TRYPTISSUE · Characterising Trypanosoma tissue tropism: new perspectives for variant surface glycoproteins

Characterising Trypanosoma tissue tropism: new perspectives for variant surface glycoproteins

Animal African trypanosomiasis (AAT) is a livestock disease in Africa and South America caused by Trypanosoma brucei, T. congolense, and T. vivax that results in frequent epidemics, high animal mortality and economic loss. There is no vaccine, and drug-resistance is swiftly rising, requiring continuous vector control and disease surveillance. T. congolense is one of the most prevalent and pathogenic African trypanosome species in Africa, but little is known about its biology. Whilst T. congolense infections in African cattle mostly cause a chronic, wasting disease, in exotic breeds and in other mammals, including dogs, goats, and horses, the parasite can cause a rapidly fatal, acute disease, characterized by inflammatory syndrome, disseminated intravascular coagulation syndrome, and neurological impairment (also called cerebral trypanosomiasis). One of the key aspects that distinguishes T. congolense from human-infective T. brucei is the mechanism of tissue tropism. T. congolense cytoadheres to the vascular endothelium, whilst T. brucei egresses the bloodstream and invades tissues (reviewed in Silva Pereira et al., 2019). T. congolense cytoadhesion causes parasite sequestration (Losos et al., 1973; Losos and Gwamaka, 1973; Ojok et al., 2002), which, for other pathogens, such as Babesia spp. and Plasmodium spp., is a key determinant of virulence (Gallego-Lopez et al., 2019; Ghazanfari et al., 2018; Rogerson et al., 2007; Van den Steen et al., 2013; Vargas et al., 2014). Currently, very little is known about the impact of T. congolense sequestration in disease. Yet, parasite presence in the vasculature, and sequestration in particular, usually results in an inflammatory response (Storm and Craig, 2014). We know that T. congolense adhesion to host cell membranes triggers antibody-complement cascades and increases vascular permeability, suggestive of endothelium damage (Banks, 1980). The parasite itself has also been reported to release soluble molecules, like trans-sialidades, that activate the endothelium in vitro, and enhance inflammation in vivo (Ammar et al., 2013). In turn, excessive inflammation is a common driver of pathology in many infectious diseases. It is therefore plausible that the physical damage caused by parasite sequestration in the brain and the resulting host’s immune response affect disease progression. Until now, the mechanism behind T. congolense sequestration and the reasons behind the differences in disease outcome remained elusive. In this project, we set out to develop mouse models of trypanosomiasis and to use them to understand the sequestration mechanism and its impact in disease progression.

Data: CORDIS, © European Union