Different PfEMP1-expressing Plasmodium falciparum variants induce divergent endothelial transcriptional responses during co-culture

Abstract

The human malaria parasite Plasmodium falciparum is responsible for the majority of mortality and morbidity caused by malaria infection and differs from other human malaria species in the degree of accumulation of parasite-infected red blood cells in the microvasculature, known as cytoadherence or sequestration. In P. falciparum, cytoadherence is mediated by a protein called PfEMP1 which, due to its exposure to the host immune system, undergoes antigenic variation resulting in the expression of different PfEMP1 variants on the infected erythrocyte membrane. These PfEMP1s contain various combinations of adhesive domains, which allow for the differential engagement of a repertoire of endothelial receptors on the host microvasculature, with specific receptor usage associated with severe disease. We used a co-culture model of cytoadherence incubating human brain microvascular endothelial cells with erythrocytes infected with two parasite lines expressing different PfEMP1s that demonstrate different binding profiles to vascular endothelium. We determined the transcriptional profile of human brain microvascular endothelial cells (HBMEC) following different incubation periods with infected erythrocytes, identifying different transcriptional profiles of pathways previously found to be involved in the pathology of severe malaria, such as inflammation, apoptosis and barrier integrity, induced by the two PfEMP1 variants.

Cytoadhesion ofPlasmodium falciparum-infected red blood cells changes the expression of cytokine-, histone- and antiviral protein-encoding genes in brain endothelial cells

“…Various studies have shown that the cytoadhesion of iRBCs strongly influences the gene expression of the ECs. Among other things, it has been shown that binding to HBEMCs mainly influences the signaling pathways involved in the inflammatory response, apoptosis, cell-cell signaling, signal transduction, and the NF-kB activation cascade (Tripathi et al, 2009; Othman et al, 2023). However, not only does cytoadhesion seem to influence the expression, but it also seems to depend on which Pf EMP1 is presented on the surface of the iRBCs (Othman et al, 2023).…”

“…However, significant differences were also found between iRBC IT4var14 and iRBC IT4var37 . Among others, atonal bHLH transcription factor 8 ( ATOH8 ), CXCL8 , CXCL10 , VCAM-1 , radical s-adenosyl methionine domain containing 2 ( RSAD2 ), and IL6 were found to be up-regulated in the presence of iRBC IT4var14 after 6 h of co-cultivation, whereas the expression of these genes was down-regulated in iRBC IT4var37 (Othman et al, 2023).…”

Transcriptional responses of brain endothelium toPlasmodium falciparumpatient-derived isolatesin vitro

“…Both PTGIS and PTGS2 are enzymes involved in the biosynthesis of prostacyclin, a bioactive lipid that is produced by vascular endothelial cells and that plays a role in regulation of endothelial inflammation and apoptosis 41 . Furthermore, a study employing a co-culture model of cytoadherence demonstrated differential gene expression of CYP1A1, PTGIS, and PTGS2 between HBMEC incubated with two parasite lines that expressed different PfEMP1s 25 . Prostacyclin (PGI2) is produced through the action of prostacyclin synthase (PTGIS; also known as prostaglandin I2 synthase, PGIS).…”

“…Although IE derived from malaria patients have exhibited different binding phenotypes, most studies employ well characterized PfEMP1 laboratory strains to investigate cytoadherence and interaction of different PfEMP1 variants to brain endothelial cells 19,[21][22][23][24] . Separate investigations have highlighted the divergent effect of both TNF stimulation and IE cytoadhesion on endothelial transcriptional responses and the pathways they induce 23,25 . IE isolated from peripheral blood of UM and CM patients have been used to study cytoadherence to human brain microvascular endothelial cells (HBMEC).…”

“…An in vitro co-culture model of cytoadherence was employed wherein patient-derived IE isolates were overlayed onto TNF-activated HBMEC and the relative gene expression of HBMEC after incubation with either RBC or IE for a panel of genes was assessed. A study utilizing two P. falciparum lab strains with different binding capacities to HBMEC found that different PfEMP1-expressing variants induced divergent endothelial transcriptional responses during cytoadherence 25 . Differentially expressed genes (DEGs) were identified in HBMEC in pathways involved in the pathology of severe malaria, such as inflammation, apoptosis, and barrier integrity.…”