title: Src-family kinase dependent disruption of endothelial barrier function by Plasmodium falciparum merozoite proteins.
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 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.
authors: Department of Microbiology and Infectious Diseases, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada.
authors: Mark R
authors: MR
authors: Gillrie
authors: Gowdahalli
authors: G
authors: Krishnegowda
authors: Kristine
authors: K
authors: Lee
authors: Andre G
authors: AG
authors: Buret
authors: Stephen M
authors: SM
authors: Robbins
authors: S
authors: S
authors: Looareesuwan
authors: D Channe
authors: DC
authors: Gowda
authors: May
authors: M
authors: Ho
mesh_terms: 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*
chemical_list: D000962:Antimalarials; D006420:Hemeproteins; D015800:Protozoan Proteins; C020753:hemozoin; D019061:src-Family Kinases
references: Ultrastruct Pathol. 2000 Jan-Feb;24(1):9-13
references: 10721147
references: Trans R Soc Trop Med Hyg. 2006 Aug;100(8):719-24
references: 16723143
references: Blood. 2000 Sep 15;96(6):2292-8
references: 10979979
references: J Exp Med. 2000 Dec 4;192(11):1563-76
references: 11104799
references: J Clin Microbiol. 2001 Mar;39(3):1025-31
references: 11230422
references: Am J Trop Med Hyg. 2001 Mar-Apr;64(3-4):207-13
references: 11442219
references: J Cell Biol. 2002 Apr 1;157(1):149-60
references: 11927607
references: J Biol Chem. 2002 Nov 15;277(46):44385-98
references: 12213803
references: Am J Respir Crit Care Med. 2003 Mar 1;167(5):684-9
references: 12411286
references: Nat Med. 2004 Feb;10(2):143-5
references: 14745442
references: J Clin Invest. 2004 Mar;113(6):885-94
references: 15067321
references: J Immunol. 2004 Sep 15;173(6):4066-74
references: 15356156
references: J Virol Methods. 2004 Nov;121(2):171-80
references: 15381354
references: Lancet. 1983 Feb 26;1(8322):434-7
references: 6131165
references: Nature. 1990 May 17;345(6272):255-8
references: 2185424
references: Adv Parasitol. 1992;31:83-173
references: 1496930
references: Arch Dis Child. 1994 Apr;70(4):281-7
references: 8185359
references: Clin Infect Dis. 1995 Aug;21(2):300-9
references: 8562735
references: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11865-70
references: 8876229
references: Am J Physiol Lung Cell Mol Physiol. 2006 Aug;291(2):L129-41
references: 16581827
references: Infect Immun. 2006 Oct;74(10):5487-96
references: 16988223
references: Am J Physiol Lung Cell Mol Physiol. 2006 Dec;291(6):L1232-45
references: 16891393
references: Treat Respir Med. 2006;5(6):419-28
references: 17154671
references: J Infect Dis. 2007 Feb 15;195(4):589-96
references: 17230420
references: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1919-24
references: 17261807
references: Infect Immun. 2007 Mar;75(3):1116-28
references: 17158894
references: J Infect Dis. 2007 Apr 1;195(7):942-50
references: 17330783
references: Lancet. 2007 May 5;369(9572):1553-64
references: 17482987
references: Infect Immun. 2007 Jul;75(7):3621-32
references: 17470539
references: Nat Rev Mol Cell Biol. 2004 Apr;5(4):261-70
references: 15071551
references: Trans R Soc Trop Med Hyg. 1998 Jan-Feb;92(1):57-62
references: 9692153
references: Am J Pathol. 1999 Aug;155(2):395-410
references: 10433933
references: Neuropathol Appl Neurobiol. 1999 Aug;25(4):331-40
references: 10476050
references: J Exp Med. 2005 Jan 3;201(1):19-25
references: 15630134
references: J Biol Chem. 2005 Mar 4;280(9):8606-16
references: 15623512
references: J Infect Dis. 2005 Dec 1;192(11):1966-74
references: 16267769
references: Infect Immun. 2006 Jan;74(1):645-53
references: 16369021
references: Physiol Rev. 2006 Jan;86(1):279-367
references: 16371600
references: J Immunol. 2006 Jan 15;176(2):1180-4
references: 16394007
references: J Biol Chem. 2006 Mar 31;281(13):8379-88
references: 16439355
references: Microcirculation. 2006 Apr-May;13(3):237-47
references: 16627366
references: Int J Parasitol. 2006 May 1;36(5):555-68
references: 16616145
references: Neurology. 2000 Jul 12;55(1):104-11
references: 10891914