Development of novel therapeutic approaches to counteract liver immunopathology and anemia during African Trypanosomiasis.

Our research unit has recently shown that tolerance to African trypanosome infection requires the down regulation of the type 1 inflammation during the chronic stage of the disease in order to avoid severe immunopathology leading to anemia, liver necrosis and finally death of the host. IL-10 plays a crucial role in this protecting anti-inflammatory process. Comparative gene expression analysis of myeloid cells elicited in mice that are naturally tolerant to trypanosomes led to the identification of several IL-10-inducible genes that: (1) may protect the liver against the detrimental effects of excessive inflammation; and (2) may protect against anemia. The specific aim of the research proposal is to proof directly that the various IL-10-inducible genes actually protect against parasite-induced inflammatory hepatic injury and anemia. To achieve this, we will clone different IL-10-inducible genes into adeno-associated viral vectors (AAV) for stable hepatic gene delivery. The recombinant AAV vectors will be injected into trypanosusceptible mice that will subsequently be challenged with a lethal dose of trypanosomes in order to evaluate the protective activity of the candidate genes. This project will establish the proof of concept that novel IL-10-inducible genes restrict inflammation and/or anemia in a model of parasite infection. In addition, it will tackle the unmet medical need to develop new modalities for the therapy of liver injury, a common infliction that affects millions worldwide.