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P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1

Nature volume 388, pages 292–295 (1997)Cite this article

Abstract

The factors determining disease severity in malaria are complex and include host polymorphisms, acquired immunity and parasite virulence1. Studies in Africa have shown that severe malaria is associated with the ability of erythrocytes infected with the parasite Plasmodium falciparum to bind uninfected erythrocytes and form rosettes2,3,4,5. The molecular basis of rosetting is not well understood, although a group of low-molecular-mass proteins called rosettins have been described as potential parasite ligands6. Infected erythrocytes also bind to endothelial cells, and this interaction is mediated by the parasite-derived variant erythrocyte membrane protein PfEMP1 (refs 7, 8), which is encoded by the var gene family9,10,11. Here we report that the parasite ligand for rosetting in a P. falciparum clone is PfEMP1, encoded by a specific var gene. We also report that complement-receptor 1 (CR1) on erythrocytes plays a role in the formation of rosettes and that erythrocytes with a common African CR1 polymorphism (Sl(a−))12 have reduced adhesion to the domain of PfEMP1 that binds normal erythrocytes. Thus we describe a new adhesive function for PfEMP1 and raise the possibility that CR1 polymorphisms in Africans that influence the interaction between erythrocytes and PfEMP1 may protect against severe malaria.

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Figure 1: Var gene expression and RBC binding in P. falciparum clone R29.
Figure 2: CR1 is required for P. falciparum rosetting.

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Acknowledgements

We thank J. Proctor, D. Mallory, L. McCall and B. Smith for negative and null erythrocytes; M. Wahlgren and R. Howard for parasite clones/lines; G. Cohen and R. Eisenberg for the pRE4 plasmid and monoclonal antibodies; J. Smith for the A4var expression construct; D. Fearon for sCR1; D. Alling for statistical advice; and B. Sullivan for assistance in identifying Sl(a−) donors. This work was funded by the Wellcome Trust (J.A.R. and C.I.N.), the National Blood Foundation (J.M.M.), and the Arthritis Foundation (J.M.M.).

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Authors and Affiliations

  1. *Laboratory of Parasitic Diseases, NIAID, NIH, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    J. Alexandra Rowe & Louis H. Miller

  2. †Molecular Parasitology Group, Institute of Molecular Medicine, John Radcliffe Hospital, OX3 9DU, Oxford, UK

    J. Alexandra Rowe & Christopher I. Newbold

  3. ‡Division of Rheumatology and Clinical Immunogenetics, University of Texas–Houston Medical School, HoustonM, 77030, Texas, USA

    Joann M. Moulds

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  1. J. Alexandra Rowe
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Correspondence to Louis H. Miller.

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Rowe, J., Moulds, J., Newbold, C. et al. P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature 388, 292–295 (1997). https://doi.org/10.1038/40888

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