Georgiadou, Athina, Naidu, Praveena, Walsh, Sophie, Kamiza, Steve, Barrera, Valentina, Harding, Simon P 
ORCID: 0000-0003-4676-1158, Moxon, Christopher A and Cunnington, Aubrey J
(2021)
Localised release of matrix metallopeptidase 8 in fatal cerebral malaria.
CLINICAL & TRANSLATIONAL IMMUNOLOGY, 10 (4).
e1263-.
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Abstract
<h4>Objective</h4>Cerebral malaria (CM) is a complication of <i>Plasmodium falciparum</i> 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).<h4>Methods</h4>We 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.<h4>Results</h4>In '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' (<i>P</i>-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%, <i>P</i>-value = 0.01). Vascular leak was rare in the absence of MMP8 staining.<h4>Conclusion</h4>Matrix 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | cerebral malaria, matrix metalloproteinase 8, neutrophils, pathogenesis |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 09 Aug 2021 09:26 |
| Last Modified: | 18 Jan 2023 21:33 |
| DOI: | 10.1002/cti2.1263 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3132895 |
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