Immunological memory to malaria liver stage antigens

Summary

Principal Investigator: JAMES WALTER KAZURA
Abstract: 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.
Funding Period: 1994-09-15 - 2008-02-28
more information: NIH RePORT

Top Publications

  1. pmc Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations
    Rajeev K Mehlotra
    Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Wolstein Research Building 4204, 2103 Cornell Road, Cleveland, OH 44106 7286, USA
    Eur J Clin Pharmacol 63:1-8. 2007
  2. pmc Reduced Plasmodium vivax erythrocyte infection in PNG Duffy-negative heterozygotes
    Laurin J Kasehagen
    Center for Global Health and Disease, Case Western Reserve University, School of Medicine, Cleveland, Ohio, United States of America
    PLoS ONE 2:e336. 2007
  3. ncbi Insight into the early spread of chloroquine-resistant Plasmodium falciparum infections in Papua New Guinea
    Rajeev K Mehlotra
    Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA
    J Infect Dis 192:2174-9. 2005
  4. ncbi Prevalence of CYP2B6 alleles in malaria-endemic populations of West Africa and Papua New Guinea
    Rajeev K Mehlotra
    Center for Global Health and Diseases, School of Medicine, Case Western Reserve University, Wolstein Research Building 4204, Cleveland, OH 44106 7286, USA
    Eur J Clin Pharmacol 62:267-75. 2006
  5. pmc CYP2B6 983T>C polymorphism is prevalent in West Africa but absent in Papua New Guinea: implications for HIV/AIDS treatment
    Rajeev K Mehlotra
    Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
    Br J Clin Pharmacol 64:391-5. 2007
  6. pmc Discordant patterns of genetic variation at two chloroquine resistance loci in worldwide populations of the malaria parasite Plasmodium falciparum
    Rajeev K Mehlotra
    Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Wolstein Research Building, room no 4204, 2103 Cornell Road, Cleveland, OH 44106 7286, USA
    Antimicrob Agents Chemother 52:2212-22. 2008
  7. pmc Enhanced detection of gametocytes by magnetic deposition microscopy predicts higher potential for Plasmodium falciparum transmission
    Stephan Karl
    Institute of Food Process and Bioprocess Engineering, University of Technology Dresden, 01062 Dresden, Germany
    Malar J 7:66. 2008
  8. pmc Application of pharmacogenomics to malaria: a holistic approach for successful chemotherapy
    Rajeev K Mehlotra
    Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Wolstein Research Building 4204, 2103 Cornell Road, Cleveland, OH 44106 7286, USA
    Pharmacogenomics 10:435-49. 2009

Scientific Experts

  • Rajeev K Mehlotra
  • Stephan Karl
  • Laurin J Kasehagen
  • James W Kazura
  • Peter A Zimmerman
  • Will Kastens
  • Charles H King
  • Benson Kiniboro
  • Moses J Bockarie
  • Christopher C Whalen
  • John C Reeder
  • Ivo Mueller
  • David T McNamara

Detail Information

Publications8

  1. pmc Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations
    Rajeev K Mehlotra
    Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Wolstein Research Building 4204, 2103 Cornell Road, Cleveland, OH 44106 7286, USA
    Eur J Clin Pharmacol 63:1-8. 2007
    ..Our aim was to analyze the prevalence of UGT1A9 (chromosome 2) and UGT2B7 (chromosome 4) nonsynonymous single nucleotide polymorphisms (SNPs) in West African (WA), Papua New Guinean (PNG), and North American (NA) populations...
  2. pmc Reduced Plasmodium vivax erythrocyte infection in PNG Duffy-negative heterozygotes
    Laurin J Kasehagen
    Center for Global Health and Disease, Case Western Reserve University, School of Medicine, Cleveland, Ohio, United States of America
    PLoS ONE 2:e336. 2007
    ..Our limited knowledge of the selective advantages or disadvantages associated with this genotype constrains our understanding of the effect that interventions against Pv may have on the health of people living in malaria-endemic regions...
  3. ncbi Insight into the early spread of chloroquine-resistant Plasmodium falciparum infections in Papua New Guinea
    Rajeev K Mehlotra
    Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA
    J Infect Dis 192:2174-9. 2005
    ..These results suggest that selection for CQR was operating on the pfcrt-SVMNT allele during the early 1980s. Thus, archival samples can provide novel insight into the dynamics of CQR...
  4. ncbi Prevalence of CYP2B6 alleles in malaria-endemic populations of West Africa and Papua New Guinea
    Rajeev K Mehlotra
    Center for Global Health and Diseases, School of Medicine, Case Western Reserve University, Wolstein Research Building 4204, Cleveland, OH 44106 7286, USA
    Eur J Clin Pharmacol 62:267-75. 2006
    ..Our aim was to analyze the prevalence of the most commonly observed CYP2B6 alleles in malaria-endemic populations of West Africa (WA) and Papua New Guinea (PNG)...
  5. pmc CYP2B6 983T>C polymorphism is prevalent in West Africa but absent in Papua New Guinea: implications for HIV/AIDS treatment
    Rajeev K Mehlotra
    Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
    Br J Clin Pharmacol 64:391-5. 2007
    ..To determine the prevalence of the novel CYP2B6 functional polymorphism 983T>C in Papua New Guinea where HIV/AIDS poses a significant health problem...
  6. pmc Discordant patterns of genetic variation at two chloroquine resistance loci in worldwide populations of the malaria parasite Plasmodium falciparum
    Rajeev K Mehlotra
    Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Wolstein Research Building, room no 4204, 2103 Cornell Road, Cleveland, OH 44106 7286, USA
    Antimicrob Agents Chemother 52:2212-22. 2008
    ....
  7. pmc Enhanced detection of gametocytes by magnetic deposition microscopy predicts higher potential for Plasmodium falciparum transmission
    Stephan Karl
    Institute of Food Process and Bioprocess Engineering, University of Technology Dresden, 01062 Dresden, Germany
    Malar J 7:66. 2008
    ..Here the utility of this method for diagnosis of human malaria is evaluated in a malaria-endemic region of Papua New Guinea (PNG)...
  8. pmc Application of pharmacogenomics to malaria: a holistic approach for successful chemotherapy
    Rajeev K Mehlotra
    Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Wolstein Research Building 4204, 2103 Cornell Road, Cleveland, OH 44106 7286, USA
    Pharmacogenomics 10:435-49. 2009
    ....