Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1997 Jun;65(6):2329–2338. doi: 10.1128/iai.65.6.2329-2338.1997

Assessment of the humoral immune response against Plasmodium falciparum rhoptry-associated proteins 1 and 2.

A Stowers 1, D Taylor 1, N Prescott 1, Q Cheng 1, J Cooper 1, A Saul 1
PMCID: PMC175323  PMID: 9169771

Abstract

Naturally occurring antibody responses to Plasmodium falciparum rhoptry-associated proteins 1 and 2 (RAP-1 and RAP-2) were measured with recombinant and parasite-derived forms of the antigens. For comparative purposes, responses to multiple forms of three other malarial antigens were also examined. The sera of 100 Papua New Guineans were screened for antibodies. Eighty-six and 82% of individuals over 30 years of age had antibodies that recognized parasite-derived RAP-1 and RAP-2, respectively. Importantly, we found that recombinant and native antigens share linear epitopes seen by the human immune system; thus, the recombinant proteins may be adequate human immunogens. However, antibodies affinity purified on recombinant RAP-1 reacted with other antigens in addition to parasite-derived RAP-1. Thus, the antigenicity of RAP-1 may have been overestimated previously. The recognition of RAP-1 and RAP-2 correlated with age and with the recognition of recombinant forms of the ring-infected erythrocyte surface antigen, merozoite surface protein 1, and merozoite surface antigen 2 (MSA2) antigens. Antibodies to these antigens appear to be generated in response to the total exposure to malaria of the host. Antibodies to conserved regions of MSA2 had stronger correlations with both age and the recognition of other antigens than did the full-length recombinant MSA2 molecule. In contrast to results with the other antigens, there was no significant difference in the ages of individuals with a certain antibody titer to the full-length recombinant or parasite-derived MSA2 molecule, but antibodies to these two antigens did correlate with parasitemia. For all antigens tested, antibody levels after two infections can approach the peak levels of antibodies obtained in immune individuals.

Full Text

The Full Text of this article is available as a PDF (978.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Brown H. J., Coppel R. L. Primary structure of a Plasmodium falciparum rhoptry antigen. Mol Biochem Parasitol. 1991 Nov;49(1):99–110. doi: 10.1016/0166-6851(91)90133-q. [DOI] [PubMed] [Google Scholar]
  2. Bushell G. R., Ingram L. T., Fardoulys C. A., Cooper J. A. An antigenic complex in the rhoptries of Plasmodium falciparum. Mol Biochem Parasitol. 1988 Mar;28(2):105–112. doi: 10.1016/0166-6851(88)90057-6. [DOI] [PubMed] [Google Scholar]
  3. Cattani J. A., Tulloch J. L., Vrbova H., Jolley D., Gibson F. D., Moir J. S., Heywood P. F., Alpers M. P., Stevenson A., Clancy R. The epidemiology of malaria in a population surrounding Madang, Papua New Guinea. Am J Trop Med Hyg. 1986 Jan;35(1):3–15. doi: 10.4269/ajtmh.1986.35.3. [DOI] [PubMed] [Google Scholar]
  4. Cooper J. A., Cooper L. T., Saul A. J. Mapping of the region predominantly recognized by antibodies to the Plasmodium falciparum merozoite surface antigen MSA 1. Mol Biochem Parasitol. 1992 Apr;51(2):301–312. doi: 10.1016/0166-6851(92)90080-4. [DOI] [PubMed] [Google Scholar]
  5. Cooper J. A., Ingram L. T., Bushell G. R., Fardoulys C. A., Stenzel D., Schofield L., Saul A. J. The 140/130/105 kilodalton protein complex in the rhoptries of Plasmodium falciparum consists of discrete polypeptides. Mol Biochem Parasitol. 1988 Jun;29(2-3):251–260. doi: 10.1016/0166-6851(88)90080-1. [DOI] [PubMed] [Google Scholar]
  6. Coppel R. L., Cowman A. F., Anders R. F., Bianco A. E., Saint R. B., Lingelbach K. R., Kemp D. J., Brown G. V. Immune sera recognize on erythrocytes Plasmodium falciparum antigen composed of repeated amino acid sequences. 1984 Aug 30-Sep 5Nature. 310(5980):789–792. doi: 10.1038/310789a0. [DOI] [PubMed] [Google Scholar]
  7. Epping R. J., Goldstone S. D., Ingram L. T., Upcroft J. A., Ramasamy R., Cooper J. A., Bushell G. R., Geysen H. M. An epitope recognised by inhibitory monoclonal antibodies that react with a 51 kilodalton merozoite surface antigen in Plasmodium falciparum. Mol Biochem Parasitol. 1988 Feb;28(1):1–10. doi: 10.1016/0166-6851(88)90173-9. [DOI] [PubMed] [Google Scholar]
  8. Früh K., Doumbo O., Müller H. M., Koita O., McBride J., Crisanti A., Touré Y., Bujard H. Human antibody response to the major merozoite surface antigen of Plasmodium falciparum is strain specific and short-lived. Infect Immun. 1991 Apr;59(4):1319–1324. doi: 10.1128/iai.59.4.1319-1324.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gentz R., Certa U., Takacs B., Matile H., Döbeli H., Pink R., Mackay M., Bone N., Scaife J. G. Major surface antigen p190 of Plasmodium falciparum: detection of common epitopes present in a variety of plasmodia isolates. EMBO J. 1988 Jan;7(1):225–230. doi: 10.1002/j.1460-2075.1988.tb02803.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Harnyuttanakorn P., McBride J. S., Donachie S., Heidrich H. G., Ridley R. G. Inhibitory monoclonal antibodies recognise epitopes adjacent to a proteolytic cleavage site on the RAP-1 protein of Plasmodium falciparum. Mol Biochem Parasitol. 1992 Oct;55(1-2):177–186. doi: 10.1016/0166-6851(92)90138-a. [DOI] [PubMed] [Google Scholar]
  11. Holder A. A., Lockyer M. J., Odink K. G., Sandhu J. S., Riveros-Moreno V., Nicholls S. C., Hillman Y., Davey L. S., Tizard M. L., Schwarz R. T. Primary structure of the precursor to the three major surface antigens of Plasmodium falciparum merozoites. Nature. 1985 Sep 19;317(6034):270–273. doi: 10.1038/317270a0. [DOI] [PubMed] [Google Scholar]
  12. Howard R. F., Jensen J. B., Franklin H. L. Reactivity profile of human anti-82-kilodalton rhoptry protein antibodies generated during natural infection with Plasmodium falciparum. Infect Immun. 1993 Jul;61(7):2960–2965. doi: 10.1128/iai.61.7.2960-2965.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Howard R. F., Peterson C. Limited RAP-1 sequence diversity in field isolates of Plasmodium falciparum. Mol Biochem Parasitol. 1996 Apr;77(1):95–98. doi: 10.1016/0166-6851(96)02576-5. [DOI] [PubMed] [Google Scholar]
  14. Howard R. F., Stanley H. A., Campbell G. H., Reese R. T. Proteins responsible for a punctate fluorescence pattern in Plasmodium falciparum merozoites. Am J Trop Med Hyg. 1984 Nov;33(6):1055–1059. doi: 10.4269/ajtmh.1984.33.1055. [DOI] [PubMed] [Google Scholar]
  15. Howard R. F. The sequence of the p82 rhoptry protein is highly conserved between two Plasmodium falciparum isolates. Mol Biochem Parasitol. 1992 Apr;51(2):327–330. doi: 10.1016/0166-6851(92)90083-v. [DOI] [PubMed] [Google Scholar]
  16. Howard R. J., Pasloske B. L. Target antigens for asexual malaria vaccine development. Parasitol Today. 1993 Oct;9(10):369–372. doi: 10.1016/0169-4758(93)90085-t. [DOI] [PubMed] [Google Scholar]
  17. Jakobsen P. H., Hviid L., Theander T. G., Afare E. A., Ridley R. G., Heegaard P. M., Stuber D., Dalsgaard K., Nkrumah F. K. Specific T-cell recognition of the merozoite proteins rhoptry-associated protein 1 and erythrocyte-binding antigen 1 of Plasmodium falciparum. Infect Immun. 1993 Jan;61(1):268–273. doi: 10.1128/iai.61.1.268-273.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kaslow D. C., Hui G., Kumar S. Expression and antigenicity of Plasmodium falciparum major merozoite surface protein (MSP1(19)) variants secreted from Saccharomyces cerevisiae. Mol Biochem Parasitol. 1994 Feb;63(2):283–289. doi: 10.1016/0166-6851(94)90064-7. [DOI] [PubMed] [Google Scholar]
  19. Müller H. M., Früh K., von Brunn A., Esposito F., Lombardi S., Crisanti A., Bujard H. Development of the human immune response against the major surface protein (gp190) of Plasmodium falciparum. Infect Immun. 1989 Dec;57(12):3765–3769. doi: 10.1128/iai.57.12.3765-3769.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Perrin L. H., Merkli B., Gabra M. S., Stocker J. W., Chizzolini C., Richle R. Immunization with a Plasmodium falciparum merozoite surface antigen induces a partial immunity in monkeys. J Clin Invest. 1985 May;75(5):1718–1721. doi: 10.1172/JCI111881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Perrin L. H., Ramirez E., Lambert P. H., Miescher P. A. Inhibition of P. falciparum growth in human erythrocytes by monoclonal antibodies. Nature. 1981 Jan 22;289(5795):301–303. doi: 10.1038/289301a0. [DOI] [PubMed] [Google Scholar]
  22. Ridley R. G., Lahm H. W., Takács B., Scaife J. G. Genetic and structural relationships between components of a protective rhoptry antigen complex from Plasmodium falciparum. Mol Biochem Parasitol. 1991 Aug;47(2):245–246. doi: 10.1016/0166-6851(91)90184-8. [DOI] [PubMed] [Google Scholar]
  23. Ridley R. G., Takacs B., Etlinger H., Scaife J. G. A rhoptry antigen of Plasmodium falciparum is protective in Saimiri monkeys. Parasitology. 1990 Oct;101(Pt 2):187–192. doi: 10.1017/s0031182000063228. [DOI] [PubMed] [Google Scholar]
  24. Ridley R. G., Takacs B., Lahm H. W., Delves C. J., Goman M., Certa U., Matile H., Woollett G. R., Scaife J. G. Characterisation and sequence of a protective rhoptry antigen from Plasmodium falciparum. Mol Biochem Parasitol. 1990 Jun;41(1):125–134. doi: 10.1016/0166-6851(90)90103-s. [DOI] [PubMed] [Google Scholar]
  25. Rooth I., Perlmann H., Bjorkman A. Plasmodium falciparum reinfection in children from a holoendemic area in relation to seroreactivities against oligopeptides from different malaria antigens. Am J Trop Med Hyg. 1991 Sep;45(3):309–318. doi: 10.4269/ajtmh.1991.45.309. [DOI] [PubMed] [Google Scholar]
  26. Saul A., Cooper J., Hauquitz D., Irving D., Cheng Q., Stowers A., Limpaiboon T. The 42-kilodalton rhoptry-associated protein of Plasmodium falciparum. Mol Biochem Parasitol. 1992 Jan;50(1):139–149. doi: 10.1016/0166-6851(92)90251-e. [DOI] [PubMed] [Google Scholar]
  27. Saul A., Myler P., Elliott T., Kidson C. Purification of mature schizonts of Plasmodium falciparum on colloidal silica gradients. Bull World Health Organ. 1982;60(5):755–759. [PMC free article] [PubMed] [Google Scholar]
  28. Schofield L., Bushell G. R., Cooper J. A., Saul A. J., Upcroft J. A., Kidson C. A rhoptry antigen of Plasmodium falciparum contains conserved and variable epitopes recognized by inhibitory monoclonal antibodies. Mol Biochem Parasitol. 1986 Feb;18(2):183–195. doi: 10.1016/0166-6851(86)90037-x. [DOI] [PubMed] [Google Scholar]
  29. Shi Y. P., Sayed U., Qari S. H., Roberts J. M., Udhayakumar V., Oloo A. J., Hawley W. A., Kaslow D. C., Nahlen B. L., Lal A. A. Natural immune response to the C-terminal 19-kilodalton domain of Plasmodium falciparum merozoite surface protein 1. Infect Immun. 1996 Jul;64(7):2716–2723. doi: 10.1128/iai.64.7.2716-2723.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sinigaglia F., Takacs B., Jacot H., Matile H., Pink J. R., Crisanti A., Bujard H. Nonpolymorphic regions of p190, a protein of the Plasmodium falciparum erythrocytic stage, contain both T and B cell epitopes. J Immunol. 1988 May 15;140(10):3568–3572. [PubMed] [Google Scholar]
  31. Smythe J. A., Coppel R. L., Brown G. V., Ramasamy R., Kemp D. J., Anders R. F. Identification of two integral membrane proteins of Plasmodium falciparum. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5195–5199. doi: 10.1073/pnas.85.14.5195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Stowers A. W., Cooper J. A., Ehrhardt T., Saul A. A peptide derived from a B cell epitope of Plasmodium falciparum rhoptry associated protein 2 specifically raises antibodies to rhoptry associated protein 1. Mol Biochem Parasitol. 1996 Nov 25;82(2):167–180. doi: 10.1016/0166-6851(96)02730-2. [DOI] [PubMed] [Google Scholar]
  33. Stowers A. W., Spring K. J., Saul A. Preparative scale purification of recombinant proteins to clinical grade by isotachophoresis. Biotechnology (N Y) 1995 Dec;13(13):1498–1503. doi: 10.1038/nbt1295-1498. [DOI] [PubMed] [Google Scholar]
  34. Stowers A., Prescott N., Cooper J., Takacs B., Stueber D., Kennedy P., Saul A. Immunogenicity of recombinant Plasmodium falciparum rhoptry associated proteins 1 and 2. Parasite Immunol. 1995 Dec;17(12):631–642. doi: 10.1111/j.1365-3024.1995.tb01009.x. [DOI] [PubMed] [Google Scholar]
  35. Sturchler D., Berger R., Rudin C., Just M., Saul A., Rzepczyk C., Brown G., Anders R., Coppel R., Woodrow G. Safety, immunogenicity, and pilot efficacy of Plasmodium falciparum sporozoite and asexual blood-stage combination vaccine in Swiss adults. Am J Trop Med Hyg. 1995 Oct;53(4):423–431. doi: 10.4269/ajtmh.1995.53.423. [DOI] [PubMed] [Google Scholar]
  36. Tanabe K., Mackay M., Goman M., Scaife J. G. Allelic dimorphism in a surface antigen gene of the malaria parasite Plasmodium falciparum. J Mol Biol. 1987 May 20;195(2):273–287. doi: 10.1016/0022-2836(87)90649-8. [DOI] [PubMed] [Google Scholar]
  37. Tolle R., Früh K., Doumbo O., Koita O., N'Diaye M., Fischer A., Dietz K., Bujard H. A prospective study of the association between the human humoral immune response to Plasmodium falciparum blood stage antigen gp190 and control of malarial infections. Infect Immun. 1993 Jan;61(1):40–47. doi: 10.1128/iai.61.1.40-47.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Trager W., Jensen J. B. Human malaria parasites in continuous culture. Science. 1976 Aug 20;193(4254):673–675. doi: 10.1126/science.781840. [DOI] [PubMed] [Google Scholar]
  39. Walliker D., Quakyi I. A., Wellems T. E., McCutchan T. F., Szarfman A., London W. T., Corcoran L. M., Burkot T. R., Carter R. Genetic analysis of the human malaria parasite Plasmodium falciparum. Science. 1987 Jun 26;236(4809):1661–1666. doi: 10.1126/science.3299700. [DOI] [PubMed] [Google Scholar]
  40. al-Yaman F., Genton B., Anders R., Taraika J., Ginny M., Mellor S., Alpers M. P. Assessment of the role of the humoral response to Plasmodium falciparum MSP2 compared to RESA and SPf66 in protecting Papua New Guinean children from clinical malaria. Parasite Immunol. 1995 Sep;17(9):493–501. doi: 10.1111/j.1365-3024.1995.tb00920.x. [DOI] [PubMed] [Google Scholar]
  41. al-Yaman F., Genton B., Falk M., Anders R. F., Lewis D., Hii J., Beck H. P., Alpers M. P. Humoral response to Plasmodium falciparum ring-infected erythrocyte surface antigen in a highly endemic area of Papua New Guinea. Am J Trop Med Hyg. 1995 Jan;52(1):66–71. doi: 10.4269/ajtmh.1995.52.66. [DOI] [PubMed] [Google Scholar]
  42. al-Yaman F., Genton B., Kramer K. J., Chang S. P., Hui G. S., Baisor M., Alpers M. P. Assessment of the role of naturally acquired antibody levels to Plasmodium falciparum merozoite surface protein-1 in protecting Papua New Guinean children from malaria morbidity. Am J Trop Med Hyg. 1996 May;54(5):443–448. doi: 10.4269/ajtmh.1996.54.443. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES