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.

Blood–Brain Barrier in Cerebral Malaria: Pathogenesis and Therapeutic Intervention

“…Postmortem analysis of children with CM showed widespread axonal and myelin damage in the cerebrum, cerebellum, and brain stem [81]. Similar to CM, axonal injury and demyelination have been reported in ECM [82]. During ECM, granzyme-B produced by pathogenic CD8 + T cells kills neurons directly by its cytotoxic function and by activating neuronal caspase-3 and calpain1 ( Figure 4) [83].…”

Developing a xenograft model of human vasculature in the mouse ear pinna

“…Using this method, we chose to examine cytoadherence of the human malarial parasite P. falciparum to human endothelium. This is a process that cannot be observed in murine Plasmodium infections due to the specific properties of the human-infective parasite 34 . Using our model, we were able to observe the behaviours associated with cytoadherence including rolling, adherence and vessel occlusion 35 .…”

In vivo noninvasive visualization of retinal perfusion dysfunction in murine cerebral malaria by camera‐phone laser speckle imaging

“…In addition to measuring global BFS, our imager along with clustering analysis showed a marked difference between the heterogeneity of the relative changes in BFS of individual retinal vessels of ECM and uninfected mice, suggesting the potential of laser speckle imaging for assessing the heterogeneous circulatory alterations in severe malaria with increased statistical sampling. Finally, despite the similarities in the pathogenesis of human and ECM, the apparently different mechanisms that alter blood flow dynamics during human CM and ECM in a murine model will require the conduct of human trials for a definitive evaluation of the clinical utility of our imager, including in monitoring blood flow restoration during recovery from CM infection.…”