Browsing by Author "Graves, P.M."
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Item Antibodies to plasmodium falciparum gamete surface antigens in papua new guinea sera(Parasite Immunology, 1988) Graves, P.M.; Carter, R.; Burkot, T.R.; Quakyi, I.A.; Kumar, N.Sera from individuals living in malaria endemic areas of Papua New Guinea were tested for their effect on infectivity of Plasmodium falciparum gametocytes grown in culture to Anopheles freeborni mosquitoes. Consistent reduction of infectivity to less than 5% of control was observed with nine out of the 41 sera from the endemic area tested and also with three out of seven sera tested from individuals rarely exposed to malaria infection. Gamete surface antigens recognized by the sera were investigated by immunoprecipitation from 125I surface-labelled gametes extracted in SDS and Triton X-100. The main antigens recognized were of the same mol. wt (230, 48 and 45 kD) as those known to be targets of transmission-blocking monoclonal antibodies. A significant negative correlation was observed between the total ct/min immunoprecipitated from surface-labelled gametes by the sera and the average number of oocysts per gut observed in membrane feeding experiments with these sera. Spearmann's rank correlation coefficient indicated that suppression of infectivity correlated strongly with the presence of antibodies against the 230 kD protein; there was no significant correlation between suppression and antibodies to the 48/45 kD proteins. The antibody response to the different gamete surface antigens varied greatly in sera from the endemic areas suggesting that individuals respond differently to each gamete antigen.Item Genomic Epidemiology in Filarial Nematodes: Transforming the Basis for Elimination Program Decisions(Frontiers in Genetics, 2020-01-09) Boakye, D.A.; Hedtke, S.M.; Kuesel, A.C.; Crawford, K.E.; Graves, P.M.; Boussinesq, M.; Lau, C.L.; Boakye, D.A.; Grant, W.N.Onchocerciasis and lymphatic filariasis are targeted for elimination, primarily using mass drug administration at the country and community levels. Elimination of transmission is the onchocerciasis target and global elimination as a public health problem is the end point for lymphatic filariasis. Where program duration, treatment coverage, and compliance are sufficiently high, elimination is achievable for both parasites within defined geographic areas. However, transmission has re-emerged after apparent elimination in some areas, and in others has continued despite years of mass drug treatment. A critical question is whether this re-emergence and/or persistence of transmission is due to persistence of local parasites—i.e., the result of insufficient duration or drug coverage, poor parasite response to the drugs, or inadequate methods of assessment and/or criteria for determining when to stop treatment—or due to re-introduction of parasites via human or vector movement from another endemic area. We review recent genetics-based research exploring these questions in Onchocerca volvulus, the filarial nematode that causes onchocerciasis, and Wuchereria bancrofti, the major pathogen for lymphatic filariasis. We focus in particular on the combination of genomic epidemiology and genome-wide associations to delineate transmission zones and distinguish between local and introduced parasites as the source of resurgence or continuing transmission, and to identify genetic markers associated with parasite response to chemotherapy. Our ultimate goal is to assist elimination efforts by developing easy-to-use tools that incorporate genetic information about transmission and drug response for more effective mass drug distribution, surveillance strategies, and decisions on when to stop interventions to improve sustainability of eliminationItem Identification of anti-plasmodium falciparum antibodies in human breast milk(Scandinavian Journal of Immunology, 1992) Leke, R.G.F.; Ndansi, R.; Southerland, N.J.; Quakyi, I.A.; Graves, P.M.; Drake, J.C.; Allegra, C.J.Malarial infections are rarely observed in neonates. It has been postulated that some immunity may be passively transferred during nursing, but anti-malarial antibodies (Abs) have not been detected in human milk. In this study milk samples collected 2-14 days after parturition from women at the Central Maternity Hospital, Yaounde were evaluated for total IgG and IgA antibody levels by radial diffusion, protein composition by SDS-PAGE, anti-malarial antibodies using an isotype-specific immunofluorescence assay, and the ability to immunoprecipitate Plasmodium falciparum antigens metabolically labelled with 35S-methionine. Results showed that anti-P. falciparum antibodies were present in breast milk, and that paired milk and serum samples from individual women contained Abs that recognized similar malarial antigens.Item Mechanism of pyrimethamine resistance in recent isolates of plasmodium falciparum(Antimicrobial Agents and Chemotherapy, 1984) McCutchan, T.F.; Welsh, J.A.; Dame, J.B.; Quakyi, I.A.; Graves, P.M.; Drake, J.C.; Allegra, C.J.Clones of Plasmodium falciparum prepared from recent isolates of infected blood were studied to determine the molecular mechanism of naturally occurring pyrimethamine resistance. Total DNA, as well as thymidylate synthetase and dihydrofolate reductase activities, were characterized from these lines. Restriction analysis of DNA from pyrimethamine-susceptible and -resistant lines of the parasite showed no obvious amplification of any DNA fragment. Further, analysis of DNA from resistant and susceptible lines by centrifugation in cesium chloride-ethidium bromide revealed no extrachromosomal amplification in the resistant line. Comparison of the dihydrofolate reductase enzyme activity in the two lines revealed similar K(m)s for substrate but a large difference in the inhibition constant for pyrimethamine. Additionally, the enzyme from the resistant line was considerably more stable in vitro than the corresponding enzyme from the susceptible line. The thymidylate synthetase activity in the two lines was similar and unaffected by pyrimethamine. The mechanism of drug resistance in this isolate involves altered properties of the dihydrofolate reductase conferring both a different affinity for the drug and increased stability.Item Properties of epitopes of pfs 48/45, a target of transmission blocking monoclonal antibodies, on gametes of different isolates of plasmodium falciparum(Parasite Immunology, 1990) Carter, R.; Graves, P.M.; Keister, D.B.; Quakyi, I.A.Summary We have studied the properties of epitopes on Plasmodium falciparum gamete surface protein Pfs 48/45, a target antigen of malaria transmission blocking antibodies. Using a two site immunoradiometric assay we have defined three spacially separate, non-repeated, epitope regions on the peptides representing this antigen. Epitope region I is a target of monoclonal antibodies (MoAbs) which strongly suppress infectivity of gametocytes of P. falciparum to mosquitoes; the effect is complement independent and is mediated as effectively by the monovalent Fab fragments as by intact MoAb. Epitope region II consists of two spacially close subregions, Ha and lib; variant forms of epitopes Ha and lib occurred in different isolates of P. falciparum. Epitope region III also showed slight structural modification between isolates. MoAbs against regions II or III were relatively ineffective in suppressing gametocyte infectivity compared to MoAbs against region I. However, certain combinations of MoAbs against regions II and III together acted synergistically to suppress infectivity to mosquitoes. All these epitopes failed to react with MoAb when the antigen was presented in reduced form. A fourth epitope, however, was identified which reacted strongly with MoAb when the antigen was presented in reduced form. The MoAb against this epitope had no effect on the infectivity of gametocytes of P. falciparum to mosquitoes.Item Restricted or absent immune responses in human populations to plasmodium falciparum gamete antigens that are targets of malaria transmission-blocking antibodies.(Journal of Experimental Medicine, 1989) Carter, R.; Graves, P.M.; Quakyi, I.A.; Good, M.F.We have studied the antibodies to sexual stage antigens of Plasmodium falciparum in human serum from Papua New Guinea where intense transmission of P. falciparum occurs as well as the less prevalent P. malariae and P. vivax. In extracts of gametes of P. falciparum we have studied the reactivity of serum antibodies with antigens labeled with 125I on the surface of the gametes as well as intracellular gamete antigens. A prominent 27-kD sexual stage-specific intracellular protein was recognized more or less in proportion to the general antibody response to gamete proteins. The response to the gamete surface proteins, however, was quite unrepresentative of the general antibody response to the intracellular gamete proteins. No antibodies were detected against Pfs25, a 21-kD protein expressed on zygotes and ookinetes of P. falciparum and known to be a sensitive target of malaria transmission-blocking antibodies. The antibody response to two other target antigens of transmission-blocking antibodies on the surface of gametes of P. falciparum, a 230- and a 48- and 45-kD protein doublet, was very variable and independent of the response to the internal protein antigens. Several possibilities are discussed that may account for the variable response to these gamete surface antigens in individuals with otherwise good antibody responses to internal sexual stage proteins. Among these is the possibility that there is MHC restriction of the immune response to the gamete surface antigens in the human population. This interpretation accords well with evidence for MHC-restricted immune response to the same P. falciparum gamete surface antigens in studies with H-2 congenic mice.