Plasmodium falciparum-infected erythrocytes induce NF-κB regulated inflammatory pathways in human cerebral endothelium

Abhai Tripathi, Wei Sha, Vladimir Shulaev, Monique Stins, David J Sullivan

Research output: Contribution to journalArticle

Abstract

Cerebral malaria is a severe multifactorial condition associated with the interaction of high numbers of infected erythrocytes to human brain endothelium without invasion into the brain. The result is coma and seizures with death in more than 20% of cases. Because the brain endothelium is at the interface of these processes, we investigated the global gene responses of human brain endothelium after the interaction with Plasmodium falciparum-infected erythrocytes with either high- or low-binding phenotypes. The most significantly up-regulated transcripts were found in gene ontology groups comprising the immune response, apoptosis and antiapoptosis, inflammatory response, cell-cell signaling, and signal transduction and nuclear factor κB (NF-κB) activation cascade. The proinflammatory NF-κB pathway was central to the regulation of the P falciparum-modulated endothelium transcriptome. The proinflammatory molecules, for example, CCL20, CXCL1, CXCL2, IL-6, and IL-8, were increased more than 100-fold, suggesting an important role of blood-brain barrier (BBB) endothelium in the innate defense during P falciparum-infected erythrocyte (Pf-IRBC) sequestration. However, some of these diffusible molecules could have reversible effects on brain tissue and thus on neurologic function. The inflammatory pathways were validated by direct measurement of proteins in brain endothelial supernatants. This study delineates the strong inflammatory component of human brain endothelium contributing to cerebral malaria.

Original languageEnglish (US)
Pages (from-to)4243-4252
Number of pages10
JournalBlood
Volume114
Issue number19
DOIs
StatePublished - Nov 5 2009

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Plasmodium falciparum
Endothelium
Brain
Erythrocytes
Cerebral Malaria
Genes
Cell signaling
Signal transduction
Gene Ontology
Erythrocyte Count
Molecules
Coma
Blood-Brain Barrier
Interleukin-8
Transcriptome
Nervous System
Ontology
Interleukin-6
Signal Transduction
Seizures

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Plasmodium falciparum-infected erythrocytes induce NF-κB regulated inflammatory pathways in human cerebral endothelium. / Tripathi, Abhai; Sha, Wei; Shulaev, Vladimir; Stins, Monique; Sullivan, David J.

In: Blood, Vol. 114, No. 19, 05.11.2009, p. 4243-4252.

Research output: Contribution to journalArticle

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