Transcriptional responses of brain endothelium to Plasmodium falciparum patient-derived isolates in vitro

Askonas, Caroline, Storm, Janet ORCID: https://orcid.org/0000-0001-7812-4220, Camarda, Grazia, Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164 and Pain, Arnab (2024) 'Transcriptional responses of brain endothelium to Plasmodium falciparum patient-derived isolates in vitro'. Microbiology Spectrum. (In Press)

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Abstract

A hallmark of cerebral malaria (CM) is sequestration of Plasmodium falciparum-infected erythrocytes (IE) within the brain microvasculature. Binding of IE to endothelium reduces microvascular flow and, combined with an inflammatory response, perturbs endothelial barrier function, resulting in breakdown of the blood-brain barrier (BBB). Cytoadherence leads to activation of the endothelium and alters a range of cell processes affecting signaling pathways, receptor expression, coagulation, and disruption of BBB integrity. Here, we investigated whether CM-derived parasites elicit differential effects on human brain microvascular endothelial cells (HBMECs), as compared to uncomplicated malaria (UM)-derived parasites. Patient-derived IE from UM and CM clinical cases, as well as non-binding skeleton-binding protein 1 knockout parasites, were overlaid onto tumour necrosis factor (TNF)-activated HBMECs. Gene expression analysis of endothelial responses was performed using probe-based assays of a panel of genes involved in inflammation, apoptosis, endothelial barrier function, and prostacyclin synthesis pathway. We observed a significant effect on endothelial transcriptional responses in the presence of IE, yet there was no significant correlation between HBMEC responses and type of clinical syndrome (UM or CM). Furthermore, there was no correlation between HBMEC gene expression and both binding itself and level of IE binding to HBMECs, as we detected the same change in endothelial responses when employing both binding and non-binding parasites. Our results suggest that interaction of IE with endothelial cells in this co-culture model induces some endothelial responses that are independent of clinical origin and independent of the expression of the major variant antigen Plasmodium falciparum erythrocyte membrane protein 1 on the IE surface.

Item Type:	Article
Subjects:	QU Biochemistry > Cells and Genetics > QU 300 General works QX Parasitology > Protozoa > QX 135 Plasmodia WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria WL Nervous System > WL 200 Meninges. Blood-brain barrier
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1128/spectrum.00727-24
Depositing User:	Clare O'Neill
Date Deposited:	20 Jun 2024 12:33
Last Modified:	20 Jun 2024 12:33
URI:	https://archive.lstmed.ac.uk/id/eprint/24779

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