Abstract
BackgroundSevere malaria has been attributed to the expression of a restricted subset of the var multi-gene family, which encodes for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 mediates cytoadherence and sequestration of infected erythrocytes into the post-capillary venules of vital organs such as the brain, lung or placenta. var genes are highly diverse and can be classified in three major groups (ups A, B and C) and two intermediate groups (B/A and B/C) based on the genomic location, gene orientation and upstream sequences. The genetic diversity of expressed var genes in relation to severity of disease in Tanzanian children was analysed.MethodsChildren with defined severe (SM) and asymptomatic malaria (AM) were recruited. Full-length var mRNA was isolated and reversed transcribed into var cDNA. Subsequently, the DBL and N-terminal domains, and up-stream sequences were PCR amplified, cloned and sequenced. Sequences derived from SM and AM isolates were compared and analysed.ResultsThe analysis confirmed that the var family is highly diverse in natural Plasmodium falciparum populations. Sequence diversity of amplified var DBL-1α and upstream regions showed minimal overlap among isolates, implying that the var gene repertoire is vast and most probably indefinite in endemic areas. var DBL-1α sequences from AM isolates were more diverse with more singletons found (p<0.05) than those from SM infections. Furthermore, few var DBL-1α sequences from SM patients were rare and restricted suggesting that certain PfEMP1 variants might induce severe disease.ConclusionsThe genetic sequence diversity of var genes of P. falciparum isolates from Tanzanian children is large and its relationship to disease severity has been studied. Observed differences suggest that different var genes might have fundamentally different roles in the host-parasite interaction. Further research is required to examine clear disease-associations of var gene subsets in different geographical settings. The importance of very strict clinical definitions and appropriate large control groups needs to be emphasized for future studies on disease associations of PfEMP1.
Highlights
Severe malaria has been attributed to the expression of a restricted subset of the var multi-gene family, which encodes for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1)
The burden of disease is highest in children below five years of age where much of the mortality is attributable to severe malaria
Using quantitative real time reverse transcription PCR, we have previously shown that group A and B var transcripts were up-regulated in children from Tanzania with severe malaria as opposed to asymptomatic infections [25]
Summary
Severe malaria has been attributed to the expression of a restricted subset of the var multi-gene family, which encodes for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). The most life threatening form of the disease is believed to be mediated by cytoadhesion of P. falciparum-infected erythrocytes to a variety of receptors on the endothelial lining of the host’s blood capillaries. This post-capillary sequestration severely affects vital organs such as the brain, kidneys, lungs or placenta [3]. Var genes present with a two-exon structure encoding a semiconserved C-terminus that contains a predicted transmembrane region, and a highly polymorphic extracellular N-terminus This part has a modular structure containing various numbers of Duffy-binding-like (DBL) domains and cysteine-rich domains that have been shown to be involved in sequestration of the infected erthrocytes [7,8,9]. Rosetting and sequestration conferred by expression of different PfEMP1 molecules has been implicated in severe disease [14]
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