Modulation of malaria virulence by determinants of Plasmodium falciparum erythrocyte membrane protein-1 display.
OBJECTIVE
Plasmodium falciparum malaria parasites carry approximately 60 var genes that encode variable adhesins termed P. falciparum erythrocyte membrane protein-1. Clonal expression of a single P. falciparum erythrocyte membrane protein-1 variant on the surface of the parasitized host erythrocyte promotes binding of the cell to blood elements (including noninfected erythrocytes, leukocytes) and walls of microvessels. These binding events enable parasitized erythrocytes to sequester and avoid clearance by the spleen, and they also contribute to disease by causing microvascular inflammation and obstruction.


RESULTS
Steps by which P. falciparum erythrocyte membrane protein-1 is exported to the parasitized erythrocyte surface have recently been elucidated. The ability of parasites to cytoadhere and cause disease depends on the variant of P. falciparum erythrocyte membrane protein-1 as well as its amount and distribution at the erythrocyte surface. An example of a host polymorphism that affects P. falciparum erythrocyte membrane protein-1 display is hemoglobin C, which may protect against malaria by impairing the parasite's ability to adhere to microvessels and induce inflammation. Interference with P. falciparum erythrocyte membrane protein-1-mediated phenomena appears to diminish cytoadherence in vivo and to protect against disease in animal models.


CONCLUSIONS
Plasmodium falciparum erythrocyte membrane protein-1-mediated sequestration of parasitized erythrocytes plays a central role in malaria pathogenesis. Clinical interventions aimed at reducing cytoadherence and microvascular inflammation may improve disease outcome.
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20852-8132, USA.
Rick M
RM
Fairhurst
Thomas E
TE
Wellems
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology*; D006444:Hemoglobin C / Q000378:metabolism; D006801:Humans; D008288:Malaria / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000235:genetics / Q000472:pathogenicity*; D021381:Protein Transport; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence / Q000235:genetics
D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D006444:Hemoglobin C