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A quantitative brain map of experimental cerebral malaria pathology

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Strangward,, Patrick, Haley, Michael, Shaw, Tovah, Schwartz, Jean-Marc, Greig, Rachel, Mironov, Aleksandr, de Souza, Brian, Cruickshank, Sheena, Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164, Milner Jr, Danny, Allan, Stuart and Couper, Kevin (2017) 'A quantitative brain map of experimental cerebral malaria pathology'. PLoS Pathogens, Vol 13, Issue 3, e1006267.

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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 parasitized 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 colocalise 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.

Item Type: Article
Subjects: QX Parasitology > Protozoa > QX 135 Plasmodia
QX Parasitology > QX 45 Host-parasite relations
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1371/journal.ppat.1006267
Depositing User: Mary Creegan
Date Deposited: 30 Mar 2017 13:21
Last Modified: 17 Jul 2019 14:14
URI: https://archive.lstmed.ac.uk/id/eprint/6923

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