Plasmodium falciparum (Pf) infected erythrocytes can activate endothelial and other myeloid cells, culminating in systemic inflammation and vascular dysfunction that underlie the pathogenesis of cerebral malaria. A subset of the polymorphic Pf Erythrocyte Membrane Protein 1 (PfEMP1) family, a virulence protein exported from the intracellular parasite to the infected erythrocyte surface, is overrepresented in persons with cerebral malaria, who also have elevated levels of circulating immune complexes that can modify endothelial and monocyte function. Members of the Kruppel-like family of factors (KLF) are nodal regulators of endothelial and immune cell function. KLF2 confers an anti-inflammatory, anti-thrombotic, and anti- permeable phenotype to endothelial and myeloid cells by a common mechanism centered on inhibition of NF?B, a key transcriptional inducer of pro-inflammatory activation. However, a causal link between malaria pathogenesis and KLF2 regulation, brain endothelial cell and monocyte function, and malaria elicited immune complexes has not been established. Our central hypothesis is that regulation of KLF2 levels in endothelial and myeloid cells is critical for the pathogenesis of vascular and monocyte dysfunction in cerebral malaria, and that this myeloid cell dysfunction results from interactions with infected erythrocytes expressing specific PfEMP1s and Pf elicited immune complexes. To test this hypothesis, we will enroll Kenyan children presenting with cerebral and uncomplicated malaria and follow them for 6 months. We will examine 1) the impact of PfEMP1 and patient parasite isolates on endothelial KLF2 and NF?B expression, 2) patient monocyte phenotype, function, KLF2 expression, and in vitro monocyte function impacted by PfEMP1 and patient parasite isolates, and 3) the role of immune complexes in vascular endothelial and monocyte dysfunction isolated from children with cerebral and uncomplicated malaria. Research proposed here will inform the rational development of adjunct therapies aimed at reducing vascular dysfunction, mortality and long- term clinical sequela of cerebral malaria by enhancing endogenous cytoprotective pathways of endothelial/myeloid lineage cells.
Mortality and long term sequelae resulting from cerebral falciparum malaria are significant health problems in Africa. The goal of research proposed here is to identify safe adjunctive therapies to reduce mortality and long term sequelae of cerebral malaria in children.
