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

Abstract

Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterized by the accumulation of infected erythrocytes (IEs) in the microvasculature of the brain caused by parasite adhesins on the surface of IEs binding to human receptors on microvascular endothelial cells. The parasite and host molecules involved in this interaction are unknown. We selected three P. falciparum strains (HB3, 3D7, and IT/FCR3) for binding to a human brain endothelial cell line (HBEC-5i). The whole transcriptome of isogenic pairs of selected and unselected parasites was analyzed using a variant surface antigen-supplemented microarray chip. After selection, the most highly and consistently up-regulated genes were a subset of group A-like var genes (HB3var3, 3D7_PFD0020c, ITvar7, and ITvar19) that showed 11-to >100-fold increased transcription levels. These var genes encode P. falciparum erythrocyte membrane protein (PfEMP)1 variants with distinct N-terminal domain types (domain cassette 8 or domain cassette 13). Antibodies to HB3var3 and PFD0020c recognized the surface of live IEs and blocked binding to HBEC-5i, thereby confirming the adhesive function of these variants. The clinical in vivo relevance of the HBEC-selected parasites was supported by significantly higher surface recognition of HBEC-selected parasites compared with unselected parasites by antibodies from young African children suffering cerebral malaria (Mann-Whitney test, P = 0.029) but not by antibodies from controls with uncomplicated malaria (Mann-Whitney test, P = 0.58). This work describes a binding phenotype for virulence-associated group A P. falciparum erythrocyte membrane protein 1 variants and identifies targets for interventions to treat or prevent cerebral malaria.adherence | pathogenesis | sequestration

Evolutionary structure of Plasmodium falciparum major variant surface antigen genes in South America: Implications for epidemic transmission and surveillance

“…This remarkable biological feature enables P. falciparum to evade the human immune response and establish chronic infections linked to specific cellular interactions. Indeed, Pf EMP1 also binds to host endothelial tissues with different variants exhibiting specific adherence characteristics for tissues, which in turn are associated with distinct disease manifestations (Avril et al., 2012; Claessens et al., 2012; Kraemer & Smith, 2003). Pf EMP1 is thereby considered a virulence factor.…”

Towards an anti-disease malaria vaccine

“…First, the PfEMP1s were arranged into groups A, B and C, depending on their chromosomal location and the domain types encoded [31]. Expression of a subset of PfEMP1s, which contain a specific set of domains, known as CIDRα1 domains, was associated with severe malaria or brain endothelial cell binding [32][33][34][35]. Later, CIDRα1 domains were found to bind to human EPCR [16], thereby preventing EPCR from interacting with its natural ligand, activated protein C [16,36] (Figure 1).…”

Pediatric Cerebral Malaria: A Scourge of Africa

“…Genes encoding this protein, termed var, are highly variant but can be grouped into five families based on promoter region. Emerging evidence future science group suggests that the type of infecting var gene family is associated with disease severity [16][17][18]. Host endothelial proteins binding to PfEMP1 and mediating sequestration are less well defined.…”