Altered Cytokine Response of Human Brain Endothelial Cells after Stimulation with Malaria Patient Plasma

Abstract

Infections with the deadliest malaria parasite, Plasmodium falciparum, are accompanied by a strong immunological response of the human host. To date, more than 30 cytokines have been detected in elevated levels in plasma of malaria patients compared to healthy controls. Endothelial cells (ECs) are a potential source of these cytokines, but so far it is not known if their cytokine secretion depends on the direct contact of the P. falciparum-infected erythrocytes (IEs) with ECs in terms of cytoadhesion. Culturing ECs with plasma from malaria patients (27 returning travellers) resulted in significantly increased secretion of IL-11, CXCL5, CXCL8, CXCL10, vascular endothelial growth factor (VEGF) and angiopoietin-like protein 4 (ANGPTL4) if compared to matching controls (22 healthy individuals). The accompanying transcriptome study of the ECs identified 43 genes that were significantly increased in expression (≥1.7 fold) after co-incubation with malaria patient plasma, including cxcl5 and angptl4. Further bioinformatic analyses revealed that biological processes such as cell migration, cell proliferation and tube development were particularly affected in these ECs. It can thus be postulated that not only the cytoadhesion of IEs, but also molecules in the plasma of malaria patients exerts an influence on ECs, and that not only the immunological response but also other processes, such as angiogenesis, are altered.

Pathogenicity and virulence of malaria: Sticky problems and tricky solutions

“…Larger cohort studies using consistent markers are required to evaluate whether a particular cytokine combination may have prognostic value for severe clinical outcomes [ 265 , 270 ]. Cytokines activate human endothelial cells in vitro [ 271 ] and circulating cytokines have been proposed to contribute to localized brain inflammation in patients with cerebral malaria, ultimately leading to impaired blood–brain barrier integrity and brain swelling that is associated with death [ 33 , 265 ]. Endothelial cells (including human brain endothelial cells) also secrete cytokines when stimulated with IEs in vitro [ 272 ] that may perpetuate localized inflammation in vivo .…”

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

“…These chemokines play a role in the attraction of neutrophil granulocytes. Recently, stimulation of ECs by plasma from malaria patients was shown to significantly increase the expression of CXCL1 and CXCL5 compared to healthy controls (Raacke et al, 2021). Interestingly, the increase in expression observed here for CXCL6 and CCL26 has not yet been described to our knowledge.…”

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

“…For example, ‘BP-positive regulation of cell-cell adhesion’, which includes genes for adhesion proteins such as ICAM-1 and VCAM as well as a range of chemokines (CX3CL1; CCL2) and cytokines (IL6; TNF; IL1B), was down-regulated in IT4var37 co-culture but showed a transient increase with IT4var14, which could influence both Pf-IE and monocyte recruitment within a pro-inflammatory microenvironment. ‘MF-metalloendopeptidase activity’ is also identified in this cluster, containing genes for ADAMTS1/4/5/6/12/18 that regulate vascular homeostasis and are involved in cell adhesion and inflammation, as well as MMP7, which through degradation of soluble VEGFR-1, promotes VEGF binding to endothelium [ 73 ], with elevated levels of VEGF being reported in patients with cerebral malaria [ 74 ] and increased VEGF expression in HBMEC treated with malaria patient sera [ 75 ]. Cluster X1 shows a major difference in the expression of Tenascin C (TNC) ( Fig 9B ) linked to the induction of expression by IT4var37, IT4var14 or RBC co-culture.…”