NEW YORK (Reuters Health) - The formation of red blood cell “rosettes,” mediated by complement receptor 1 (CR1), is associated with malarial microvascular obstruction. However, certain CR1 polymorphisms, common in areas where malaria is endemic, appear to reduce rosetting, a multicenter team reports.
And if new evidence of positive selection pressure for CR1 polymorphisms conferring protection against severe malaria is confirmed, strategies aimed at inhibiting CR1-mediated rosette formation could represent new prophylactic or therapeutic options for severe malaria.
Rosettes are formed by adhesion of parasitized RBCs to uninfected RBCs, senior investigator Dr. J. Alexandra Rowe, at the University of Edinburgh in the UK, and her associates explain in the Proceedings of the National Academy of Sciences, published online December 22. This adhesion is mediated by the parasite ligand PfEMP1 on the surface of infected cells binding to CR1 and other receptors on uninfected RBCs.
There is evidence that CR1 deficiency may be relatively common in some areas where severe malaria is endemic. The scientists therefore theorized that CR1 deficiency protects against severe disease by reducing the ability of RBCs to clump together.
To further investigate, Dr. Rowe’s team analyzed blood samples from healthy volunteers from Madang and New Ireland in Papua New Guinea, where severe malaria is endemic, and from Edinburgh. The average number of CR1 molecules per RBC was significantly lower in Papua New Guinea than in Edinburgh (p < 0.001).
Carriers of a single nucleotide polymorphism in exon 22 of the CR1 gene exhibited significantly lower CR1 levels (p < 0.001). This CR1 low-expression (L) allele was significantly more prevalent in Papua New Guinea than in Edinburgh.
A case-control study carried out in Madang, which involved 180 severe malaria cases and 179 community controls, showed that individuals heterozygous for the L allele were significantly protected against severe anemia and cerebral malaria.
“Positive selection of rosette-reducing polymorphisms in a human population with high malaria mortality is strong evidence that CR1-mediated rosetting plays a causal role in the pathogenesis of severe malaria,” Dr. Rowe and her colleagues write.
They suggest that interventions to inhibit rosette formation could be used to treat severe malaria, and that a vaccine against the parasite rosette-mediating ligand PfEMP1 could prevent some cases of severe disease.
Source: Proc Natl Acad Sci USA 2003. [ Google search on this article ]
MeSH Headings:Biological Phenomena: Biological Phenomena, Cell Phenomena, and Immunity: Immunologic Techniques: Microbiologic Phenomena: Investigative Techniques: Rosette Formation: Virulence: Analytical, Diagnostic and Therapeutic Techniques and Equipment: Biological SciencesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
