: Schistosomes are extracellular blood worms that infect over 200 million people globally and cause several thousand deaths annually. Large-scale genome sequencing projects for each of the three major human schistosome species: Schistosoma mansoni, S. haematobium and S. japonicum, are currently underway. Despite the wealth of new data to be generated by all of these undertakings, there is still no routine technique available that allows us to exploit the data through manipulation of the schistosome genome. Because of this, our understanding of the molecular and cellular biology of schistosomes has been severely hampered and lags behind that of most other important human pathogens. In this application, we propose to utilize a relatively new technology in gene manipulation called RNA-mediated interference (RNAi) to examine gene function in schistosomes. In preliminary experiments, we have achieved considerable inhibition of select genes involved in nutrient acquisition by the parasites. We plan to build on this success by first optimizing the protocol for gene suppression using RNAi in different schistosome life cycle stages by varying the amount and nature of the dsRNA employed, the mode of delivery and the duration of exposure. Such a systematic assessment of the relative importance of the factors that impinge on the phenomenon could have wider applicability for researchers using RNAi in other biological systems. Next we will utilize the optimized protocol to test specific hypotheses concerning an important area of schistosome biology: The involvement of proteases in hemoglobin degradation and nutrient acquisition. The work proposed here is designed to provide a simple, powerful and widely applicable protocol for the schistosome research community to facilitate functional schistosome genomics. In addition, our application of the technology is designed to provide significant new information about schistosome metabolism and biology. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI056273-04
Application #
7195716
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Mcgugan, Glen C
Project Start
2004-03-15
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$375,716
Indirect Cost
Name
Tufts University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Elzoheiry, Manal; Da'dara, Akram A; Bhardwaj, Rita et al. (2018) Intravascular Schistosoma mansoni Cleave the Host Immune and Hemostatic Signaling Molecule Sphingosine-1-Phosphate via Tegumental Alkaline Phosphatase. Front Immunol 9:1746
Wang, Qiang; Da'dara, Akram A; Skelly, Patrick J (2018) The blood fluke Schistosoma mansoni cleaves the coagulation protein high molecular weight kininogen (HK) but does not generate the vasodilator bradykinin. Parasit Vectors 11:182
Wang, Qiang; Da'dara, Akram A; Skelly, Patrick J (2017) The human blood parasite Schistosoma mansoni expresses extracellular tegumental calpains that cleave the blood clotting protein fibronectin. Sci Rep 7:12912
Krautz-Peterson, Greice; Debatis, Michelle; Tremblay, Jacqueline M et al. (2017) Schistosoma mansoni Infection of Mice, Rats and Humans Elicits a Strong Antibody Response to a Limited Number of Reduction-Sensitive Epitopes on Five Major Tegumental Membrane Proteins. PLoS Negl Trop Dis 11:e0005306
Da'dara, Akram A; Siddons, Giles; Icaza, Melissa et al. (2017) How schistosomes alter the human serum proteome. Mol Biochem Parasitol 215:40-46
Da'dara, Akram A; de Laforcade, Armelle M; Skelly, Patrick J (2016) The impact of schistosomes and schistosomiasis on murine blood coagulation and fibrinolysis as determined by thromboelastography (TEG). J Thromb Thrombolysis 41:671-7
Figueiredo, Barbara C; Da'dara, Akram A; Oliveira, Sergio C et al. (2015) Schistosomes Enhance Plasminogen Activation: The Role of Tegumental Enolase. PLoS Pathog 11:e1005335
Da'dara, Akram A; Skelly, Patrick J (2015) Gene suppression in schistosomes using RNAi. Methods Mol Biol 1201:143-64
Figueiredo, Barbara C; Assis, Natan R G; Morais, Suellen B et al. (2014) Schistosome syntenin partially protects vaccinated mice against Schistosoma mansoni infection. PLoS Negl Trop Dis 8:e3107
Da'dara, Akram A; Krautz-Peterson, Greice (2014) New insights into the reaction of Schistosoma mansoni cercaria to the human complement system. Parasitol Res 113:3685-96

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