New research has identified the critical role of pericytes, cells that wrap around the brain’s smallest blood vessels, in the catastrophic breakdown of the blood-brain barrier during cerebral malaria infections. A study published in EMBO Molecular Medicine reveals that byproducts from the malaria parasite halt the protective functions of these cells, leading to the vascular damage that makes the disease so deadly. The findings open a new front in the battle against a disease that claims more than half a million lives each year and can leave survivors with severe, long-term neurological damage.
Scientists have long sought to understand the precise mechanisms that cause the brain’s defenses to fail during infection by the Plasmodium falciparum parasite. This new work, conducted by researchers at EMBL Barcelona, used a sophisticated 3D model of human brain microvasculature to demonstrate that parasite byproducts disrupt pericytes, stopping them from secreting a crucial protective molecule. This disruption leads directly to leaky blood vessels, a hallmark of cerebral malaria. The research not only clarifies the cellular process behind the damage but also highlights a promising pathway for developing treatments that could prevent or even reverse it.
An Unstable Signaling Pathway
The integrity of the brain’s delicate blood vessels is maintained by a finely tuned molecular signaling system known as the angiopoietin-Tie pathway. This system relies on a balance between two key molecules: angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2). Ang-1, primarily secreted by pericytes, acts as a stabilizing force, keeping the endothelial cells that form the vessel walls tightly packed and preventing leaks. In contrast, Ang-2 is a destabilizing molecule. In patients with cerebral malaria, this delicate balance is thrown into disarray; they exhibit dangerously low levels of the protective Ang-1 and a surplus of the destabilizing Ang-2. This imbalance has been a known feature of the disease, but the exact role of pericytes in this process remained unclear until now.
Recreating the Barrier in the Lab
To investigate the cellular interactions at the heart of the blood-brain barrier, the research team engineered an advanced “blood-brain barrier on a chip.” This 3D human brain microvasculature model is a significant step forward, as it successfully reproduces the critical interactions between human brain endothelial cells and the pericytes that support them. The model recapitulates the way pericytes cover blood vessels in the living brain, providing a realistic environment to study the disease process. “In this study, we generated an advanced 3D human brain microvasculature model that reproduces important in vivo interactions between human brain endothelial cells and pericytes,” stated Rory Long, a Postdoctoral Fellow in the Bernabeu Group at EMBL Barcelona and the study’s first author.
Simulating a Malaria Infection
With a functional model established, the scientists exposed it to the byproducts released by P. falciparum parasites during their egress from red blood cells. This step was designed to mimic the conditions within the brain’s blood vessels during an active cerebral malaria infection. By introducing these parasitic materials, the researchers could directly observe their effects on the cells of the blood-brain barrier and measure the subsequent changes in vascular integrity and cellular function. This controlled environment allowed them to isolate the specific impact of the parasite on the pericyte-endothelial cell relationship.
How Pericytes Trigger a Breakdown
The experiment revealed a clear and damaging sequence of events. When exposed to the parasite byproducts, the pericytes in the 3D model immediately stopped secreting the protective Ang-1 molecule. This cessation of Ang-1 production was a critical failure, directly contributing to the breakdown of the vascular barrier. The team observed that the endothelial vessels became significantly more permeable, or “leaky,” which in a patient allows harmful substances to enter the brain. Furthermore, the researchers noted subtle but important ultrastructural changes in the morphology of the pericytes themselves, indicating that the parasite byproducts inflicted direct damage on these vital cells. The study showed that this process also involved a decrease in the expression of claudin-5, a key protein that helps seal the junctions between endothelial cells.
Restoring Vascular Stability
A crucial part of the study involved testing potential interventions to counter the damage. The researchers found that the parasite-mediated barrier disruption could be partially reversed. By pre-treating the 3D model with recombinant Ang-1—essentially, by adding back the protective molecule that the pericytes had stopped producing—they were able to restore a degree of vascular stability. This result established a direct link between the loss of pericyte-secreted Ang-1 and the breakdown of the blood-brain barrier. It demonstrated that the damage was not necessarily permanent and could be mitigated if the key molecular deficiency was addressed. “We show that disruption of the crucial role of pericytes in protecting and restoring the blood vessels promotes blood-brain barrier damage during cerebral malaria,” Long explained.
Targeting the Tie-2 Receptor
The team also tested another therapeutic strategy targeting the same pathway. They introduced a compound known as AKB-9778, which is a Tie-2 activator. The Tie-2 receptor is what Ang-1 and Ang-2 act upon to regulate vessel stability. By directly activating this receptor, AKB-9778 was able to rapidly improve the integrity of the vascular barrier even in the presence of the damaging malaria parasite byproducts. This finding is particularly promising, as it suggests that drugs designed to activate Tie-2 could offer a powerful and fast-acting method to counteract the vascular dysfunction central to cerebral malaria.
Significance for Future Treatments
This research provides a novel mechanistic understanding of how pericytes contribute to the pathogenesis of cerebral malaria. By identifying the halt in Ang-1 secretion as a key event, the study clarifies a previously unexplored aspect of the disease. For the hundreds of thousands of people who die from cerebral malaria annually, and for the many survivors who face lifelong cognitive and physical disabilities like epilepsy and speech disorders, these findings offer a new sense of hope. The success in reversing vascular damage in the lab model points toward a new class of potential therapeutics. By focusing on the angiopoietin-Tie axis, future drugs could work to protect the blood-brain barrier, mitigate brain injury, and ultimately prevent the devastating consequences of this parasitic infection.
