PfEMP1-DBL1α amino acid motifs in severe disease states of Plasmodium falciparum malaria

Abstract

An infection with Plasmodium falciparum may lead to severe malaria as a result of excessive binding of infected erythrocytes in the microvasculature. Vascular adhesion is mediated by P. falciparum erythrocyte membrane protein-1 (PfEMP1), which is encoded for by highly polymorphic members of the var-gene family. Here, we profile var gene transcription in fresh P. falciparum trophozoites from Ugandan children with malaria through var-specific DBL1␣-PCR amplification and sequencing. A method for subsectioning region alignments into homology areas (MOTIFF) was developed to examine collected sequences. Specific PfEMP1-DBL1␣ amino acid motifs correlated with rosetting and severe malaria, with motif location corresponding to distinct regions of receptor interaction. The method is potentially applicable to other families of variant proteins and may be useful in identifying sequencephenotype relationships. The results suggest that certain PfEMP1 sequences are predisposed to inducing severe malaria.homology areas ͉ antigenic variation ͉ rosetting P lasmodium falciparum malaria infection is one of the primary contributors to childhood mortality in many developing countries. Despite exhaustive research efforts, no vaccine capable of conferring an adequate level of immunity has been developed to date. Vaccine development is encouraged by the fact that children attain conditional immunity to severe malaria after relatively few infections. However, a lack of insight into the molecular interplay between the parasite and the host continues to thwart efforts at vaccine development. One of the key factors in this process is the ability of the parasite to continually express a plethora of antigenic variants of gene families, whose selection appears to correspond with interactions with the host immune system.Severe malaria, a highly lethal form of the disease, is, in part, attributable to the sequestration of P. falciparum-infected erythrocytes (IE) and uninfected erythrocytes in postcapillary venules of the brain, the lungs, or other organs (1). P. falciparum expresses a number of proteins at the erythrocyte surface that are closely involved in the excessive sequestration characteristic of severe malaria. The polypeptide most closely scrutinized to date, PfEMP1, is a large 200-to 400-kDa clonally variant antigen encoded by a repertoire of Ϸ60 var genes (2). The var genes present a two-exon structure encoding a conserved C terminus that contains a predicted transmembrane region and a polymorphic submodular N terminus. This N terminus region possesses a number of cysteine-rich domains that are intimately involved in the sequestration of the parasite in the microvasculature (3-5). The Duffy binding-like domain-␣ (DBL1␣) located in the Nterminal head structure of PfEMP1 mediates rosetting and endothelial binding of IE. These binding processes occur by means of a range of different receptors, including heparan sulfate, complement receptor 1, and/or the blood group A antigen (6-9). Rosetting and endothelial binding are intimately associa...

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

“…The majority of studies addressing the relationship between var genes and clinical disease have found an association between group A var gene transcription and severe malaria or CM (16)(17)(18)(19)51). Previously, the only known binding phenotype for group A PfEMP1 variants was rosetting (20)(21)(22)(23), with two group A domain cassettes (DC11 and DC16) being linked to rosette formation (24).…”

The impact of malaria parasitism: from corpuscles to communities

“…As children grow and expand their antibody repertoire (83-85), they become susceptible to fewer and fewer P. falciparum strains. Genome and expression analyses have shown that the PfEMP-1 family has a vast capacity for sequence diversification (86,87), and some PfEMP-1 variants may cause more severe clinical outcomes than others (88,89). Structural constraints on the extracellularbinding domains of PfEMP-1 may restrain the ability of different variants to escape recognition by cross-reactive antibodies, thus allowing some degree of protection between strains (90,91).…”

Association of high plasma TNF-alpha levels and TNF-alpha/IL-10 ratios with TNF2 allele in severeP. falciparummalaria patients in Sri Lanka

“…3 Both host and parasite determinants were attributed to severe malarial disease. [4][5][6] Several studies have shown the involvement of proinflammatory cytokines in pathogenesis of severe falciparum malaria where high plasma TNF-alpha, IL-1beta, IL-6, IL-10, and IFN-gamma levels were associated with severe disease. [7][8][9][10] Cerebral malaria patients were shown to have high TNF-alpha levels, 7 whereas severely anemic children had low TNF-alpha levels comparable to that of mild malaria.…”