Last Updated: 27/12/2025
Vascular Dysfunction in the Pathogenesis of Severe Malaria
Objectives
This study seeks to elucidate the cellular and molecular mechanisms of cerebral vascular endothelial dysfunction that are responsible for CM mortality.
The specific aims of this are to:
- provide annotated biological samples (archived and prospectively collected) from clinically well-characterized patients;
- assess the effects on key endothelial functions (e.g., proinflammatory activation, increased permeability), triggered by samples from selected CM patients, in a human BMVEC-astrocyte co-culture model; and
- define and progressively validate differentially regulated, genome-wide, human BMVEC transcriptional programs that correlate with clinical disease.
Nearly 80% of African children who die of malaria die of cerebral malaria (CM). The unifying pathological feature in malaria pathogenesis is the sequestration of parasitized erythrocytes in the microvasculature of various organs, including the brain. However, attempts to identify the pathogenetic mechanisms of CM have been thwarted by imprecise clinical definitions and the inability to subject relevant clinical samples t in-depth cellular and molecular biological analyses. In a significant clinical advance, the Malawi-based Blantyre Malaria Project recently identified raised intracranial pressure associated with massively increased brain volume as the clinical feature most strongly associated with death in children with stringently defined CM. While evidence of generalized endothelial dysfunction is ubiquitous in children with CM, the potential etiologies of brain swelling, e.g., vasogenic edema (blood-brain-barrier breakdown); cytotoxic edema (anoxia secondary to impaired blood flow); hyperemia (increased blood flow in response to fevers, anemia and seizures); and vascular congestion (the result of impaired venous drainage), remain poorly defined. This project represents a synergistic, collaborative effort between clinical investigators in the Blantyre Malaria Project (University of Malawi College of Medicine, Michigan State University), and investigators in the Center for Excellence in Vascular Biology at the Brigham and Women’s Hospital, Harvard Medical School where the phenomenon of endothelial dysfunction has been extensively studied. The central hypothesis is that endothelial cell dysfunction is a pathogenetic link between the defining histological feature of CM, cytoadherence of parasitized red blood cells to brain microvascular endothelial cells (BMVEC), and the predominant clinical feature, massively increased brain volume. Taken together, these collaborative efforts should provide a better understanding of CM pathophysiology, and identify novel therapeutic targets for adjunct therapies, and candidate biomarkers-thus advancing the goal of ending pediatric CM mortality in Africa.
Sep 2015 — Dec 2019
$1.82M
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