This application for continuing studies of immunity to P. falciparum (Pf) will test the hypothesis that a stable pool of CD8+ memory T-cells to liver-stage antigens (Ags) develops by adulthood in residents of malaria endemic areas and that these cells evolve from a genetically diverse repertoire of T-cells elicited by exposure to sporozoites (spz) during infancy. Ongoing studies in Papua New Guinea indicate this area is well suited for examination of immunologic memory in malaria because HLA heterogeneity is limited (HLA-A* 1101 frequency = 67 percent and peptides of vaccine candidate Ags have been confirmed to bind to HLA-A* 1101 and drive T-cell cytokine recall responses.
Aims of continuing studies are to 1) determine whether a genetically stable pool of CD8+ memory T-cells to Pf liver-stage epitopes exists in adults. T-cell lines will be derived from HLA-A* 1101 individuals in order to expand peptide-specific CD8+ T-cell clones. Stability of the pattern of Vbeta expression, CDR3 sequences, and cytokine production will be evaluated over a 2-year period, and 2) assess the relationship between spz exposure and evolution of CD8+ memory cells in a prospective cohort study on children from 4-6 months to 3 years of age. Cytokine responses and TCR usage by HLA-A11-restricted LSA1 peptide-specific T-cells will be correlated with the frequency of infection, high-density parasitemia, genotypic complexity of infection, and uncomplicated morbidity. The studies are relevant to the development of malaria vaccines because these immunogens will ultimately be evaluated in persons with active or previous infection and because maintenance of vaccine-induced immunity will depend on boosting through continuing exposure to spz.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI036478-08
Application #
6442334
Study Section
Special Emphasis Panel (ZRG1-SSS-K (01))
Program Officer
Hall, B Fenton
Project Start
1994-09-15
Project End
2007-02-28
Budget Start
2002-09-01
Budget End
2003-02-28
Support Year
8
Fiscal Year
2002
Total Cost
$263,775
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Mehlotra, Rajeev K; Henry-Halldin, Cara N; Zimmerman, Peter A (2009) Application of pharmacogenomics to malaria: a holistic approach for successful chemotherapy. Pharmacogenomics 10:435-49
Mehlotra, Rajeev K; Mattera, Gabriel; Bockarie, Moses J et al. (2008) Discordant patterns of genetic variation at two chloroquine resistance loci in worldwide populations of the malaria parasite Plasmodium falciparum. Antimicrob Agents Chemother 52:2212-22
Karl, Stephan; David, Makindi; Moore, Lee et al. (2008) Enhanced detection of gametocytes by magnetic deposition microscopy predicts higher potential for Plasmodium falciparum transmission. Malar J 7:66
Kasehagen, Laurin J; Mueller, Ivo; Kiniboro, Benson et al. (2007) Reduced Plasmodium vivax erythrocyte infection in PNG Duffy-negative heterozygotes. PLoS One 2:e336
Mehlotra, Rajeev K; Bockarie, Moses J; Zimmerman, Peter A (2007) CYP2B6 983T>C polymorphism is prevalent in West Africa but absent in Papua New Guinea: implications for HIV/AIDS treatment. Br J Clin Pharmacol 64:391-5
Mehlotra, Rajeev K; Ziats, Mark N; Bockarie, Moses J et al. (2006) Prevalence of CYP2B6 alleles in malaria-endemic populations of West Africa and Papua New Guinea. Eur J Clin Pharmacol 62:267-75
Mehlotra, Rajeev K; Mattera, Gabriel; Bhatia, Kuldeep et al. (2005) Insight into the early spread of chloroquine-resistant Plasmodium falciparum infections in Papua New Guinea. J Infect Dis 192:2174-9
Patel, Sheral S; King, Christopher L; Mgone, Charles S et al. (2004) Glycophorin C (Gerbich antigen blood group) and band 3 polymorphisms in two malaria holoendemic regions of Papua New Guinea. Am J Hematol 75:1-5
Zimmerman, Peter A; Patel, Sheral S; Maier, Alexander G et al. (2003) Erythrocyte polymorphisms and malaria parasite invasion in Papua New Guinea. Trends Parasitol 19:250-2
Maier, Alexander G; Duraisingh, Manoj T; Reeder, John C et al. (2003) Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations. Nat Med 9:87-92

Showing the most recent 10 out of 20 publications