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Bernabeu Group

In vitro 3D blood-brain barrier model and cerebral malaria

The Bernabeu group aims to understand the mechanisms that lead to vascular dysfunction in cerebral malaria by developing new in vitro models of the human blood-brain barrier.

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Previous and current research

The blood-brain barrier (BBB) plays a key role in maintaining neural function, as it prevents the entry of toxins and infectious agents into the brain parenchyma. The highly specialized function of the BBB is accomplished by the establishment of endothelial tight junctions and transporters that provide refined control of the paracellular and transcellular permeability. BBB disruption has been associated with multiple severe diseases, including malaria. Plasmodium spp. cause around 200 million new malaria infections and half a million deaths every year. Among the multiple severe complications that malaria patients can suffer, cerebral malaria is one of the deadliest.

One of the key pathogenic features of cerebral malaria is adhesion of Plasmodium falciparum-infected red blood cells (iRBC) in the brain microvasculature. Parasite sequestration prevents parasitic clearance by the spleen, but it can have severe consequences when multiple iRBC sequester in organs with a critical function, such as the brain. The P. falciparum parasite is species-specific to humans, and thus cannot be studied in model species. Therefore, we do not have yet a clear understanding of what happens in the brains of these patients. 3D culture of human tissues is therefore an exciting approach to tackle this question.

Future research and goals

  • Develop a 3D-BBB model

We have recently developed an endothelial-only 3D brain microvessel model (Figure 1), in which infected cells can be perfused through the in vitro vasculature. Our work has shown that P. falciparum-iRBC present high sequestration levels within 3D brain microvessels, and provided new information on host-parasite interactions (Figure 1 and Video 1). However, pericytes and astrocytes have a key role in establishing BBB properties. Our lab is developing an in vitro 3D brain microvascular model that incorporate these cell types to better recapitulate BBB function. The model is composed by primary cells and/or iPSC-differentiated endothelial cells. Our studies will focus on the role that perivascular cells and flow play in vessel integrity and function.

  • Understanding the mechanisms of BBB breakdown after P. falciparum sequestration

We aim to understand the biomechanical and molecular mechanisms that drive cerebral malaria pathogenesis. We will model parasite-mediated microvessel obstruction and whether alterations in blood flow cause endothelial and BBB damage. Moreover, we will study the molecular mechanisms of BBB dysfunction mediated by either P. falciparum-iRBC cytoadhesion to endothelial receptors or release of parasitic toxins. To achieve this goal, we will follow an interdisciplinary approach that combines bioengineering, biophysics, advanced imaging and omics.

  • Role of inflammation and altered coagulation in cerebral malaria

In addition to P. falciparum­-iRBC sequestration, other host factors have been associated to cerebral malaria pathogenesis. These include plasma cytokines, neutrophils, platelets, and altered coagulation. We will study how these factors contribute to brain microvascular obstruction and BBB breakdown independently, or in combination with P. falciparum­-iRBC.  

Figure 1: Top: 3D reconstruction of 3D brain microvessels. Bottom: Ultrastructural imaging showing multiple P. falciparum-iRBCs binding to a primary human brain microvascular endothelial cell (EC) within the 3D brain microvessels. The major focus of the lab is to understand how P. falciparum­ mediates brain vascular damage.
Figure 1: Top: 3D reconstruction of 3D brain microvessels. Bottom: Ultrastructural imaging showing multiple P. falciparum-iRBCs binding to a primary human brain microvascular endothelial cell (EC) within the 3D brain microvessels. The major focus of the lab is to understand how P. falciparum­ mediates brain vascular damage.
Video 1: Perfusion of P. falciparum-iRBCs within the 3D brain microvessels. (WSS: Wall Shear Stress)

News about Bernabeu group

25 May 2021

Barriers against malaria

The Bernabeu Group aims to increase our knowledge of cerebral malaria, using in vitro engineered networks of human blood vessels and brain cells.

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02 Dec 2020

Tackling tropical diseases

Members of the EMBL community are working to improve our understanding of the parasites that cause malaria and sleeping sickness

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10 Nov 2020

Understanding malaria

To help understand cerebral malaria the Bernabeu group has created in vitro engineered networks of human blood vessels.

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13 Oct 2020

How deadly parasites ‘glide’ into human cells

A group of scientists led by EMBL Hamburg’s Christian Löw provide insights into the molecular structure of proteins involved in the gliding movements through which the parasites causing malaria and…

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