Degradation of endothelial glycocalyx in Tanzanian children with falciparum malaria

Abstract

A layer of glycocalyx covers the vascular endothelium serving important protective and homeostatic functions. The objective of this study was to determine if breakdown of the endothelial glycocalyx (eGC) occurs during malaria infection in children. Measures of eGC integrity, endothelial activation, and microvascular reactivity were prospectively evaluated in 146 children: 44 with moderately severe malaria (MSM), 42 with severe malaria (SM), and 60 healthy controls (HC). Biochemical measures of eGC integrity included plasma syndecan‐1 and total urinary glycosaminoglycans (GAG). Side‐stream dark field imaging was used to quantitatively assess integrity of eGC. Plasma angiopoietin‐2 (Ang‐2) was measured as a marker of endothelial activation and also as a possible mediator of eGC breakdown. Our results show that urinary GAG, syndecan‐1, and Ang‐2 were elevated in patients with MSM and SM compared with HC. Syndecan‐1 and GAG levels correlated significantly with each other and with plasma Ang‐2. The eGC breakdown products also inversely correlated significantly with hemoglobin and platelet count. In the MSM group, imaging results provided further evidence for eGC degradation. Although not correlated with markers of eGC degradation, vascular function (assessed by non‐invasive near infrared spectroscopy [NIRS]) demonstrated reduced microvascular reactivity, particularly affecting the SM group. Our findings provide further evidence for breakdown of eGC in falciparum malaria that may contribute to endothelial activation and adhesion of parasitized red blood cells, with reduced nitric oxide formation, and vascular dysfunction.

The endothelial glycocalyx in critical illness: A pediatric perspective

“…Children with severe Plasmodium falciparum infection, one of the five protozoan species that cause human malaria, demonstrate higher circulating levels of SDC1, GPC1, heparan sulfate, and hyaluronan than healthy controls [114] , [115] . Further, using videomicroscopy, children with severe malaria were observed to have EG thinning [114] .…”

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

“…The key message from these results is that the presence of IE causes significant changes in endothelial cell transcription and identifies pathways that have been previously associated with malaria infection and pathology of severe disease. To highlight some of the interesting pathways, changes in the endothelial glycocalyx associated with CM pathology were originally identified in mouse models [50] but recent data from several groups have validated a role for the glycocalyx in human disease [51][52][53][54]. This work has identified downstream effects of this phenotype based on genes linked to Syndecan-1 mediated signalling (e.g., HGF) that have the potential to alter several endothelial phenotypes, including the induction of pro-inflammatory and pro-adhesive states [55].…”

Vascular Dysfunction in Malaria: Understanding the Role of the Endothelial Glycocalyx

“…Mouse cerebral malaria (Hempel et al, 2014) P. falciparum in Indonesian adults (Yeo et al, 2019b) Mouse cerebral malaria (Hempel et al, 2019) P. falciparum in Tanzanian children (Yeo et al, 2019a) CD36 binding in vitro (Hempel et al, 2017) P. falciparum in Tanzanian children (Lyimo et al, 2020) iRBC cytoadhesion and flow characteristics (Introini et al, 2018) P. falciparum or P. vivax, experimentally induced in human volunteers (Woodford et al, 2020) P. vivax and P. knowlesi in Malaysian adults (Barber et al, 2021) P. falciparum in Tanzanian children (Bush et al, 2021) was used to calculate the perfused boundary region (PBR), a measure used to assess the ability of perfused RBC to penetrate the eGC. The PBR measurement for children with either uncomplicated or severe malaria was significantly increased compared with healthy children, supporting breakdown of the eGC barrier (Lyimo et al, 2020).…”

“…We initially reported evidence of degradation of the eGC in falciparum malaria in 129 Indonesian adults ( Yeo et al, 2019b ) and 100 Tanzanian children ( Yeo et al, 2019a ); and subsequently in 146 Tanzanian children ( Bush et al, 2021 ). In both children and adults, there were significant increases in total sulfated GAG in urine.…”