Plasmodium falciparum-infected erythrocytes decrease the integrity of human blood-brain barrier endothelial cell monolayers

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Abstract

Background. Central to the pathologic progression of human cerebral malaria (CM) is sequestration of Plasmodium falciparum-infected red blood cells (Pf-IRBCs) to the blood-brain barrier (BBB) endothelium. The molecular interactions between Pf-IRBCs and the BBB endothelium and their implications for barrier function are unclear. Methods. The effects of Pf-IRBCs on the integrity of the BBB were assessed by electrical cell substrate sensing and by transendothelial electrical resistance measurements in an in vitro human BBB model. In addition, Pf-IRBCs were subfractionated and treated with trypsin, artemisinin, or brefeldin A. Results. Pf-IRBCs, but not normal red blood cells, significantly decreased BBB resistance. Subfractionation showed that both membrane-associated and soluble Pf-IRBC factors mediate the decrease in BBB resistance. Trypsin treatment significantly reduced Pf-IRBC binding but not their ability to decrease electrical resistance. Likewise, P. falciparum isolates with increased binding to human brain microvascular endothelial cells did not alter the electrical resistance response. Soluble factors from Pf-IRBC culture supernatant decreased resistance by 50%-70% and precipitated with 40% ammonium sulfate saturation. Brefeldin-A partially blocked the ability of Pf-IRBCs to reduce resistance. Conclusion. The results suggest that, in CM, trypsin-resistant membrane components and soluble factors of Pf-IRBCs contribute to the impedance of BBB integrity in a multistep and multifactorial process.

Original languageEnglish (US)
Pages (from-to)942-950
Number of pages9
JournalJournal of Infectious Diseases
Volume195
Issue number7
DOIs
StatePublished - Apr 1 2007

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Plasmodium falciparum
Blood-Brain Barrier
Endothelial Cells
Erythrocytes
Electric Impedance
Trypsin
Cerebral Malaria
Brefeldin A
Endothelium
Membranes
Ammonium Sulfate
Brain

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Immunology

Cite this

@article{0061ee8e4b1c4ea7a1cc47a5f56f1c0b,
title = "Plasmodium falciparum-infected erythrocytes decrease the integrity of human blood-brain barrier endothelial cell monolayers",
abstract = "Background. Central to the pathologic progression of human cerebral malaria (CM) is sequestration of Plasmodium falciparum-infected red blood cells (Pf-IRBCs) to the blood-brain barrier (BBB) endothelium. The molecular interactions between Pf-IRBCs and the BBB endothelium and their implications for barrier function are unclear. Methods. The effects of Pf-IRBCs on the integrity of the BBB were assessed by electrical cell substrate sensing and by transendothelial electrical resistance measurements in an in vitro human BBB model. In addition, Pf-IRBCs were subfractionated and treated with trypsin, artemisinin, or brefeldin A. Results. Pf-IRBCs, but not normal red blood cells, significantly decreased BBB resistance. Subfractionation showed that both membrane-associated and soluble Pf-IRBC factors mediate the decrease in BBB resistance. Trypsin treatment significantly reduced Pf-IRBC binding but not their ability to decrease electrical resistance. Likewise, P. falciparum isolates with increased binding to human brain microvascular endothelial cells did not alter the electrical resistance response. Soluble factors from Pf-IRBC culture supernatant decreased resistance by 50{\%}-70{\%} and precipitated with 40{\%} ammonium sulfate saturation. Brefeldin-A partially blocked the ability of Pf-IRBCs to reduce resistance. Conclusion. The results suggest that, in CM, trypsin-resistant membrane components and soluble factors of Pf-IRBCs contribute to the impedance of BBB integrity in a multistep and multifactorial process.",
author = "Abhai Tripathi and Sullivan, {David J} and Monique Stins",
year = "2007",
month = "4",
day = "1",
doi = "10.1086/512083",
language = "English (US)",
volume = "195",
pages = "942--950",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
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T1 - Plasmodium falciparum-infected erythrocytes decrease the integrity of human blood-brain barrier endothelial cell monolayers

AU - Tripathi, Abhai

AU - Sullivan, David J

AU - Stins, Monique

PY - 2007/4/1

Y1 - 2007/4/1

N2 - Background. Central to the pathologic progression of human cerebral malaria (CM) is sequestration of Plasmodium falciparum-infected red blood cells (Pf-IRBCs) to the blood-brain barrier (BBB) endothelium. The molecular interactions between Pf-IRBCs and the BBB endothelium and their implications for barrier function are unclear. Methods. The effects of Pf-IRBCs on the integrity of the BBB were assessed by electrical cell substrate sensing and by transendothelial electrical resistance measurements in an in vitro human BBB model. In addition, Pf-IRBCs were subfractionated and treated with trypsin, artemisinin, or brefeldin A. Results. Pf-IRBCs, but not normal red blood cells, significantly decreased BBB resistance. Subfractionation showed that both membrane-associated and soluble Pf-IRBC factors mediate the decrease in BBB resistance. Trypsin treatment significantly reduced Pf-IRBC binding but not their ability to decrease electrical resistance. Likewise, P. falciparum isolates with increased binding to human brain microvascular endothelial cells did not alter the electrical resistance response. Soluble factors from Pf-IRBC culture supernatant decreased resistance by 50%-70% and precipitated with 40% ammonium sulfate saturation. Brefeldin-A partially blocked the ability of Pf-IRBCs to reduce resistance. Conclusion. The results suggest that, in CM, trypsin-resistant membrane components and soluble factors of Pf-IRBCs contribute to the impedance of BBB integrity in a multistep and multifactorial process.

AB - Background. Central to the pathologic progression of human cerebral malaria (CM) is sequestration of Plasmodium falciparum-infected red blood cells (Pf-IRBCs) to the blood-brain barrier (BBB) endothelium. The molecular interactions between Pf-IRBCs and the BBB endothelium and their implications for barrier function are unclear. Methods. The effects of Pf-IRBCs on the integrity of the BBB were assessed by electrical cell substrate sensing and by transendothelial electrical resistance measurements in an in vitro human BBB model. In addition, Pf-IRBCs were subfractionated and treated with trypsin, artemisinin, or brefeldin A. Results. Pf-IRBCs, but not normal red blood cells, significantly decreased BBB resistance. Subfractionation showed that both membrane-associated and soluble Pf-IRBC factors mediate the decrease in BBB resistance. Trypsin treatment significantly reduced Pf-IRBC binding but not their ability to decrease electrical resistance. Likewise, P. falciparum isolates with increased binding to human brain microvascular endothelial cells did not alter the electrical resistance response. Soluble factors from Pf-IRBC culture supernatant decreased resistance by 50%-70% and precipitated with 40% ammonium sulfate saturation. Brefeldin-A partially blocked the ability of Pf-IRBCs to reduce resistance. Conclusion. The results suggest that, in CM, trypsin-resistant membrane components and soluble factors of Pf-IRBCs contribute to the impedance of BBB integrity in a multistep and multifactorial process.

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