Interferon type I mediates resistance to Trypanosomes

The intracellular parasite Trypanosoma cruzi causes Chagas disease in over 16 million people worldwide, mostly in poor and rural areas in Central and South America. Chagas disease has a variety of debilitating symptoms and kills about 50,000 people annually. Prevention focuses on killing the insect vectors; treatment is expensive and not entirely effective. Resistance to T. cruzi in humans is thought to be initiated by TLRs and effected by interferon (IFN)-gamma and nitric oxide (NO), produced by host T cells and NK cells, which kill the parasite. Here, Koga and colleagues investigated the pathway between TRL activation by the parasite and effector mechanisms. They found that resistance requires TLR signaling because infected macrophages and dendritic cells cultured from mice without the TLR adapter proteins MyD88 and TRIFF support T. cruzi proliferation. Since TRIFF signals the production of type I interferons, namely the IFN-alphas and IFN-beta, the investigators tested cells from mice without a receptor for these IFNs: IFNAR1-/-. As expected, these cells were unable to control T. cruzi in culture (Figure, panel A). Moreover, these mice quickly succumb to infection (panel B). A gene expression analysis found that IRG47 was strongly induced and previous reports had implicated this GTPase in the IFN response. When IRG47 expression was “knocked down” with RNAi, even wild type cells were rendered susceptible to T. cruzi, demonstrating the critical role of type I IFNs and induced IRG47 in resistance to this trypanosome.
"TLR-Dependent Induction of IFN-beta Mediates Host Defense against Trypanosoma cruzi." Koga et al. J Immunol. 2006, 177: 7059