The Biology of Stem Cells in the Human Parasite Schistosoma Mansoni

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 DESCRIPTION (provided by applicant): Schistosomiasis is a neglected tropical disease that affects more than 200 million people in the developing world. Currently only a single drug (praziquantel) is available to treat this disease, highlighting the importance of studies aimed at understanding basic biological processes in these organisms. One remarkable characteristic of schistosomiasis is that the parasites responsible for this disease (i.e., schistosomes) can live in the blood stream of their human hosts for decades. How these parasites thrive in this immunologically hostile environment is not known. To address the longevity of these parasites in their mammalian host we previously demonstrated that schistosomes possess a population of somatic stem cells, which we refer to as neoblasts, which are capable of generating new intestine and muscle cells. Our preliminary studies for this proposal led us to a striking observation: a large fraction of these neoblasts differentiate to produce parts of the parasite's surface coat, a syncytial tissue known as the tegument. Our data suggest that tegumental cells are rapidly turned over, relying on neoblasts for their continuous renewal. As a result, many tegument-associated molecules are drastically down regulated within days following stem cell depletion. Since the tegument is the primary interface between the parasite and its host, understanding the stem cell-tegument relationship will provide important clues about how schistosomes defend themselves from immune attack. Based on these observations, we hypothesize that an important function of the neoblasts is to rapidly regenerate the parasite's tegument, thereby ensuring a functional host-parasite interface and evasion of host immunity. To address this hypothesis we propose the following two specific aims: (1) discover regulators of the neoblast-to-tegument transition and (2) understand the role for neoblasts in maintaining tegumental function in vivo. In the first aim, we will use transcriptional profiling and in situ hybridization to identify genes expressed in schistosome stem cells. We will then use RNA interference to determine which of these genes are required for the differentiation of the neoblasts into tegumental cells. In the second aim, we will use a combination of electron microscopy and immunological approaches to determine the effects that neoblast ablation has on tegumental morphology and function. Concurrently, we will surgically-transplant parasites incapable of making new tegumental cells into mice and examine the effects on worm survival. These studies are innovative as they are the first to explore the function of the neoblasts in the biology of this devastating parasite and bring a number of new methodologies to the table for studying these organisms. Collectively, these studies will determine how neoblasts contribute to parasite survival in the context of the host immune system, potentially leading to new therapeutic approaches targeting these important pathogens.