Skip to main content Accessibility help

Erythrocyte invasion profiles are associated with a common invasion ligand polymorphism in Senegalese isolates of Plasmodium falciparum

  • P. M. LANTOS (a1), A. D. AHOUIDI (a2), A. K. BEI (a1), C. V. JENNINGS (a1), O. SARR (a2), O. NDIR (a2), D. F. WIRTH (a1), S. MBOUP (a2) and M. T. DURAISINGH (a1)...


Plasmodium falciparum parasites use multiple ligand-receptor interactions to invade human erythrocytes. Variant expression levels of members of the PfRh and PfEBA ligand families are associated with the use of different erythrocyte receptors, defining invasion pathways. Here we analyse a major polymorphism, a large sequence deletion in the PfRh2b ligand, and erythrocyte invasion profiles in uncultured Senegalese isolates. Parasites vary considerably in their use of sialic acid-containing and protease-sensitive erythrocyte receptors for invasion. The erythrocyte selectivity index was not related to invasion pathway usage, while parasite multiplication rate was associated with enhanced use of a trypsin-resistant invasion pathway. PfRh2b protein was expressed in all parasite isolates, although the PfRh2b deletion was present in a subset (~68%). Parasites with the PfRh2b deletion were found to preferentially utilize protease-resistant pathways for erythrocyte invasion. Sialic acid-independent invasion is reduced in parasites with the PfRh2b deletion, but only in isolates derived from blood group O patients. Our results suggest a significant role for PfRh2b sequence polymorphism in discriminating between alternative erythrocyte receptors for invasion and as a possible determinant of virulence.


Corresponding author

*Corresponding author: Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. Tel: +1 617 432 2675. Fax: +1 617 436 4766. E-mail:


Hide All
Baum, J., Maier, A. G., Good, R. T., Simpson, K. M. and Cowman, A. F. (2005). Invasion by Plasmodium falciparum merozoites suggests a hierarchy of molecular interactions. PLoS Pathogens 1, e37.
Baum, J., Pinder, M. and Conway, D. J. (2003). Erythrocyte invasion phenotypes of Plasmodium falciparum in The Gambia. Infection and Immunity 71, 18561863.
Bei, A. K., Membi, C. D., Rayner, J. C., Mubi, M., Ngasala, B., Sultan, A. A., Premji, Z. and Duraisingh, M. T. (2007). Variant merozoite protein expression is associated with erythrocyte invasion phenotypes in Plasmodium falciparum isolates from Tanzania. Molecular and Biochemical Parasitology 153, 6671.
Chotivanich, K., Udomsangpetch, R., Simpson, J. A., Newton, P., Pukrittayakamee, S., Looareesuwan, S. and White, N. J. (2000). Parasite multiplication potential and the severity of falciparum malaria. Journal of Infectious Diseases 181, 12061209.
Cowman, A. F. and Crabb, B. S. (2006). Invasion of red blood cells by malaria parasites. Cell 124, 755766.
Cserti, C. M. and Dzik, W. H. (2007). The ABO blood group system and Plasmodium falciparum malaria. Blood 110, 22502258.
Deans, A. M., Lyke, K. E., Thera, M. A., Plowe, C. V., Kone, A., Doumbo, O. K., Kai, O., Marsh, K., Mackinnon, M. J., Raza, A. and Rowe, J. A. (2006). Low multiplication rates of African Plasmodium falciparum isolates and lack of association of multiplication rate and red blood cell selectivity with malaria virulence. American Journal of Tropical Medicine and Hygiene 74, 554563.
Deans, A. M., Nery, S., Conway, D. J., Kai, O., Marsh, K. and Rowe, J. A. (2007). Invasion pathways and malaria severity in Kenyan Plasmodium falciparum clinical isolates. Infection and Immunity 75, 30143020.
Dolan, S. A., Miller, L. H. and Wellems, T. E. (1990). Evidence for a switching mechanism in the invasion of erythrocytes by Plasmodium falciparum. Journal of Clinical Investigation 86, 618624.
Dolan, S. A., Proctor, J. L., Alling, D. W., Okubo, Y., Wellems, T. E. and Miller, L. H. (1994). Glycophorin B as an EBA-175 independent Plasmodium falciparum receptor of human erythrocytes. Molecular and Biochemical Parasitology 64, 5563.
Duraisingh, M. T., Maier, A. G., Triglia, T. and Cowman, A. F. (2003 a). Erythrocyte-binding antigen 175 mediates invasion in Plasmodium falciparum utilizing sialic acid-dependent and -independent pathways. Proceedings of the National Academy of Sciences, USA 100, 47964801.
Duraisingh, M. T., Triglia, T., Ralph, S. A., Rayner, J. C., Barnwell, J. W., McFadden, G. I. and Cowman, A. F. (2003 b). Phenotypic variation of Plasmodium falciparum merozoite proteins directs receptor targeting for invasion of human erythrocytes. EMBO Journal 22, 10471057.
Gaur, D., Storry, J. R., Reid, M. E., Barnwell, J. W. and Miller, L. H. (2003). Plasmodium falciparum is able to invade erythrocytes through a trypsin-resistant pathway independent of glycophorin B. Infection and Immunity 71, 67426746.
Gilberger, T. W., Thompson, J. K., Triglia, T., Good, R. T., Duraisingh, M. T. and Cowman, A. F. (2003). A novel erythrocyte binding antigen-175 paralogue from Plasmodium falciparum defines a new trypsin-resistant receptor on human erythrocytes. Journal of Biological Chemistry 278, 1448014486.
Hadley, T. J., Klotz, F. W., Pasvol, G., Haynes, J. D. and McGinniss, M. H. (1987). Falciparum malaria parasites invade erythrocytes that lack glycophorin A and B (MkMk). Strain differences indicate receptor heterogeneity and two pathways for invasion. Journal of Clinical Investigation 80, 11901193.
Jay, D. G. (1986). Glycosylation site of band 3, the human erythrocyte anion-exchange protein. Biochemistry 25, 554556.
Jennings, C. V., Ahouidi, A. D., Zilversmit, M., Bei, A., Rayner, J., Sarr, O., Ndir, O., Wirth, D. F., Mboup, S. and Duraisingh, M. T. (2007). Molecular analysis of erythrocyte invasion in Plasmodium falciparum isolates from Senegal. Infection and Immunity 75, 35313538.
Kaneko, O., Mu, J., Tsuboi, T., Su, X. and Torii, M. (2002). Gene structure and expression of a Plasmodium falciparum 220-kDa protein homologous to the Plasmodium vivax reticulocyte binding proteins. Molecular and Biochemical Parasitology 121, 275278.
Kwiatkowski, D. P. and Luoni, G. (2006). Host genetic factors in resistance and susceptibility to malaria. Parassitologia 48, 450467.
Lobo, C. A., De Frazao, K., Rodriguez, M., Reid, M., Zalis, M. and Lustigman, S. (2004). Invasion profiles of Brazilian field isolates of Plasmodium falciparum: phenotypic and genotypic analyses. Infection and Immunity 72, 58865891.
Lobo, C. A., Rodriguez, M., Reid, M. and Lustigman, S. (2003). Glycophorin C is the receptor for the Plasmodium falciparum erythrocyte binding ligand PfEBP-2 (baebl). Blood 101, 46284631.
Lobo, C. A., Rodriguez, M., Struchiner, C. J., Zalis, M. G. and Lustigman, S. (2006). Associations between defined polymorphic variants in the PfRH ligand family and the invasion pathways used by Plasmodium falciparum field isolates from Brazil. Molecular and Biochemical Parasitology 149, 246251.
Maier, A. G., Duraisingh, M. T., Reeder, J. C., Patel, S. S., Kazura, J. W., Zimmerman, P. A. and Cowman, A. F. (2003). Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations. Nature Medicine 9, 8792.
Mitchell, G. G., Hadley, T. J., McGinniss, M. H., Klotz, F. W. and Miller, L. H. (1986). Invasion of erythrocytes by Plasmodium falciparum malaria parasites: evidence for receptor heterogeneity and two receptors. Blood 67, 15191521.
Okoyeh, J. N., Pillai, C. R. and Chitnis, C. E. (1999). Plasmodium falciparum field isolates commonly use erythrocyte invasion pathways that are independent of sialic acid residues of glycophorin A. Infection and Immunity 67, 57845791.
Peterson, D. S. and Wellems, T. E. (2000). EBL-1, a putative erythrocyte binding protein of Plasmodium falciparum, maps within a favored linkage group in two genetic crosses. Molecular and Biochemical Parasitology 105, 105113.
Rayner, J. C., Galinski, M. R., Ingravallo, P. and Barnwell, J. W. (2000). Two Plasmodium falciparum genes express merozoite proteins that are related to Plasmodium vivax and Plasmodium yoelii adhesive proteins involved in host cell selection and invasion. Proceedings of the National Academy of Sciences, USA 97, 96489653.
Rayner, J. C., Vargas-Serrato, E., Huber, C. S., Galinski, M. R. and Barnwell, J. W. (2001). A Plasmodium falciparum homologue of Plasmodium vivax reticulocyte binding protein (PvRBP1) defines a trypsin-resistant erythrocyte invasion pathway. Journal of Experimental Medicine 194, 15711581.
Sim, B., Orlandi, P. A., Haynes, J. D., Klotz, F. W., Carter, J. M., Camus, D., Zegans, M. E. and Chulay, J. D. (1990). Primary structure of the 175K Plasmodium falciparum erythrocyte binding antigen and identification of a peptide which elicits antibodies that inhibit malaria merozoite invasion. Journal of Cell Biology 111, 18771884.
Sim, B. K. L., Chitnis, C. E., Wasniowska, K., Hadley, T. J. and Miller, L. H. (1994). Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum. Science 264, 19411944.
Simpson, J. A., Silamut, K., Chotivanich, K., Pukrittayakamee, S. and White, N. J. (1999). Red cell selectivity in malaria: a study of multiple-infected erythrocytes. Transactions of the Royal Society of Tropical Medicine and Hygiene 93, 165168.
Stubbs, J., Simpson, K. M., Triglia, T., Plouffe, D., Tonkin, C. J., Duraisingh, M. T., Maier, A. G., Winzeler, E. A. and Cowman, A. F. (2005). Molecular mechanism for switching of Plasmodium falciparum invasion pathways into human erythrocytes. Science 309, 13841387.
Taylor, H. M., Grainger, M. and Holder, A. A. (2002). Variation in the expression of a Plasmodium falciparum protein family implicated in erythrocyte invasion. Infection and Immunity 70, 57795789.
Thompson, J. K., Triglia, T., Reed, M. B. and Cowman, A. F. (2001). A novel ligand from Plasmodium falciparum that binds to a sialic acid-containing receptor on the surface of human erythrocytes. Molecular Microbiology 41, 4758.
Triglia, T., Duraisingh, M. T., Good, R. T. and Cowman, A. F. (2005). Reticulocyte-binding protein homologue 1 is required for sialic acid-dependent invasion into human erythrocytes by Plasmodium falciparum. Molecular Microbiology 55, 162174.
Triglia, T., Thompson, J., Caruana, S. R., Delorenzi, M., Speed, T. and Cowman, A. F. (2001). Identification of proteins from Plasmodium falciparum that are homologous to reticulocyte binding proteins in Plasmodium vivax. Infection and Immunity 69, 10841092.
Viriyakosol, S., Siripoon, N., Zhu, X. P., Jarra, W., Seugorn, A., Brown, K. N. and Snounou, G. (1994). Plasmodium falciparum: selective growth of subpopulations from field samples following in vitro culture, as detected by the polymerase chain reaction. Experimental Parasitology 79, 517525.


Erythrocyte invasion profiles are associated with a common invasion ligand polymorphism in Senegalese isolates of Plasmodium falciparum

  • P. M. LANTOS (a1), A. D. AHOUIDI (a2), A. K. BEI (a1), C. V. JENNINGS (a1), O. SARR (a2), O. NDIR (a2), D. F. WIRTH (a1), S. MBOUP (a2) and M. T. DURAISINGH (a1)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed