SECRETS OF BLOOD BRAIN BARRIER DISRUPTION IN MALARIA

Malaria is a life-threatening parasitic disease and remains a major global health concern. Plasmodium falciparum infection is particularly associated with high morbidity and mortality, as it can lead to parasite sequestration in the microvasculature of vital organs, resulting in severe disease. Cerebral malaria (CM), a severe complication, manifests as a neurological syndrome characterized by loss of consciousness, cerebral seizures, and coma in the presence of asexual parasitemia. The exact mechanisms underlying CM pathogenesis are not fully understood. However, it is known to involve inflammation, endothelial dysfunction, blood-brain barrier (BBB) disruption, and reduced cerebral perfusion in response to parasite sequestration. Since BBB impairment leads to blood-borne protein infiltration into the brain, our group has been exploring the potential role of albumin extravasation in modulating the inflammatory response from the abluminal side. Using a murine model of experimental cerebral malaria, our group has demonstrated that caveolae-dependent albumin transport leads to albumin accumulation in the brain parenchyma prior to BBB breakdown. Furthermore, we observed that inhibiting caveolae-dependent albumin transport with nystatin prevented the development of cerebral malaria, which was associated with an increased lifespan of infected animals without affecting parasitemia levels. In microglial cell cultures, we found that high albumin concentrations trigger microglial activation, which may play a role in cerebral malaria pathogenesis. In this presentation, we will discuss our latest findings on the biophysical mechanisms of protein transport in endothelial cells and their potential link to microglial activation, cell death, and blood-brain barrier breakdown.

This work was supported by CNPq, FAPERJ and CAPES.