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Study of the inflammation-associated anemia in African trypanosomiasis and development of anti-disease and drug-targetting strategies

Friday, 19 May, 2006 - 16:00
Campus: Brussels Humanities, Sciences & Engineering campus
Faculty: Science and Bio-engineering Sciences
D
0.07
Benoit Stijlemans
phd defence

African trypanosomiasis is a lethal parasitic disease affecting both humans and
animals in sub-Saharan Africa. Due to the wide distribution of trypanosomes throughout the
human population, livestock and game animals, and the lack of persistent disease control
efforts, African trypanosomiasis remains a major to date health problem.

African trypanosomes are extracellular parasites that have developed two efficient
immune escape mechanisms, i.e. antigenic variation of their VSG surface glycoprotein coat,
and immune modulation involving both innate and adaptive immunity. The intricate balance
of activating and deactivating signals delivered by trypanosomes, in conjunction with host
immune activating signals, determines the course of infections. Interestingly, while
experimental trypanosomiasis always results in death of the infected animal, the clinical
aspects of the disease development and survival time greatly depend upon this parasite-host
interplay. In disease-susceptible mammals, cattle and laboratory rodents, trypanosomiasis is
marked by the occurrence of severe pathology, with anemia being the major pathological sign.
To date, all available data point to the fact that macrophage hyper-activation is one of the
hallmarks of this pathology. Therefore identification of trypanosome factors implicated in
macrophage activation is crucial for the design of new treatment modalities for
trypanosomiasis.

In this work, we have identified the GPI-anchor of VSG as the main trypanosome
molecule involved in systemic induction of TNF, a crucial pro-inflammatory cytokine
involved in trypanosomiasis-induced immunopathology. This GPI-moiety was shown to
encompass two distinct parts: (i) the GIP-part (i.e. the carbohydrate moiety) of sVSG which is
released in massive amounts during infection and in conjunction with IFN-γ leads to the
release of pro-inflammatory cytokines by macrophages, and (ii) the DMG-part, the lipid
moiety of the GPI-anchor which during the later phase of infection results in overactivation of
macrophages and LPS-hyperresponsiveness.

Having identified the major trypanosome-derived pathology inducing molecule, we
generated a GPI-based vaccination strategy that resulted in prolongation of host survival
through modulation of the macrophage activation and alleviation of infection-associated
inflammation and pathology.

Furthermore, since extravascular red blood cell destruction (erythrophagocytosis) is
considered to be the major factor associated with anemia, we analyzed infection-associated
problems of iron acquisition at the level of the liver, the major player in erythrophagocytosis
and iron regulation. Our observations are suggestive for alterations at the level of ironhomeostasis,
with iron accumulating within macrophages resulting in withholding of iron for
erythropoiesis.

Finally we evaluated the applicability of camel antibodies in the field of
trypanosomiasis by generating Nbs against the VSG-coat of trypanosomes, and found that
these small sized molecules have promising potential as diagnostic and therapeutic aid. In
addition, some of these Nbs were found to encompass a trypanolytic potential, most likely
through their interference with the endocytic pathway. Therefore, Nbs could be useful tools to
unravel the endocytosis mechanism and they might disclose novel treatments for
trypanosomiasis by developing trypanotoxic compounds that impede the recycling of VSG
through endocytosis/exocytosis.

In conclusion, the work presented here tackles trypanosomiasis on four different
levels, i.e. (i) the characterization of trypanosome molecules involved in immune hyperactivation
and the development of immunopathology, (ii) the development of a disease
intervention strategy based upon the neutralization of this macrophage hyper-activation, (iii)
the characterization of molecular pathways possibly involved in the occurrence of infectionassociated
anemia, and (iv) the development of camel antibody based tools for research,
diagnostics and treatment of trypanosomiasis.