07

Nov 2024

PhD Dissertation Defense

Transcriptional impact of cytoadherence and stimulation on microvascular endothelium

Presenter
Caroline Askonas
Date
07 Nov, 2024
Time
03:00 PM – 04:00 PM

Abstract:
Cerebral malaria (CM) is the most prevalent and deadly complication of severe Plasmodium falciparum infection. A hallmark of CM is the sequestration of Plasmodium falciparum-infected erythrocytes (IE) within the brain microvasculature. The binding of IE to endothelium reduces microvascular flow and combined with an inflammatory response, perturbs endothelial barrier function, resulting in the breakdown of the blood-brain barrier. Cytoadherence leads to activation of the endothelium and alters a range of cell processes affecting signalling pathways, receptor expression, coagulation, and disruption of BBB integrity. This binding to the endothelium is mediated by Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on IE and composed of different adhesion domains that may characterise host-receptor binding. In conjunction with IE sequestration, inflammation leads to the production of the pro-inflammatory cytokine tumour necrosis factor (TNF), which in turn activates the endothelium. To that end, we investigated whether CM-derived parasites elicit differential effects on human brain microvascular endothelial cells (HBMECs), as compared to uncomplicated malaria (UM) derived parasites using probe-based gene expression assays. We observed a significant effect on the endothelial transcriptional response in the presence of IE, yet there is no significant correlation between HBMEC responses and the type of clinical syndrome (UM or CM). Further, there was no correlation between HBMEC gene expression and both binding itself and the level of IE binding to HBMEC. Following on from this, the patient-derived isolates were sequenced to explore the diversity of the predicted PfEMP1 adhesion domains. Additionally, bulk RNA-sequencing was utilised to examine the transcriptional profiles of two types of microvascular endothelial cells stimulated with varied concentrations of TNF over a short time course in vitro. It was observed that temporal modulation had a greater impact on differential gene expression when compared to the differences between the two dosing treatments. Despite being distinct cell types, these microvascular endothelial cells shared a proportion of shared upregulated differentially expressed genes. Overall, this study provides further insight into the dynamic effects of patient-derived parasite isolates and TNF on the transcriptional responses of microvascular endothelium.

Bio:
Caroline Askonas is a PhD candidate in Bioscience in the Pathogen Genomics Laboratory under the supervision of Professor Arnab Pain. Her work focuses on host-pathogen interactions in malaria. Caroline obtained her BSc in Chemistry from Hope College in the USA followed by an MSc in Immunology of Infectious Diseases from the London School of Hygiene and Tropical Medicine in the UK.

Event Quick Information

Date
07 Nov, 2024
Time
03:00 PM - 04:00 PM
Venue
Zoom only