A quantitative brain map of experimental cerebral malaria pathology

• Published in: PLoS pathogens Vol. 13; no. 3; p. e1006267
• Main Authors: Strangward, Patrick, Haley, Michael J., Shaw, Tovah N., Schwartz, Jean-Marc, Greig, Rachel, Mironov, Aleksandr, de Souza, J. Brian, Cruickshank, Sheena M., Craig, Alister G., Milner, Danny A., Allan, Stuart M., Couper, Kevin N.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.03.2017; Public Library of Science (PLoS)
• Subjects: Accumulation; Adults; Alzheimer's disease; Angiogenesis; Animal models; Animals; Apoptosis; Biochemistry; Biology; Biology and Life Sciences; Blood cells; Blood flow; Blood vessels; Blood-brain barrier; Brain; Brain - parasitology; Brain - pathology; Brain mapping; Breast cancer; Capillaries; Careers; Central nervous system; Central nervous system diseases; Cerebrovascular system; Children; Complications; Data acquisition; Data collection; Demyelination; Destruction; Disease Models, Animal; Erythrocytes - parasitology; Female; Fluorescent Antibody Technique; Health aspects; Hemodynamics; Histopathology; Historical account; Humans; Hygiene; Hypoxia; Image Processing, Computer-Assisted; Immunohistochemistry; Immunology; Infections; Infectious diseases; Inflammation; Injuries; Life cycles; Malaria; Malaria, Cerebral - parasitology; Malaria, Cerebral - pathology; Male; Medical research; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Mortality; Nervous system; Parasites; Pathological histology; Pathology; Permeability; Plasmodium berghei; Rodents; Stimulation; Sun; Tropical diseases; Tumors; Vascular endothelial growth factor; Vector-borne diseases; β-Amyloid
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006267

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.