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Localised release of matrix metallopeptidase 8 in fatal cerebral malaria

Athina Georgiadou1,2, Praveena Naidu1, Sophie Walsh1

  • 1Department of Infectious Disease Section of Paediatric Infectious Disease Imperial College London London UK.

Clinical & Translational Immunology
|May 10, 2021
PubMed
Abstract

Insights

Matrix metallopeptidase 8 (MMP8) is linked to retinal vascular leak in cerebral malaria (CM). This finding suggests MMP8 contributes to fatal brain swelling in children with CM.

Area of Science:

  • Ophthalmology
  • Infectious Diseases
  • Pathology

Background:

  • Cerebral malaria (CM) involves brain swelling due to parasite sequestration and impaired cerebral microvascular endothelium barrier function.
  • The role of specific enzymes like matrix metallopeptidase 8 (MMP8) in CM-related vascular dysfunction is not fully understood.

Purpose of the Study:

  • To investigate the hypothesis that localized release of MMP8 in the retina contributes to microvascular leak in CM.
  • To examine MMP8 expression and its association with extravascular fibrinogen leak in post-mortem retinal samples from children with and without CM.

Main Methods:

  • A case-control study was conducted using post-mortem retinal samples from Malawian children.
  • Immunofluorescence microscopy was employed to assess MMP8 expression and extravascular fibrinogen (vascular leak indicator).
  • Two independent assessors, blinded to CM status, evaluated MMP8 and fibrinogen co-localization in retinal microvasculature.

Main Results:

  • MMP8 staining was significantly higher in children with 'true-CM' (parasite sequestration in brain vessels) compared to 'faux-CM' (alternative causes of death).
  • A substantial percentage of capillaries in 'true-CM' subjects showed co-localization of MMP8 staining and extravascular fibrinogen leak.
  • Vascular leak was infrequent in the absence of MMP8 staining, indicating a strong association.

Conclusions:

  • Matrix metallopeptidase 8 is extensively expressed in the retinal capillaries of children with malarial retinopathy.
  • MMP8 strongly correlates with vascular leak in the retina during CM.
  • These findings suggest MMP8 plays a causal role in the disruption of the vascular endothelial barrier in CM, potentially leading to fatal brain swelling.
Keywords:
cerebral malariamatrix metalloproteinase 8neutrophilspathogenesis

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