Experimental Cerebral Malaria Pathogenesis—Hemodynamics at the Blood Brain Barrier

摘要: Cerebral malaria claims the lives of over 600,000 African children every year. To better understand pathogenesis this devastating disease, we compared cellular dynamics in cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral (ECM), and P. yoelii 17XL (PyXL) succumb to malarial hyperparasitemia without neurological impairment. Using a combination intravital imaging flow cytometry, show that significantly more CD8+ T cells, neutrophils, macrophages are recruited postcapillary venules during ECM hyperparasitemia. correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated The arrest large numbers leukocytes larger caused microrheological alterations restricted venous blood flow. Treatment FTY720, inhibits leakage, signs, death from ECM, prevented recruitment subpopulation CD45hi ICAM-1+ neutrophils venules. FTY720 had no effect ECM-associated expression pattern recognition receptor CD14 suggesting endothelial activation is insufficient cause pathology. Expression tight junction proteins claudin-5, occludin, ZO-1 cortex cerebellum PbA-infected mice was unaltered FTY720-treated or PyXL-infected Thus, brain barrier opening does not involve injury likely reversible, consistent rapid recovery many patients CM. We conclude activated leukocytes, particular cells ICAM+ causes severe restriction efflux brain, exacerbates vasogenic edema increases intracranial pressure. could potentially occur as consequence hypertension.