Src-family kinase dependent disruption of endothelial barrier function by Plasmodium falciparum merozoite proteins.
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 and the cytosolic and nuclear 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.
Gillrie
Mark R
MR
Department of Microbiology and Infectious Diseases, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada.
Krishnegowda
Gowdahalli
G
Lee
Kristine
K
Buret
Andre G
AG
Robbins
Stephen M
SM
Looareesuwan
S
S
Gowda
D Channe
DC
Ho
May
M
D022005:Adherens Junctions / Q000473:pathology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D018916:Blood-Aqueous Barrier / Q000187:drug effects* / Q000503:physiopathology*; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006420:Hemeproteins / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000473:pathology; D016778:Malaria, Falciparum / Q000503:physiopathology; D052940:Merozoites / Q000737:chemistry; D010963:Plasmodium falciparum; D015800:Protozoan Proteins / Q000378:metabolism / Q000494:pharmacology*; D013010:Sonication; D019108:Tight Junctions / Q000473:pathology; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
D000962:Antimalarials; D006420:Hemeproteins; D015800:Protozoan Proteins; C020753:hemozoin; D019061:src-Family Kinases
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