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Multiple adhesive phenotypes linked to rosetting binding of erythrocytes in Plasmodium falciparum malaria
V Fernandez1, C J Treutiger, G B Nash
1Microbiology and Tumor Biology Center, Karolinska Institutet, and Swedish Institute for Infectious Disease Control, S-171 77 Stockholm, Sweden.
Abstract:
The cerebral form of severe malaria is associated with excessive intravascular sequestration of Plasmodium falciparum-infected erythrocytes (PRBC). Retention and accumulation of PRBC may lead to occlusion of brain microvessels and direct the triggering of acute pathologic changes. Here we report that by selection, cloning, and subcloning, we have identified rare P. falciparum parasites expressing a pan-adhesive phenotype linked to erythrocyte rosetting, a previously identified correlate of cerebral malaria. Rosetting PRBC not only bound uninfected erythrocytes but also formed autoagglutinates, adhered to endothelial cells, and bound to CD36, immunoglobulins, and the blood group A antigen. The linkage of rosetting, autoagglutination, and cytoadherence involved the coexpression on a single PRBC of ligands with multiple specificities and the binding to two or more receptors on erythrocytes and to at least two other cell adhesion molecules, including a new endothelial cell receptor for P. falciparum-infected erythrocytes. Limited proteolysis that differentially cleaved the rosetting ligand PfEMP1 from the PRBC surface abrogated all the binding phenotypes of these parasites, implicating the variant antigen PfEMP1 as a carrier of multiple ligand specificities. The results encourage the further study of pan-adhesion as a potentially important parasite phenotype in the pathogenesis of severe P. falciparum malaria.
Insights
Researchers identified rare Plasmodium falciparum parasites with a pan-adhesive phenotype linked to severe malaria. These parasites exhibit erythrocyte rosetting and adhere to various cells and molecules, mediated by the PfEMP1 variant antigen.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- Severe malaria, particularly cerebral malaria, is linked to Plasmodium falciparum-infected erythrocyte sequestration in blood vessels.
- Erythrocyte rosetting, where infected cells bind uninfected ones, is a known factor in cerebral malaria pathogenesis.
Purpose of the Study:
- To identify and characterize Plasmodium falciparum parasites with a pan-adhesive phenotype associated with severe malaria.
- To elucidate the molecular mechanisms underlying the multi-ligand specificities and binding capabilities of these parasites.
Main Methods:
- Selection, cloning, and subcloning of Plasmodium falciparum parasites.
- Analysis of parasite binding to uninfected erythrocytes, endothelial cells, CD36, immunoglobulins, and blood group A antigen.
- Investigation of the role of PfEMP1 using limited proteolysis.
Main Results:
- Rare Plasmodium falciparum parasites exhibiting a pan-adhesive phenotype, including erythrocyte rosetting, autoagglutination, and cytoadherence, were identified.
- These parasites coexpressed multiple ligands on a single infected erythrocyte, binding to various receptors.
- Cleavage of the PfEMP1 ligand abrogated all observed binding phenotypes, implicating PfEMP1 in mediating these adhesive properties.
Conclusions:
- The variant antigen PfEMP1 carries multiple ligand specificities, contributing to the pan-adhesive phenotype of these Plasmodium falciparum parasites.
- Pan-adhesion is a significant parasite phenotype potentially involved in the pathogenesis of severe Plasmodium falciparum malaria.