EGR1 regulates oral epithelial cell responses toCandida albicansvia the EGFR- ERK1/2 pathway

Abstract

ABSTRACTCandida albicansis a fungal pathobiont colonising mucosal surfaces of the human body, including the oral cavity. Under certain predisposing conditions,C. albicansinvades mucosal tissues activating EGFR-MAPK signalling pathways in epithelial cells via the action of its peptide toxin candidalysin. However, our knowledge of the epithelial mechanisms involved duringC. albicanscolonisation is rudimentary. Here, we describe the role of the transcription factor early growth response protein 1 (EGR1) in human oral epithelial cells (OECs) in response toC. albicans. EGR1 expression increases in OECs when exposed toC. albicansindependently of fungal viability, morphology, or candidalysin release, suggesting EGR1 is involved in the fundamental recognition ofC. albicans, rather than in response to invasion or ‘pathogenesis’. Upregulation of EGR1 is mediated by EGFR via Raf1, ERK1/2 and NF-κB signalling but not PI3K/mTOR signalling. Notably, EGR1 mRNA silencing impacts on anti-C. albicansimmunity, reducing GM-CSF, IL-1α and IL-1β release, and increasing IL-6 and IL-8 production. These findings identify an important role for EGR1 in priming epithelial cells to respond to subsequent invasive infection byC. albicansand elucidate the regulation circuit of this transcription factor after contact.