The protozoan Trypanosoma brucei, responsible for animal and human trypanosomiasis, has a family of major surface proteases (MSPs) and phospholipase-C (PLC), both involved in some mechanisms of virulence during mammalian infections. During parasitism in the mammalian host, this protozoan is exclusively extracellular and presents a robust mechanism of antigenic variation that allows the persistence of infection. There has been incredible progress in our understanding of how variable surface glycoproteins (VSGs) are organised and expressed, and how expression is switched, particularly through recombination. The objective of this manuscript is to create a reflection about the mechanisms of antigenic variation in T. brucei, more specifically, in the process of variable surface glycoprotein (VSG) release. We firstly explore the mechanism of VSG release as a potential pathway and target for the development of anti-T. brucei drugs.

Sleeping sickness and malaria are parasitic diseases with overlapping geographical distributions in sub-Saharan Africa. We hypothesized that the immune response elicited by an infection with Trypanosoma brucei, the etiological agent of sleeping sickness, would inhibit a subsequent infection by Plasmodium, the malaria parasite, decreasing the severity of its associated pathology. To investigate this, we established a new co-infection model in which mice were initially infected with T. brucei, followed by administration of P. berghei sporozoites. We observed that a primary infection by T. brucei significantly attenuates a subsequent infection by the malaria parasite, protecting mice from experimental cerebral malaria and prolonging host survival. We further observed that an ongoing T. brucei infection leads to an accumulation of lymphocyte-derived IFN-γ in the liver, limiting the establishment of a subsequent hepatic infection by P. berghei sporozoites. Thus, we identified a novel host-mediated interaction between two parasitic infections, which may be epidemiologically relevant in regions of Trypanosoma/Plasmodium co-endemicity. Despite the geographical overlap between the parasites that cause sleeping sickness and malaria, the reciprocal impact of a co-infection by T. brucei and Plasmodium had hitherto not been assessed. We hypothesized that the strong immune response elicited by a T. brucei infection could potentially limit the ability of Plasmodium parasites infect the same host. In this study, we showed that a primary infection by T. brucei significantly attenuates a subsequent infection by the malaria parasite. Importantly, a significant proportion of the co-infected mice do not develop Plasmodium parasitemia, and those few that do, do not display symptoms of severe malaria and survive longer than their singly infected counterparts. We further showed that the prevention or delay in appearance of malaria parasites in the blood results from a dramatic impairment of the preceding liver infection by Plasmodium, which is mediated by the strong immune response mounted against the primary T. brucei infection. Our study provides new insights for a novel inter-pathogen interaction that may bear great epidemiological significance in regions of Trypanosoma/Plasmodium co-endemicity.

Malaria, a disease caused byPlasmodiumparasites, remains a major threat to public health globally. It is the most common disease in patients with sleeping sickness, another parasitic illness, caused byTrypanosoma brucei. We have previously shown that aT.bruceiinfection impairs a secondaryP.bergheiliver infection and decreases malaria severity in mice. However, whether this effect requires an active trypanosome infection remained unknown. Here, we show thatPlasmodiumliver infection can also be inhibited by the serum of a mouse previously infected byT.bruceiand by total protein lysates of this kinetoplastid. Biochemical characterisation showed that the anti-Plasmodiumactivity of the totalT.bruceilysates depends on its protein fraction, but is independent of the abundant variant surface glycoprotein. Finally, we found that the protein(s) responsible for the inhibition ofPlasmodiuminfection is/are present within a fraction of ~350 proteins that are excreted to the bloodstream of the host. We conclude that the defence mechanism developed by trypanosomes againstPlasmodiumrelies on protein excretion. This study opens the door to the identification of novel antiplasmodial intervention strategies.