Plasmodium falciparum-infected erythrocytes induce NF-kappaB regulated inflammatory pathways in human cerebral endothelium.
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 kappaB (NF-kappaB) activation cascade. The proinflammatory NF-kappaB 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.
Tripathi
Abhai K
AK
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Sha
Wei
W
Shulaev
Vladimir
V
Stins
Monique F
MF
Sullivan
David J
DJ
D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000469:parasitology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000469:parasitology / Q000473:pathology / Q000502:physiology; D004912:Erythrocytes / Q000469:parasitology / Q000502:physiology; D055106:Genome-Wide Association Study; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology; D016779:Malaria, Cerebral / Q000235:genetics* / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology*; D016778:Malaria, Falciparum / Q000235:genetics* / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology*; D008954:Models, Biological; D016328:NF-kappa B / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D015398:Signal Transduction
D016328:NF-kappa B