Schistosomiasis, which results from infection by a parasitic trematode, affects approximately 200 million people worldwide. Despite the availability of effective treatments, high rates of re- infection, the sequelae of chronic infection, and the threat of drug resistance remain major health concerns. Previous studies suggest that Schistosoma mansoni requires host-derived factors for normal development and sexual maturation. Understanding the intricate interactions between host and parasite may suggest methods to prevent the development of patent infections. Adult parasites survive for years within the mesenteric veins of their host, with intimate contact occurring between the dorsal surface of the male parasite and the vascular endothelium of the host. This training proposal will focus on host-parasite interactions at the level of the vascular endothelium, investigating how the parasite may respond to endothelial-derived growth factors and may modulate the intravascular environment through the release of vasoactive factors and parasite antigens. The S. mansoni receptor kinase (SmRK1), a transforming growth factor-beta (TGF-beta) receptor-like molecule on the dorsal surface of the male parasite, is a likely candidate for mediating both parasite development and host-parasite interactions, since members of the TGF-beta superfamily are known to be involved in a variety of regulatory processes in a wide range of species. Our preliminary studies suggest that SmRKl can be activated by recombinant human TGF-beta and signal through the schistosome Smad2 (smSmad2) when both schistosome proteins are expressed in a heterologous system Specific aim one of this proposal will investigate the ability of endogenous SmRKl to become activated and signal in response to exogenous TGF-beta. The role of host accessory proteins present on the vascular endothelium and known to bind TGF-Beta will also be studied for their ability to facilitate TGF-beta interactions with SmRK1.
Specific aim two will investigate parasite-derived factors which may influence vascular homeostasis and immune evasion. Preliminary studies have identified a nitric oxide synthase-like protein from the parasite and experiments will be performed to sequence, clone and characterize this enzyme and its role in parasite survival. Other experiments will address the ability of certain antigens derived from adult male parasites to induce specific immunological tolerance through their interactions with liver sinusoidal endothelial cells, thereby facilitating the parasite's ability to evade the host immune response.
