Differential var gene expression in the organs of patients dying of falciparum malaria

Abstract

Sequestration of parasitized erythrocytes in the microcirculation of tissues is thought to be important in the pathogenesis of severe falciparum malaria. A major variant surface antigen, var/Plasmodium falciparum erythrocyte membrane protein 1, expressed on the surface of the infected erythrocyte, mediates cytoadherence to vascular endothelium. To address the question of tissue-specific accumulation of variant types, we used the unique resource generated by the clinicopathological study of fatal paediatric malaria in Blantyre, Malawi, to analyse var gene transcription in patients dying with falciparum malaria. Despite up to 102 different var genes being expressed by P. falciparum populations in a single host, only one to two of these genes were expressed at high levels in the brains and hearts of these patients. These major var types differed between organs. However, identical var types were expressed in the brains of multiple patients from a single malaria season. These results provide the first evidence of organ-specific accumulation of P. falciparum variant types and suggest that parasitized erythrocytes can exhibit preferential binding in the body, supporting the hypothesis of cytoadherence-linked pathogenesis.

Fig. 1

Frequency of var types in the organs of paediatric malaria patients. Each graph represents one patient (labelled above with final diagnosis in parentheses) with organs denoted by shading. var types are listed on the y-axis by accession number and the frequency of cloning is adjusted for the number of complete sequences analysed from each organ. Single copy var types are represented together and labelled 1× var.

Fig. 2

Frequency of sequence groups in var transcripts from the organs of paediatric malaria patients. Shading represents the sequence groups as identified by Bull et al. (2005), which are characterized by the number of cysteine residues and other semi-conserved motifs known as positions of limited variance. The data are expressed as the percentage of var types within each organ containing the corresponding sequence motifs. Brn, brain; Lng, lung; Hrt, heart; Spl, spleen.