 70%/herd) and great economic loss (~US$4.5 billion/year in Africa). This may soon be exacerbated due to climate change [1]. Besides being a major constraint for African socio-economic development, Trypanosoma species may infect Humans, causing sleeping sickness. Resolving trypanosomiasis is an enormous challenge, demonstrated by the absence of an effective vaccine and the rapid increase in drug resistance. Current disease management strategies rely on continuous vector
control and epidemiological surveillance.

One of the greatest difficulties in trypanosomiasis control is the complexity of the trypanosome interaction with the mammalian host. Trypanosomes have evolved sophisticated mechanisms to survive in a wide range of mammalian species and tissue microenvironments. To study such multifaceted interactions, we require innovative, cross-disciplinary approaches. An important virulence mechanism is parasite adhesion to the vasculature, or vascular sequestration.

Previously, we discovered that sequestration affects disease progression and clinical outcome [2]. However, we are still uncertain how sequestration is mediated at the molecular level and we lack the appropriate systems to address it. Sequestration is a complex host-parasite interaction that triggers multidimensional signaling cascades that are complicated to either reproduce or control in mice. Still, current 2-dimensional (2D) in vitro models for parasite adhesion lack complexity and
physiological significance. Therefore, there is an urgent need for in vitro vascular systems that reproduce vascular architecture, allow tight control of the extracellular environment, and overcome the variability and ethical impact of animal models.

In this project, we will develop a state-of-the-art model of 3-dimensional (3D) bovine brain vasculature to characterize the parasite proteins and biomechanical factors determining T. congolense sequestration.

Results from this project will directly prime further research into the interactions between the parasite and the host cells, of which the vascular endothelium is the first encounter (in the case of T. brucei) or the only player (for T. congolense). Due to the model’s compatibility with high-throughput and high-resolution methods, including single-cell RNA sequencing, single-cell proteomics, automated image analysis, and flow cytometry, we will be able to address important questions of trypanosomiasis pathogenesis that were previously unattainable. Collectively, the scientific and technological knowledge arising from this project will open novel avenues for drug design and offer a versatile platform to investigate host-pathogen interactions and vascular diseases.

Furthermore, this project will contribute to the training of a MSc student and dissemination of knowledge to scientific and non-scientific audiences. Importantly, it addresses several United Nations Sustainable Development Goals, including contributing to the reduction of poverty and hunger (UNSDG1), the promotion of sustainable agriculture (UNSDG2), the eradication of neglected tropical diseases (UNSDG3), and the commitment to quality education (UNSDG4).