Abstract
Cytoadhesion of Plasmodium falciparum-infected red blood cells is a virulence determinant associated with microvascular obstruction and organ complications. The gastrointestinal tract is a major site of sequestration in fatal cerebral malaria cases and kidney complications are common in severe malaria, but parasite interactions with these microvascular sites are poorly characterized. To study parasite tropism for different microvascular sites, we investigated binding of parasite lines to primary human microvascular endothelial cells from intestine (HIMEC) and peritubular kidney (HKMEC) sites. Of the three major host receptors for P. falciparum, CD36 had low or negligible expression; endothelial protein C receptor (EPCR) had the broadest constitutive expression; and intercellular adhesion molecule 1 (ICAM-1) was weakly expressed on resting cells and was strongly upregulated by TNF-α on primary endothelial cells from the brain, intestine, and peritubular kidney sites. By studying parasite lines expressing var genes linked to severe malaria, we provide evidence that both the DC8 and Group A EPCR-binding subsets of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family encodes binding affinity for brain, intestinal, and peritubular kidney endothelial cells, and that DC8 parasite adhesion was partially dependent on EPCR. Collectively, these findings raise the possibility of a brain-gut-kidney binding axis contributing to multi-organ complications in severe malaria.
Highlights
The distinctive virulence of Plasmodium falciparum is caused in part through the cytoadhesion of P. falciparum-infected erythrocytes (IEs) in the microcirculation of different organs
To investigate parasite tropism for brain, gut, and kidney microvascular sites, we first characterized the expression of CD36, intercellular adhesion molecule 1 (ICAM-1) and endothelial protein C receptor (EPCR) on CD31+ primary human microvascular endothelial cells
ICAM-1 had very low constitutive expression levels on a minority of cells (HBMEC, 10%; human intestinal microvascular endothelial cells (HIMEC), 1-2%; human kidney peritubular microvascular endothelial cells (HKMEC), 10-57%), but its expression was substantially increased by TNF-a treatment reaching nearly 100% surface positive for all three endothelial cell types (Figure 1 and Supplementary Figure 2)
Summary
The distinctive virulence of Plasmodium falciparum is caused in part through the cytoadhesion of P. falciparum-infected erythrocytes (IEs) in the microcirculation of different organs. Mature forms of P. falciparum-IEs have broad sequestration in diverse microvascular beds, including the brain, gastrointestinal tract, subcutaneous adipose tissue of the skin, heart, lung, spleen and to a lesser extent, the kidney (Spitz, 1946; MacPherson et al, 1985; Milner et al, 2014; Milner et al, 2015), but parasite tropism for most organ sites remains poorly characterized. Whereas the kidney is not a major site of parasite sequestration (Spitz, 1946; Milner et al, 2014), kidney injury is common in severe malaria. The gastrointestinal tract was the most intense site of parasite sequestration in fatal pediatric CM cases (Seydel et al, 2012; Milner et al, 2014) and blocked capillaries in the rectal mucosa correlate to disease severity and metabolic acidosis in adult SM cases (Dondorp et al, 2008a). While kidney and gut pathogenesis are not well understood, autopsy studies have led to the hypothesis that organ injury may result from common pathological processes, precipitated by cytoadherence of P. falciparum-IEs
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call