Schistosomes are parasitic flatworms that cause a chronic, debilitating disease afflicting over 200 million people in over 70 countries. The parasites live for years, sometimes decades, in what should be a very hostile environment - the blood of vertebrates - yet they appear to solicit little if any protective reaction from two of the host's major defensive systems: the hemostatic system and the immune system. We hypothesize that proteins at the host-interactive surface are central to the parasites ability to dampen host immunity and hemostasis while, at the same time, permitting metabolite exchange. In this competing renewal, we propose to use new molecular methods such as RNA interference that were first developed for use with schistosomes under our previous grant, RO1 AI056273, to test several key hypotheses concerning: 1) the role of tegumental ecto-enzymes in hemostasis and immunomodulation, 2) the ability of tegumental sphingomyelinase to alter permeability properties at the parasite surface, and 3) the molecular mechanisms of trans- tegumental metabolite exchange. The functional genomics approach we adopt here coupled with independent and direct, follow-up experiments employing more traditional cell biology and biochemistry techniques are designed to provide significant new information concerning the schistosome host interactive surface. In addition the work is designed to identify tegumental proteins critical for parasite survival in the host and subsequent screens will be undertaken to discover drugs that inhibit these molecules. In this way, our planned experiments have the potential to reveal novel and valid targets, as well as new treatments, for intervention in a parasite that remains a widespread and major cause of human disease.

Public Health Relevance

Schistosomes are parasite worms that live in the blood streams of over 200 million people in more than 70 countries. These parasites are a major cause of death and disability worldwide. The worms have remarkable properties that allow them live inside people for many years. These properties include an ability to block our immune responses from targeting them, an ability to take in nutrients from our blood and an ability to detect environmental stresses and respond appropriately. By understanding more precisely how the parasites achieve these ends, we aim to block these capabilities and kill the worms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI056273-09
Application #
8466272
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
2003-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$383,873
Indirect Cost
$151,223
Name
Tufts University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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
Skelly, Patrick J; Da'dara, Akram A; Li, Xiao-Hong et al. (2014) Schistosome feeding and regurgitation. PLoS Pathog 10:e1004246
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
Da'dara, Akram A; Faghiri, Zahra; Krautz-Peterson, Greice et al. (2013) Schistosome Na,K-ATPase as a therapeutic target. Trans R Soc Trop Med Hyg 107:74-82
Skelly, P J (2013) The use of imaging to detect schistosomes and diagnose schistosomiasis. Parasite Immunol 35:295-301
Farias, Leonardo P; Krautz-Peterson, Greice; Tararam, Cibele A et al. (2013) On the three-finger protein domain fold and CD59-like proteins in Schistosoma mansoni. PLoS Negl Trop Dis 7:e2482
Da'dara, Akram; Skelly, Patrick J (2011) Manipulation of vascular function by blood flukes? Blood Rev 25:175-9
Swain, Martin T; Larkin, Denis M; Caffrey, Conor R et al. (2011) Schistosoma comparative genomics: integrating genome structure, parasite biology and anthelmintic discovery. Trends Parasitol 27:555-64
Bhardwaj, Rita; Skelly, Patrick J (2011) Characterization of schistosome tegumental alkaline phosphatase (SmAP). PLoS Negl Trop Dis 5:e1011
Bhardwaj, Rita; Krautz-Peterson, Greice; Skelly, Patrick J (2011) Using RNA interference in Schistosoma mansoni. Methods Mol Biol 764:223-39

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