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

Mark R. Gillrie, Gowdahalli Krishnegowda, Kristine Lee, Andre G. Buret, Stephen M. Robbins, S. Looareesuwan, D. Channe Gowda, May Ho

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Pulmonary complication in severe Plasmodium falciparum malaria is manifested as a prolonged impairment of gas transfer or the more severe acute respiratory distress syndrome (ARDS). In either clinical presentation, vascular permeability is a major component of the pathologic process. In this report, we examined the effect of clinical P falciparum isolates on barrier function of primary dermal and lung microvascular endothelium in vitro. We showed that parasite sonicates but not intact infected erythrocytes disrupted endothelial barrier function in a Src-family kinase-dependent manner. The abnormalities were manifested both as discontinuous immunofluorescence staining of the junctional proteins ZO-1, claudin 5, and VE-cadherin and the formation of interendothelial gaps in monolayers. These changes were associated with a loss in total protein content of claudin 5 and redistribution of ZO-1 from the cytoskeleton to the membrane andthe cytosolicandnuclear fractions. There was minimal evidence of a proinflammatory response or direct cellular cytotoxicity or cell death. The active component in sonicates appeared to be a merozoite-associated protein. Increased permeability was also induced by P falciparum glycophosphatidylinositols (GPIs) and food vacuoles. These results demonstrate that parasite components can alter endothelial barrier function and thus contribute to the pathogenesis of severe falciparum malaria.

Original languageEnglish (US)
Pages (from-to)3426-3435
Number of pages10
JournalBlood
Volume110
Issue number9
DOIs
StatePublished - Nov 1 2007

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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