Molecular signaling during early larval development in Schistosoma mansoni

Schistosomiasis is a debilitating disease resulting from infection by blood flukes in the genus Schistosoma. The disease is endemic in over 70 countries with estimates of 250 million people infected worldwide. The primary goal of my research is to identify and characterize the molecular mechanisms underlying the early developmental changes in the miracidium that lead to successful infection of Biomphalaria glabrata , obligate intermediate host of S. mansoni. Penetration of the snail host by the miracidium and subsequent transformation into the primary sporocyst stage are essential steps in the establishment of S. mansoni infections. This transition from a free-living to parasitic existence is believed to be accompanied by many physiological and biochemical changes, although very little is known about the molecular basis of larval transformation. Previous studies have demonstrated that the key initiating stimulus for the in vitro miracidial transformation process is an increase in osmolarity and although the exact biochemical cascade activated by the change in osmolarity is unknown, 3'-5'-cyclic adenosine monophosphate (cAMP) and calcium mobililization may be involved. Therefore the purpose of this work is to identify genes and molecular pathways involved in the miracidium-to-sporocyst transformation and early larval development process. We utilized Serial Analysis of Gene Expression (SAGE) to identify novel genes that may play a role during this transition and early larval development and further characterized two calmodulin genes that are involved in these early developmental processes. Additionally, we performed a small-molecule chemical compound screen to identify compounds that block or delay miracidial transformation, resulting in the identification of a subset of compounds that inhibited in vitro miracidial transformation. Overall my findings show that the miracidium-to-sporocyst transformation is a calmodulin dependent process and very likely utilizes a cAMP signaling pathway to regulate this complex developmental transition.