title: Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier.
abstract: Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8(+) T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45(hi) CD8(+) T cells, ICAM-1(+) macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8(+) T cells and ICAM(+) macrophages, causes a severe restriction in the venous blood efflux from the brain, which exacerbates the vasogenic edema and increases the intracranial pressure. Thus, death from ECM could potentially occur as a consequence of intracranial hypertension.
authors.affiliation: Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Adéla
authors.initials: A
authors.lastname: Nacer
authors.affiliation: Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Movila
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Fabien
authors.initials: F
authors.lastname: Sohet
authors.affiliation: Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Girgis
authors.affiliation: Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Uma Mahesh
authors.initials: UM
authors.lastname: Gundra
authors.affiliation: Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: P'ng
authors.initials: P
authors.lastname: Loke
authors.affiliation: Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Daneman
authors.affiliation: Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Ute
authors.initials: U
authors.lastname: Frevert
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002540:Cerebral Cortex / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D062507:Claudin-5 / Q000276:immunology; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D016779:Malaria, Cerebral / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D062793:Occludin / Q000276:immunology; D010962:Plasmodium berghei / Q000276:immunology*; D010967:Plasmodium yoelii / Q000276:immunology*; D011409:Propylene Glycols / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein / Q000276:immunology
chemical_list: D062507:Claudin-5; C491511:Cldn5 protein, mouse; C090509:Icam1 protein, mouse; D007166:Immunosuppressive Agents; D062793:Occludin; C568986:Ocln protein, mouse; D011409:Propylene Glycols; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D018799:Intercellular Adhesion Molecule-1; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine