Malaria is a major cause of morbidity and mortality worldwide. The majority of deaths are due to infections with Plasmodium falciparum (P. falciparum) parasites. Cerebral malaria (CM) is a major cause of death in these patients. Despite its virulence, the pathophysiologic basis of P. falciparum disease and cerebral malaria are poorly understood. Sequestration of infected red blood cells (iRBCs) in the microvasculature is a major pathologic finding in P. falciparum infections. iRBCs' adherence to endothelial cells is mediated by knobs on their surface. This interaction results in endothelial cell damage, as indicated by pathology and elevated plasma von Willebrand's factor levels (vWF). Repair of damaged microvasculature may occur either by the proliferation or migration of local endothelial cells or the recruitment of bone marrow derived circulating endothelial progenitor cells (EPCs). The reduction of circulating EPCs has been associated with the development of symptoms in diseases associated with microvascular damage, such as cardiovascular disease. We hypothesize that P. falciparum infection results in an imbalance between microvascular damage and repair. Cerebral malaria occurs when circulating EPCs are diminished and damaged endothelial cells cannot be replaced.
The Specific Aims of this proposal will test the hypothesis that the host response to microvascular damage is responsible for the development of CM. P. falciparum infected patients in southern Ghana with different degrees of disease severity (CM, uncomplicated malaria and asymptomatic parasitemia) will be compared with normal controls.
Aim 1) To determine if levels of circulating EPCs are associated with the development of CM. Circulating EPC levels will be determined by FACS analysis. Patients with CM are predicted to have low levels of circulating EPCs.
Aim 2) To evaluate the bone marrow response to microvascular damage in P. falciparum infections. Plasma SDF-1 and VEGF levels will be determined by ELISA. All infected patients are predicted to have elevated SDF-1 and VEGF levels.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CRFS (01))
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Desruisseaux, Mahalia S; Machado, Fabiana S; Weiss, Louis M et al. (2010) Cerebral malaria: a vasculopathy. Am J Pathol 176:1075-8
Gyan, Ben; Goka, Bamenla Quarm; Adjei, George O et al. (2009) Cerebral malaria is associated with low levels of circulating endothelial progenitor cells in African children. Am J Trop Med Hyg 80:541-6