Candida albicans-induzierte Genexpression in primären ... - OPUS

8 Summary
Endothelial cells (ECs) actively participate in the innate defence against microbial
pathogens. Under unfavourable conditions defence reactions can even turn into lifethreatening
responses resulting in sepsis. Here the so far largely unknown EC
reaction patterns to Candida albicans were studied. C. albicans is a facultative
human pathogenic fungus and a major cause of lethality in septic patients.
Oligonucleotide microarray analysis revealed 56 genes that were transcriptionally upregulated
and 69 that were suppressed upon exposure of ECs to C. albicans. A
major portion of these genes is involved in defence mechanisms of the innate
immune system with a high representation of genes serving the recruitment of
neutrophils to sites of infection. Further examination of candidate signalling cascades
established a central role of the proinflammatory NF-κB pathway in the regulation of
the Candida-modulated transcriptome of ECs. It was shown that the NF-κB signalling
pathway becomes activated at various levels. In addition, expression of a dominant
negative mutant of a NF-κB signalling pathway compound blocked the Candidainduced
κB-dependent gene expression. Using a pharmacological approach the
stress-activated p38 mitogen-activated protein (MAP) kinase pathway was identified
as a second major regulatory pathway which critically contributes to the regulation of
selected Candida target genes such as CXCL8/IL-8. Candida-induced NF-κB
activation is mediated independently of Toll-like receptors (TLR) 2 and 4 that
commonly have been implicated with microbial pattern recognition. Nevertheless,
knock-down of the adapter molecule MyD88 and the essential downstream kinase of
TLR-, IL-1R- and IL-18R-signalling, IRAK1, suggested that recognition and signalling
via a TLR apart from TLR2/TLR4 is crucial for Candida-induced gene expression in
primary ECs. Finally, RNAi experiments indicate that most likely TLR3 represents this
receptor.
These data provide the first comprehensive analysis of endothelial gene responses
to Candida albicans and present novel insights into the complex signalling patterns
triggered by this important pathogen.
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