Abstract
ObjectiveCerebral malaria (CM) is a complication of Plasmodium falciparum malaria, in which progressive brain swelling is associated with sequestration of parasites and impaired barrier function of the cerebral microvascular endothelium. To test the hypothesis that localised release of matrix metallopeptidase 8 (MMP8) within the retina is implicated in microvascular leak in CM, we examined its expression and association with extravascular fibrinogen leak in a case–control study of post‐mortem retinal samples from 13 Malawian children who met the clinical case definition of CM during life. Cases were seven children who were found on post‐mortem examination to have ‘true‐CM’ (parasite sequestration in brain blood vessels), whilst controls were six children who had alternative causes of death (‘faux‐CM’, no parasite sequestration in blood vessels).MethodsWe used immunofluorescence microscopy and independent scoring, by two assessors blinded to the CM status, to assess MMP8 expression, extravascular fibrinogen as an indicator of vascular leak and their co‐localisation in the retinal microvasculature.ResultsIn ‘true‐CM’ subjects, MMP8 staining was invariably associated with sequestered parasites and a median of 88% (IQR = 74–91%) of capillaries showed MMP8 staining, compared with 14% (IQR = 3.8–24%) in ‘faux‐CM’ (P‐value = 0.001). 41% (IQR = 28–49%) of capillaries in ‘true‐CM’ subjects showed co‐localisation of extravascular fibrinogen leak and MMP8 staining, compared with 1.8% of capillaries in ‘faux‐CM’ (IQR = 0–3.9%, P‐value = 0.01). Vascular leak was rare in the absence of MMP8 staining.ConclusionMatrix metallopeptidase 8 was extensively expressed in retinal capillaries of Malawian children with malarial retinopathy and strongly associated with vascular leak. Our findings implicate MMP8 as a cause of the vascular endothelial barrier disruption in CM, which may precipitate fatal brain swelling.
Highlights
Cerebral malaria (CM) is characterised by coma and the detection of asexual blood-stage malaria parasites, without other identifiable cause.[1]
matrix metalloproteinase 8 (MMP8) gene expression is increased in CM,[11] and MMP8 is a plausible mediator of the vascular endothelial barrier disruption occurring in CM, systemic levels of MMP8 are elevated in subjects with severe and uncomplicated malaria compared to healthy controls.[5,7]
Preceding work has indicated that increased expression of MMP8 in blood leukocytes is associated with CM,[6,7] systemic concentrations of MMP8 in blood did not differ significantly between severe and uncomplicated malaria.[5,7]
Summary
Cerebral malaria (CM) is characterised by coma and the detection of asexual blood-stage malaria parasites, without other identifiable cause.[1] In fatal cases, the pathognomonic histological feature is sequestration of parasitised erythrocytes in the microvasculature of the brain and retina, the latter being strongly associated with a characteristic malarial retinopathy which can be visualised during life.[1] Recent studies have revealed that brain swelling is the final common pathway to death in paediatric CM, occurring in close association with rapid fluid egress from focal leaks in the blood–retinal barrier and with histological evidence of similar microvascular leak in the post-mortem brain.[1,2,3,4] The molecular mechanisms which disrupt vascular integrity in human CM are not well established but may be important therapeutic targets. In order to establish plausibility of MMP8 release as a cause of fatal brain swelling, we reasoned that there should be additional evidence that any vascular leak associated with MMP8 was initiated before death
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