DC8 and DC13 var Genes Associated with Severe Malaria Bind Avidly to Diverse Endothelial Cells

Abstract

During blood stage infection, Plasmodium falciparum infected erythrocytes (IE) bind to host blood vessels. This virulence determinant enables parasites to evade spleen-dependent killing mechanisms, but paradoxically in some cases may reduce parasite fitness by killing the host. Adhesion of infected erythrocytes is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1), a family of polymorphic adhesion proteins encoded by var genes. Whereas cerebral binding and severe malaria are associated with parasites expressing DC8 and DC13 var genes, relatively little is known about the non-brain endothelial selection on severe malaria adhesive types. In this study, we selected P. falciparum-IEs on diverse endothelial cell types and demonstrate that DC8 and DC13 var genes were consistently among the major var transcripts selected on non-brain endothelial cells (lung, heart, bone marrow). To investigate the molecular basis for this avid endothelial binding activity, recombinant proteins were expressed from the predominant upregulated DC8 transcript, IT4var19. In-depth binding comparisons revealed that multiple extracellular domains from this protein bound brain and non-brain endothelial cells, and individual domains largely did not discriminate between different endothelial cell types. Additionally, we found that recombinant DC8 and DC13 CIDR1 domains exhibited a widespread endothelial binding activity and could compete for DC8-IE binding to brain endothelial cells, suggesting they may bind the same host receptor. Our findings provide new insights into the interaction of severe malaria adhesive types and host blood vessels and support the hypothesis that parasites causing severe malaria express PfEMP1 variants with a superior ability to adhere to diverse endothelial cell types, and may therefore endow these parasites with a growth and transmission advantage.

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

“…However, DC8 variants encode multiple endothelial binding domains (53), and it is possible that other undefined coadhesion traits may also increase the risk for SM. Furthermore, our study, to our knowledge for the first time, implicates specific C-terminal PfEMP1 domains in SM.…”

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…2) compared with the relatively sparse IRBC adhesion to endothelial monolayers in vitro. It has also been demonstrated that IRBC adhesion at a given time may be mediated by multiple, some as yet unidentified, endothelial receptors, 75 so that the downstream effect is likely the summation of the activation of multiple pathways.…”

EPCR: holy grail of malaria cytoadhesion?

“…This may provide an option when compatible donors are unavailable but will still need to be coupled in ARTEMIS SCIDs with an appropriate conditioning regime. Clearly challenges remain, but this study and others 10 highlight the problems faced by specific SCID forms and make the case for us to deliver more gene-specific transplant strategies.…”

“…This notion is consistent with the finding that each of the DBL domains of the EPCR-binding IT4var19 parasite line could adhere to multiple types of endothelial cells through as yet undetermined receptors. 10 In this context, EPCR may be the new kid on the block that could either initiate adhesion or be recruited to a molecular complex on endothelial cells in the brain and/or other vital organs with resultant downstream functional effects. …”