Over 200 million people are infected with trematodes of the genus Schistosoma and another 600 million people are at risk of becoming infected. If left untreated, infections can be long-lived (5-10 years) highlighting the parasites ability to manipulate and evade the immune system allowing the continued spread of disease. A better understanding of how the parasites persist in the host and how eggs from the parasite develop to spread disease may provide novel strategies for disease intervention. Murine schistosomiasis caused by S. mansoni was chosen as a model of the human disease as this model lends itself well to laboratory manipulation. Preliminary evidence suggests a parasite-derived member of the TGF-beta superfamily of ligands (SmlnAct) plays a role in both maturation of the egg and maintenance of the parasite surface (tegument), an important structure for host-parasite interactions and immune evasion. The overall goals of the proposed study are to evaluate the role of SmlnAct in egg development and maintaining tegumental structure, to investigate the ability of SmlnAct to modulate the immune response, and examine how the immune response regulates SmlnAct expression. This study will identify the signaling pathway SmlnAct uses to mediate its affects on egg development by targeting the knockdown of pathway components in the egg using RNA interference and examining the resulting phenotype. How SmlnAct regulates egg development will be characterized through examining its spatial expression pattern in the egg and analyzing eggs through electron-microscopy that do not develop when SmlnAct expression is suppressed via RNAi. Affects of SmlnAct knockdown on the maintenance of the adult parasite surface will be evaluated through electron-microscopy and the significance tested in vivo by infection of the definitive host. Due to the similarity between host and parasite-derived TGF-beta, this study will determine whether SmlnAct can directly modulate immune responses by dissecting its effects on dendritic cell and macrophage maturation. Lastly, preliminary data suggests SmlnAct expression is regulated by signals from the host, therefore an in vitro approach will be taken to determine how the parasite receives signals to regulate expression of SmlnAct and potentially other genes important for worm development. Schistosoma mansoni debilitates millions of people with no vaccine available and only one drug at hand for treating the disease. This study will investigate the role of a parasite-derived protein in regulating parasite development and immune evasion. A better understanding of these processes may lead to novel drug targets for intervention in the schistosome life cycle and for blocking progression of this neglected disease.
| Freitas, Tori C; Pearce, Edward J (2010) Growth factors and chemotactic factors from parasitic helminths: molecular evidence for roles in host-parasite interactions versus parasite development. Int J Parasitol 40:761-73 |
| Freitas, Tori C; Jung, Euihye; Pearce, Edward J (2009) A bone morphogenetic protein homologue in the parasitic flatworm, Schistosoma mansoni. Int J Parasitol 39:281-7 |
