The Journal of Experimental Medicine
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Published 3 May 2004. doi:10.1084/jem.20040274
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 9, 1179-1190
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Plasmodium falciparum Associated with Severe Childhood Malaria Preferentially Expresses PfEMP1 Encoded by Group A var Genes

Anja T.R. Jensen1, Pamela Magistrado1, Sarah Sharp3, Louise Joergensen1, Thomas Lavstsen1, Antonella Chiucchiuini3, Ali Salanti1, Lasse S. Vestergaard1, John P. Lusingu4, Rob Hermsen5, Robert Sauerwein5, Jesper Christensen2, Morten A. Nielsen1, Lars Hviid1, Colin Sutherland3, Trine Staalsoe1, and Thor G. Theander1

1 Department of Medical Microbiology and Immunology, Centre for Medical Parasitology, Department of Infectious Diseases, and 2 Department of Medical Biochemistry and Genetics, University of Copenhagen, Copenhagen University Hospital, 2200 Copenhagen, Denmark
3 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
4 National Institute for Medical Research, Amani, Tanga, Tanzania
5 Department of Medical Microbiology, University Medical Center, 6525 GA Nijmegen, Netherlands

Address correspondence to Anja T.R. Jensen, Department of Medical Microbiology and Immunology, The Panum Institute, Building 24-2, Blegdamsvej 3, 2200 Copenhagen, Denmark. Phone: 45-35-32-76-82; Fax: 45-35-32-78-51; email: atrj{at}biobase.dk

Parasite-encoded variant surface antigens (VSAs) like the var gene–encoded Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family are responsible for antigenic variation and infected red blood cell (RBC) cytoadhesion in P. falciparum malaria. Parasites causing severe malaria in nonimmune patients tend to express a restricted subset of VSA (VSASM) that differs from VSA associated with uncomplicated malaria and asymptomatic infection (VSAUM). We compared var gene transcription in unselected P. falciparum clone 3D7 expressing VSAUM to in vitro–selected sublines expressing VSASM to identify PfEMP1 responsible for the VSASM phenotype. Expression of VSASM was accompanied by up-regulation of Group A var genes. The most prominently up-regulated Group A gene (PFD1235w/MAL7P1.1) was translated into a protein expressed on the infected RBC surface. The proteins encoded by Group A var genes, such as PFD1235w/MAL7P1.1, appear to be involved in the pathogenesis of severe disease and are thus attractive candidates for a vaccine against life-threatening P. falciparum malaria.

Key Words: var gene • Plasmodium falciparum • malaria • PfEMP1 • antibody selection

The online version of this article contains supplemental material.

Abbreviations used in this paper: CIDR, cysteine-rich interdomain region; Ct, threshold cycle; DBL, Duffy binding–like domain; DIG, digoxigenin; GST, glutathione S-transferase; PfEMP1, Plasmodium falciparum erythrocyte membrane protein 1; TrHBMEC, transformed human bone marrow endothelial cell; VSA, variant surface antigen.


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