Upregulation of Neuronal VEGF in Experimental Cerebral Malaria Coincides with Disease Severity Biomarkers in Humans: A Novel Mechanism of Pathophysiology

Abstract

Abstract Cerebral malaria (CM) is a deadly neurological complication of Plasmodium falciparum infection resulting in high mortality or severe cognitive deficit. Current therapeutics are highly ineffective, namely due to drug resistance and lack of mechanistic insight into pathophysiology. CM is characterized by VEGF upregulation, disruption of blood-brain barrier (BBB), vascular permeability, and severe edema detectable by MRI. Using small animal MRI and the established animal model of CM Plasmodium berghei ANKA, we recapitulate these features of human disease. Here we show that regions of brain permeability during CM as identified by T1-weighted gadolinium-enhanced and T2-weighted MRI coincide with VEGF mRNA upregulation. Regions of analysis include granular and glomerular cell layers of main olfactory bulb and superior medullary brainstem. We determined through RNA in situ hybridization that neurons are the major cell type responsible for the increased VEGF production during CM. Interestingly, we identified another cell type found to minimally upregulate VEGF in close proximity to these neurons. These VEGF expressing cells may play a role in support or induction of the neuronal response. Intriguingly, astrocytes show no VEGF upregulation during this pathology. Overall, these findings suggest a novel role for neuronal-VEGF in promoting CNS pathology, and a putative mechanism of BBB disruption and vascular permeability during CM.