Abstract
This study examined the ability of P.falciparum-infected erythrocytes (IE) to induce a pro-adhesive environment in the host endothelium during malaria infection, prior to the systemic cytokine activation seen in the later phase of disease. Previous work had shown increases in receptor levels but had not measured to actual impact on IE binding. Using a co-culture system with a range of endothelial cells (EC) and IE with different cytoadherent properties, we have characterised the specific expression of adhesion receptors and subsequent IE binding by FACS and adhesion assays. We have also examined the specific signalling pathways induced during co-culture that are potentially involved in the induction of receptor expression. The results confirmed that ICAM-1 is up-regulated, albeit at much lower levels than seen with TNF activation, in response to co-culture with infected erythrocytes in all three tissue endothelial cell types tested but that up-regulation of VCAM-1 is tissue-dependent. This small increase in the levels of EC receptors correlated with large changes in IE adhesion ability. Co-culture with either RBC or IE increased the potential of subsequent adhesion indicating priming/modulation effects on EC which make them more susceptible to adhesion and thereby the recruitment of IE. Trypsin surface digestion of IE and the use of a Pfsbp1-knockout (ko) parasite line abrogated the up-regulation of ICAM-1 and reduced IE binding to EC suggesting that PfEMP-1 and other molecules exported to the IE surface via the PfSBP1 pathway are major mediators of this phenotype. This was also supported by the higher induction of EC adhesion receptors by adherent IE compared to isogenic, non-adherent lines.
Highlights
Plasmodium falciparum infection is a major cause of severe disease associated with a range of clinical syndromes including cerebral malaria (CM)
We and others have shown that co-culturing endothelial cells (EC) with infected erythrocytes (IE) increases ICAM-1 protein at the cell surface, and in our work this response was contactdependent as this increase was not seen when IE and EC were cocultured using a transwell system [28]
We have examined the pro-adhesiveness caused by the increase in surface expression of endothelial receptors contributed by the interaction of EC and IE during the co-culture processes
Summary
Plasmodium falciparum infection is a major cause of severe disease associated with a range of clinical syndromes including cerebral malaria (CM). The primary mechanism of cytoadherence of the asexual-stage P. falciparum IE is complex involving a range of host receptors (e.g. intercellular adhesion molecule-1 (ICAM-1), CD36, CD31 and Pselectin) interacting with a family of parasite-encoded proteins (mainly the variable and diverse var gene products, encoding PfEMP-1 (Plasmodium falciparum erythrocyte membrane protein-1)), that are displayed on the surface of IE [8]. This is further complicated by the ability of these receptors to cooperate in achieving efficient IE binding to EC [9,10,11]. ICAM-1 is markedly up-regulated in severe malaria and has been implicated as being involved in progression to cerebral disease [15,16,17]
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