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Src-family kinase dependent disruption of endothelial barrier function by Plasmodium falciparum merozoite proteins

Mark R Gillrie1, Gowdahalli Krishnegowda, Kristine Lee

  • 1Department of Microbiology and Infectious Diseases, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada.

Blood
|August 19, 2007
PubMed

Insights

Severe malaria damages lung function by increasing vascular permeability. Plasmodium falciparum components, not the intact parasite, disrupt endothelial cells, contributing to severe malaria pathogenesis.

Area of Science:

  • Pathology
  • Vascular Biology
  • Infectious Diseases

Background:

  • Severe Plasmodium falciparum malaria can cause acute respiratory distress syndrome (ARDS) and impaired gas transfer.
  • Increased vascular permeability is a key pathological feature in severe malaria.
  • The specific mechanisms by which malaria parasites affect endothelial barrier function require further elucidation.

Purpose of the Study:

  • To investigate the impact of Plasmodium falciparum isolates on the barrier function of human microvascular endothelial cells in vitro.
  • To identify parasite-derived components responsible for endothelial barrier dysfunction.

Main Methods:

  • Primary human dermal and lung microvascular endothelial cells were exposed to clinical isolates of Plasmodium falciparum (sonicates, intact infected erythrocytes, purified components).
  • Endothelial barrier function was assessed by measuring changes in junctional protein localization (ZO-1, claudin 5, VE-cadherin) and interendothelial gap formation.
  • The role of Src-family kinases and specific parasite components (merozoite proteins, GPIs, food vacuoles) was examined.

Main Results:

  • Plasmodium falciparum sonicates, but not intact infected erythrocytes, disrupted endothelial barrier integrity.
  • Disruption involved discontinuous staining of junctional proteins (ZO-1, claudin 5, VE-cadherin) and formation of interendothelial gaps.
  • These changes were associated with reduced claudin 5 protein levels and altered ZO-1 localization, dependent on Src-family kinases.
  • Increased permeability was also induced by parasite glycophosphatidylinositols (GPIs) and food vacuoles.
  • Minimal evidence of inflammation, cytotoxicity, or cell death was observed.

Conclusions:

  • Specific components of Plasmodium falciparum, including merozoite-associated proteins, GPIs, and food vacuoles, can directly impair endothelial barrier function.
  • This disruption of endothelial integrity, mediated by parasite factors, contributes significantly to the pathogenesis of severe falciparum malaria.
  • The findings highlight parasite components as key players in malaria-induced vascular complications, independent of direct host inflammatory responses or cytotoxicity.

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