Understanding parasite–brain microvascular interactions with engineered 3D blood–brain barrier models

Abstract

The brain is composed of a highly diverse array of neurons and glial cells that functionally interact to support healthy cognitive and motor functions. To satisfy the high energy requirements of the brain, the cerebral parenchyma is heavily vascularized, providing continuous access of nutrients and oxygen while also facilitating the removal of waste products. This is achieved through a highly specialized vascular interface known as the blood-brain barrier (BBB) that precisely controls influx of ions and molecules into the brain while preventing the entry of toxic agents and pathogens from the blood (Obermeier et al., 2013). Despite the presence of this selective barrier, parasites have developed complex interactions with the BBB that can lead to either (a) widespread dysfunction of the brain microvasculature or (b) transmigration of parasites into the brain parenchyma.Cerebral malaria is a paradigmatic example of parasite-induced brain microvascular pathogenesis without crossing into the brain parenchyma. It is characterized by extensive cytoadhesion of Plasmodium falciparum-infected red blood cells (iRBC) to endothelial brain receptors, such as intracellular adhesion molecule 1 (ICAM-1; Ockenhouse et al., 1992) or endothelial protein C receptor (EPCR;Turner et al., 2013). P. falciparum-iRBC interaction with EPCR has been proposed as one of the main contributors to brain microvascular dysfunction, by blocking cytoprotective, anti-inflammatory, and junctional stabilizing pathways regulated by this endothelial receptor (Bernabeu & Smith, 2017). Another barrier-disruptive mechanism that has been proposed is the release of toxic components upon P. falciparum-iRBC egress of new asexual infective parasites, known as merozoites (Gallego-Delgado et al., 2016;Tripathi et al., 2007). These toxic agents might include parasite histones or proteins such as P. falciparum

Biophysical Tools and Concepts Enable Understanding of Asexual Blood Stage Malaria

“…These devices are built using microfabrication techniques, in hydrogels such as collagen or fibrin enclosed in PDMS or acrylic housing jigs. The dimensions of the endothelial microvessel networks can be controlled with micrometre precision by soft lithography patterning ( Long et al., 2021 ). Bernabeu et al examined the binding affinity of Pf- iRBC to 3D brain microvessels along a shear gradient ( Bernabeu et al., 2019 ).…”

Emerging technologies in microbiology

“…In this issue, we highlight advances in the engineering of novel three-dimensional BBB models. These new models allow for more precise regulation of the tissue microenvironment to study infection and better emulate the fine vessel structure of the brain microvasculature (Long et al, 2022). This offers significant advantages over traditional animal models and twodimensional cell culture.…”

On the quest of reliable 3D dynamic in vitro blood-brain barrier models using polymer hollow fiber membranes: Pitfalls, progress, and future perspectives

“…These adherens junctions, located more basally, are composed by catenins and cadherins proteins contributing to the barrier function and connecting the actin cytoskeleton. Among them, the most important is the vascular endothelial cadherin (VE-cadherin) ( Long et al, 2022 ). The molecular composition of the endothelial tight junctions is also presented in Figure 1 .…”

“…Remarkably, GLUT-1 and LAT-1 transporters are bidirectional moving in or out of the endothelial cells by the concentration gradient, being the GLUT-1 transporter the primary source of energy for the brain ( Sweeney et al, 2019 ). A battery of ATP-driven drug efflux pumps, i.e., ATP-binding cassette transporters (ABCs) such as P-glycoprotein (P-gp), breast cancer resistance proteins (BCRPs), and multidrug resistance proteins (MRPs), prevents brain accumulation of drugs and xenobiotics via active efflux of these compounds from the brain or endothelial cells to the blood ( Wong et al, 2013 ; Long et al, 2022 ). Then, some lipoproteins as insulin and transferrin penetrate the brain through receptors-mediated transcytosis.…”