Cellular, subcellular, and molecular elements of cerebral malaria pathogenesis

Abstract

A complex network of elements is responsible for cerebral malaria (CM) development, but interactions between these elements are still being explored. Annually, there are 212 million cases of malaria with 1-2% progressing to CM. Plasma microvesicles (MV) are increased in patients and mice with CM and blocking their release protects against CM. The miRNA content of circulating plasma MV and brain tissue during murine CM and non-CM was assessed using microarray and RT-qPCR techniques. Following infection, MV and brain miRNA were altered in CM mice, coinciding with neurological syndrome onset. Particularly, miR-146a and miR-193b were dysregulated in plasma MV from CM mice and play roles in apoptosis, cytokine regulation and inflammatory cell recruitment. Several other miRNA were dysregulated in the brains of CM mice and play roles in TGF- signalling, endocytosis, FoxO signalling and adherens junctions. Using confocal microscopy, we investigated monocyte, platelet, T cell, parasite and ICAM-1-positive cell accumulation in CM brains. These cells accumulate at vessel branch points, associated with haemorrhaging and the development of tissue hypoxia, consistent with previous findings. As monocytes were the most numerous cells in the brains of CM mice, we targeted them therapeutically. Treatment in vivo with immuno-modulatory particles and artesunate resulted in 88% protection when administered at CM onset, while monotherapies resulted in greatly reduced protection. All successfully treated mice displayed reduced clinical signs of CM and monocyte and MV numbers, and were immune to reinfection. This thesis reinforces existing findings regarding CM pathogenesis and highlights several novel candidates as players in CM development. We explore the potential of miRNA as biomarkers of the neurological syndrome. We show that monocytes displaying a Ly6Clo phenotype aggravate CM development and that therapy targeting this cell subset is a novel strategy to abrogate late-stage CM.