African Trypanosomiasis is a debilitating disease that affects humans as well as livestock in large parts of subSahara Africa. The main trypanosome defense against elimination by the hosts' immune system relies on antigenic variation of its surface coat. Indeed, trypanosomes have an estimated 1000 genes that can encode for immunological distinct 'variant surface glycoproteins' or VSGs that constitute the surface coat. VSG molecules are embedded into the parasites' outer surface membrane by means of a glycosylphostphatidyl inositol (GPI) anchor. These GPIs carry a gallactose carbohydrate modification that makes them distinct from any mammalian host GPI. We have shown that this sugar modification provides the pro-inflammatory properties of VSG (1). Inflammatory complications are a hallmark of all trypanosome infections, with inflammation-associated anemia as the most common cause of death in for example infected cattle. Interestingly, many endemic African mammals that appear 'resistant' to trypanosomiasis, are not free of infections. In contrast, they do not suffer from clinical complications during infection. It is this knowledge that underlies all the ongoing research at CMIM (the laboratory for Cellular and Molecular Immunology / Vrije Universiteit Brussel), as it suggest that diseases such as 'Nagana' (animal trypanosomiasis) and 'Sleeping Sickness' (human trypanosomiasis) are due to an ill controlled anti-parasite immune reaction, rather than to a direct pathogenic effect of the parasite. Inflammatory immune reactions in Trypanosomiasis have been linked to the induction of 'cachectin' since the early 1980s (2). Here it was found that the upregulation of a 'hormone' that gave rise to accumulation of serum triglycerides causes a wasting syndrome through its lipid metabolism disturbing activity. Soon after this discovery, the same molecule was found to have a tumor growth inhibiting effect. Based on the fast accumulation of data on this anti-tumor effect of cachectin, the molecule was rapidly named 'Tumor Necrosis Factor' or TNF. Since the discovery that TNF and cachectin are two sides of the same molecular coin (3), unfortunately research into the role of TNF in trypanosomiasis soon lost its momentum. However, at CMIM we have been involved in the investigation of the role of TNF in experimental trypanosomiasis since the early 1990s. We were the first to report on the potential direct anti-trypanosome effect of TNF (4), and subsequently were also the first to report on trypanosome infections in TNF-deficient mice (5). Soon after, the trypanosome GPI molecule was found to be the main TNF-inducing molecule released during infection (1), which gave rise to the development of a GPI-based anti-pathology intervention strategy at CMIM (6). During the development of this strategy it became clear that modulation of the immune system by GPI had a major corrective impact on the infection-associated anemia. Also the earlier TNF-KO results had suggested that a lack of TNF was beneficial for the host, due to a significant correction of RBC levels, despite a rise in parasitemia levels (7). Although the anemia of Trypanosomiasis is well documented, the underlying reasons for its induction are still ill understood. Despite earlier reports of the involvement of toxic trypanosoom components, we have shown that the anemia occurs independent of the parasite load (5,7). More recently we have shown that anemia occurs independently of anti-trypanosome antibody induction, despite earlier reports on a possible involvement of a cross-reactive anti-VSG response in RBC lysis (8). Finally, our most recent (still unpublished) results show that the anemia of trypansomiasis involves two separate events being (i) inhibition of erythropoiesis through TNFR1 signaling, and (ii) increased eryhtrophagocytosis involving TNF-R2 signaling. Concerning the latter, our research hypothesis is that accelerated erythrophagocytosis occurs due to alterations in the hosts' lipid metabolism, and the remodeling of the RBC lipid membrane. The observations that supported this hypothesis are the fact that RBCs from infected mice are hypersensitive to osmolarity changes, and the notion that TNF-R2 KO macrophages show a reduced trypanosomiasis-induced phagocytosis potential (unpublished results CMIM).
Effective start/end date1/01/1031/12/13

    Research areas

  • Applied Biology

    Flemish discipline codes

  • Biological sciences

ID: 3349098