Parasitic helminths induce chronic infections in their hosts, the parasite often surviving for years without obvious rejection. With most human helminthiases there is evidence that the host develops an 'acquired immunity'over time. However, with hookworm infections, protection does not develop with age, suggesting these parasites have evolved unique mechanisms to actively evade host immune responses. Larval and adult stages of the human hookworm, Necator americanus, secrete a battery of molecules, many with immunomodulatory properties. In preliminary experiments, we report that a protein(s) from excretory/secretory (ES) products of adult N. americanus binds exclusively to natural killer (NK) cells from mice and humans. In addition, in vitro incubation of purified mouse or human NK cells with ES products stimulated the cells to produce augmented levels (4 to 24-fold) of IFN-g within 24 hours of culture. These findings have led us to postulate that N. americanus secretes a protein (NKBP) that binds to NK cells and stimulates them to produce IFN-g, possibly as a means of cross-regulating deleterious TH2 immune responses. The current proposal is designed to characterize the interactions between host leukocytes and N. americanus ES products and to establish their potential role during human hookworm infection. The following specific aims are proposed: (1) To establish the effects of NKBP binding on NK cell function, (2) To characterize NKBP and its receptor on NK cells, and (3) To determine the profile of NKBP bindingand- resulting cytokine production in patients with active hookworm infections. By identifying hookworm proteins that bind to and interfere with innate and cell-mediated host responses against the parasite, we will gain insight into the molecular mechanisms that these highly adapted pathogens use to survive. In turn these have the potential to provide novel targets for therapeutic and/or preventative strategies for infections by hookworms, as well as other types of pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059280-04
Application #
7581033
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$415,375
Indirect Cost
Name
George Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Bower, Molly A; Constant, Stephanie L; Mendez, Susana (2008) Necator americanus: the Na-ASP-2 protein secreted by the infective larvae induces neutrophil recruitment in vivo and in vitro. Exp Parasitol 118:569-75
Teixeira-Carvalho, Andrea; Fujiwara, Ricardo T; Stemmy, Erik J et al. (2008) Binding of excreted and/or secreted products of adult hookworms to human NK cells in Necator americanus-infected individuals from Brazil. Infect Immun 76:5810-6
Bethony, Jeffrey M; Loukas, Alex (2008) The schistosomiasis research agenda--what now? PLoS Negl Trop Dis 2:e207