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Schistosoma mansoni c-AMP-dependent Protein Kinase (PKA): A Potential New Drug Target

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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Schistosomiasis, a disease caused by parasitic blood flukes of the genus Schistosoma, afflicts over 200 million people in tropical and subtropical regions of the world and is responsible for approximately 280,000 deaths in Sub-Saharan Africa alone annually. Currently, praziquantel PZQ is the sole drug that is used for treatment due to its ability to kill the mature adult worms of the medically important Schistosoma species S. mansoni, S. haematobium, and S. japonicum. However, it is unrealistic to expect that reliance on this single drug for all treatment and control of schistosomiasis will be sustainable in the long term and highlights the necessity for the identification of new chemotherapeutic targets in schistosomes. We therefore explored the anti-parasite potential of targeting cAMP-dependent protein kinase PKA enzymes in S. mansoni. Here we provide biochemical evidence for the presence of a PKA signaling pathway in adult S. mansoni and show that PKA activity is required for parasite viability in vitro. We identified a cDNA which encodes for a PKA catalytic subunit homologue in S. mansoni, named SmPKA-C. RNA interference studies showed that SmPKA-C is an essential gene and is required for S. mansoni viability in vitro. SmPKA-C mRNA was shown to be differentially expressed throughout the parasite life cycle with highest levels being present in the infectious larval stage of the parasite, cercariae, and adult females by real-time PCR. PKA activity, similar to adult worms, was shown to be required for cercariae viability. Our data also suggests that PKA signaling may be required for parasite growth and development and egg production both in vivo and in vitro.


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