: Schistosomiasis afflicts several hundred million people, causing substantial morbidity and premature death as well as major economic hardship in many developing countries. Over a billion people are at risk of infection. Advances in genomics and proteomics, as well as new technologies such as phage display and recombinant antibodies, offer important new opportunities to develop and test hypotheses relating to these worm parasites and for new schistosomiasis control strategies. Schistosomes are trematode worms that are able to survive for many years within the vasculature of permissive vertebrate hosts. Although schistosomes reportedly possess a variety of immune evasive tools, these blood flukes clearly can become susceptible to immune killing by effectors mediated by antibody directed against the host-exposed tegument. Compelling evidence comes from the rat model, which, unlike mice and humans, becomes strongly immune to schistosomiasis mansoni, and produces antibodies against adult worm surface epitopes that direct the killing of larval and adult schistosomes. Based on these and other data, we hypothesize that schistosomes can be killed in vivo through an immune process that is mediated by protective antibodies directed against a discrete subset of worm surface epitopes. In this R21 grant application, we propose to employ an innovative in vivo phage display technique to identify single-chain antibodies (scFvs) able to bind to the surface of schistosomes as they reside within their host and then test these antibodies for their ability to direct killing of the parasites.
The Specific Aims are: #1. Use """"""""in vivo panning"""""""" of an antibody (scFv) phage display library prepared from rats immune to schistosomiasis to identify and then characterize host-interactive surface epitopes. #2. Engineer recombinant antibodies that bind to host-interactive schistosome epitopes and test their ability to mediate parasite killing within mice. This research is designed to identify new targets of protective immunity that will serve as vaccine candidates. Furthermore, it will produce new information on the biochemistry of the host-interactive parasite surface in vivo and create genetically modifiable scFv reagents that will lead to a range of unique research opportunities to investigate helminth parasite rejection and immune evasion strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI061517-02
Application #
6919822
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Wali, Tonu M
Project Start
2004-07-15
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$198,125
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
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
Sepulveda, Jorge; Tremblay, Jacqueline M; DeGnore, Jon P et al. (2010) Schistosoma mansoni host-exposed surface antigens characterized by sera and recombinant antibodies from schistosomiasis-resistant rats. Int J Parasitol 40:1407-17
Sepulveda, Jorge; Shoemaker, Charles B (2008) Design and testing of PCR primers for the construction of scFv libraries representing the immunoglobulin repertoire of rats. J Immunol Methods 332:92-102
Maass, David R; Sepulveda, Jorge; Pernthaner, Anton et al. (2007) Alpaca (Lama pacos) as a convenient source of recombinant camelid heavy chain antibodies (VHHs). J Immunol Methods 324:13-25