Program Director/Principal Investigator (Last, First, Middle): Adema, Coenraad, 2R01AI52363-06A1 Schistosomiasis, a debilitating parasitic disease caused by flatwonns of the genus Schistosoma affects 200 million humans, with 600 million more at risk. No vaccine is available. Current control efforts emphasize mass chemotherapy to yield welcome relief of human suffering, but can render the existing drugs ineffective by selecting for resistant parasites. Long tenn control of this global health problem will benefit from a reduction in new schistosome infections. Schistosomiasis is transmitted by snail intennediate hosts (such as Biomphalaria glabrata) in which the parasites undergo obligatory development. A long tenn objective of this proposal is to characterize determinants for suitability of snails as host for schistosomes. Insight into the potential of local snail populations to support development of schistosomes allows monitoring and possibly predicting transmission of schistosomiasis. This could help to focus control efforts on areas with increased risk of schistosome transmission to optimize use of limited resources for (global) health management.
I aim to expand the understanding of snail host-schistosome compatibility by identification and functional characterization of (novel) candidate immune genes of B. glabrata. Previous transcriptome analysis revealed many (new and putative) immune factors, indicating that B. glabrata has potent multi-faceted immune capabilities. However, B. glabrata responded modestly to compatible schistosomes, relative to other pathogens. This suggests that the response was incomplete or ineffective. Microarrays and custom macro arrays will be used to identify common factors of effective immune responses in both schistosomeresistant and -susceptible B. glabrata. Field collected snails will be used to validate results obtained with laboratory strains of B. glabrata. Analysis will include putative immune factors among novel (unknown) sequences to expand understanding of immunity ofB. glabrata. Up to 5 (groups of) candidate defense genes will be characterized by full-length sequencing;detailed study of expression over time in response to challenge with (in)compatible schistosomes or bacteria;RNAi knockdown to investigate phenotypic changes in anti-pathogen responses, and insitu hybridization to localize expression in B. glabrata (untreated, challenged and following RNAi knockdown). Any data forthcoming from the ongoing B. glabrata genome sequencing will further facilitate this study of immune function of B. glabrata in the context of transmission of schistosomiasis
To learn why some Biomphalaria glabrata snails fail to kill Schistosoma mansoni and subsequently transmit this parasite to humans, functional and regulatory aspects of immunity in the snail will be characterized with modern molecular methods. The ability to test whether snails are suitable hosts for schistosomes will benefit public health by making it possible to monitor, predict and potentially control transmission of schistosomiasis, a debilitating parasitic disease of humans.
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