title: A quantitative brain map of experimental cerebral malaria pathology.
abstract: The murine model of experimental cerebral malaria (ECM) has been utilised extensively in recent years to study the pathogenesis of human cerebral malaria (HCM). However, it has been proposed that the aetiologies of ECM and HCM are distinct, and, consequently, no useful mechanistic insights into the pathogenesis of HCM can be obtained from studying the ECM model. Therefore, in order to determine the similarities and differences in the pathology of ECM and HCM, we have performed the first spatial and quantitative histopathological assessment of the ECM syndrome. We demonstrate that the accumulation of parasitised red blood cells (pRBCs) in brain capillaries is a specific feature of ECM that is not observed during mild murine malaria infections. Critically, we show that individual pRBCs appear to occlude murine brain capillaries during ECM. As pRBC-mediated congestion of brain microvessels is a hallmark of HCM, this suggests that the impact of parasite accumulation on cerebral blood flow may ultimately be similar in mice and humans during ECM and HCM, respectively. Additionally, we demonstrate that cerebrovascular CD8+ T-cells appear to co-localise with accumulated pRBCs, an event that corresponds with development of widespread vascular leakage. As in HCM, we show that vascular leakage is not dependent on extensive vascular destruction. Instead, we show that vascular leakage is associated with alterations in transcellular and paracellular transport mechanisms. Finally, as in HCM, we observed axonal injury and demyelination in ECM adjacent to diverse vasculopathies. Collectively, our data therefore shows that, despite very different presentation, and apparently distinct mechanisms, of parasite accumulation, there appear to be a number of comparable features of cerebral pathology in mice and in humans during ECM and HCM, respectively. Thus, when used appropriately, the ECM model may be useful for studying specific pathological features of HCM.
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Patrick
authors.identifier: 0000-0001-5952-2864
authors.initials: P
authors.lastname: Strangward
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Michael J
authors.identifier: 0000-0003-2485-8485
authors.initials: MJ
authors.lastname: Haley
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Tovah N
authors.identifier: 0000-0002-8107-2836
authors.initials: TN
authors.lastname: Shaw
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Schwartz
authors.affiliation: Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Greig
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Mironov
authors.affiliation: Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: J Brian
authors.initials: JB
authors.lastname: de Souza
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Sheena M
authors.initials: SM
authors.lastname: Cruickshank
authors.affiliation: Department of Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Alister G
authors.initials: AG
authors.lastname: Craig
authors.affiliation: Department of Pathology, The Brigham & Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Danny A
authors.initials: DA
authors.lastname: Milner
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allan
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Kevin N
authors.identifier: 0000-0003-4659-8960
authors.initials: KN
authors.lastname: Couper
mesh_terms: D000818:Animals; D001921:Brain / Q000469:parasitology* / Q000473:pathology*; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D016779:Malaria, Cerebral / Q000469:parasitology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D010962:Plasmodium berghei