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

ABSTRACT: Introduction Malaria remains a significant global health problem, particularly due to the human malaria parasite Plasmodium falciparum, which is responsible for most fatal infections. Infected red blood cells (iRBCs) evade spleen clearance by adhering to endothelial cells (ECs), triggering capillary blockage, inflammatory cytokine release, endothelial dysfunction, and altered vascular permeability, prompting an endothelial transcriptional response. Methods The iRBCIT4var04/HBEC-5i model, where iRBCs present IT4var04 (VAR2CSA) on their surface was employed to analyse the effects of iRBC binding on ECs. We used this model to investigate how cytoadhesion of iRBCs to ECs influences their expression profile depending on the temperature (37°C vs 40°C). Results Binding of non-infected RBCs (niRBCs) and fever alone significantly changes expression of hundreds of genes in ECs. Comparing the expression profile of HBEC-5i cultured either in the presence of iRBCs or in the presence of niRBCs, genes encoding proteins assigned to the GO terms immune response, nucleosome assembly, NF-kappa B signaling, angiogenesis, and antiviral immune response/interferon-alpha/beta signaling pathway were significantly up-regulated. If the cultivation temperature is increased from 37°C to 40°C, which simulates fever, a further significant increase in expression can be observed for most regulated genes, especially for genes coding for cytokines and proteins involved in angiogenesis. Conclusion The presence of iRBCs leads to the stimulation of ECs, activating several immunological signaling pathways and affecting antiviral (-parasitic) mechanisms and angiogenesis. Furthermore, to our knowledge, the induction of the interferon-alpha/beta signaling pathway in ECs in response to iRBCs has been described for the first time.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266399 | GEO | 2024/05/03

REPOSITORIES: GEO

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Project description:Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterised by the accumulation of infected erythrocytes in the microvasculature of the brain, due to parasite adhesins on the surface of infected erythrocytes binding to human receptors on microvascular endothelial cells. The parasite and host molecules involved in this interaction are unknown. We used the Human Brain Endothelial Cell line HBEC-5i to identify the malaria parasite ligands responsible for binding to human brain endothelial cells. Three P. falciparum strains (HB3, 3D7 and IT/FCR3) were selected for binding to HBEC5i and the whole transcriptome of selected and unselected parasites was analysed using a variant surface antigen-supplemented microarray chip. After selection, the only highly upregulated genes were a subset of group A-like var genes (HB3var3, 3D7_PFD0020c, ITvar7 and ITvar19), that showed 11 to >100-fold higher transcription levels in selected parasites. These genes are highly diverse in sequence, but do however show strong similarities in PfEMP1 architecture. Antibodies raised to the HB3var3 variant recognized the surface of infected erythrocytes and abolished the binding of infected erythrocytes to brain endothelial cells. The subset of Group A PfEMP1 variants identified here provides a new target for interventions to treat or prevent cerebral malaria. Unselected Plasmodium falciparum parasites (Uns) only poorly cytoadhere to human brain endothelial cells (HBEC-5i). Plasmodium falciparum HB3, 3D7 and IT/FCR3 strains were selected for binding to HBEC-5i (HB3-HBEC1, HB3-HBEC2, HB3-HBEC-TNF, 3D7-HBEC and IT-HBEC). HBEC-selected and unselected cultures were tightly synchronised before a timecourse experiment was performed. 6 samples, named time points 1 to 6, were taken every 8 hours. 12μg of RNA from the unselected parasites (HB3-Uns, 3D7-Uns or IT-Uns) at each of the 6 time points was combined together to form the reference pool. The pool and 12μg of each individual time point sample from both selected and unselectedparasites were then used for cDNA synthesis. For HB3-HBEC1 (pilot experiment), each HB3-HBEC1 time point (pilot experiment) was hybridised directly with HB3-Uns1 time points. For microarray hybridizations, each cDNA sample was coupled to Cy5 (red dye) while Cy3 (green dye) was added to the pool. Cy5-labelled time point samples were mixed with the same amount of Cy3-labelled pool sample. The solution was loaded on a microarray slide and hybridized for 14–16 h.

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

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