| Autor: |
Nikou, Spyridoula-Angeliki, Zhou, Chunsheng, Griffiths, James S., Kotowicz, Natalia K., Coleman, Bianca M., Green, Mary J., Moyes, David L., Gaffen, Sarah L., Naglik, Julian R., Parker, Peter J. |
| Předmět: |
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| Zdroj: |
Science Signaling; 4/5/2022, Vol. 15 Issue 728, p1-16, 16p |
| Abstrakt: |
The fungal pathogen Candida albicans secretes the peptide toxin candidalysin, which damages epithelial cells and drives an innate inflammatory response mediated by the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) pathways and the transcription factor c-Fos. In cultured oral epithelial cells, candidalysin activated the MAPK p38, which resulted in heat shock protein 27 (Hsp27) activation, IL-6 release, and EGFR phosphorylation without affecting the induction of c-Fos. p38 activation was not triggered by EGFR but by two nonredundant pathways involving MAPK kinases (MKKs) and the kinase Src, which differentially controlled p38 signaling outputs. Whereas MKKs mainly promoted p38-dependent release of IL-6, Src promoted p38-mediated phosphorylation of EGFR in a ligand-independent fashion. In parallel, candidalysin also activated the EGFR-ERK pathway in a ligand-dependent manner, resulting in c-Fos activation and release of the neutrophil-activating chemokines G-CSF and GM-CSF. In mice, early clearance events of oral C. albicans infection required p38 but not c-Fos. These findings delineate how candidalysin activates the pathways downstream of the MAPKs p38 and ERK that differentially contribute to immune activation during C. albicans infection. MAPK pathways in Candida infection: Candidalysin, a toxin secreted by the opportunistic fungal pathogen Candida albicans, induces inflammation by stimulating EGFR signaling and several MAPK pathways in host cells. Nikou et al. found that stimulation of human oral epithelial cells with candidalysin induced distinct host cell responses mediated by pathways downstream of the MAPKs ERK and p38. Depending on the activating stimulus, p38 promoted the release of the inflammatory cytokine IL-6 or the phosphorylation of EGFR in a ligand-independent manner. Ligand-dependent EGFR signaling promoted the release of neutrophil-stimulating cytokines through ERK and the transcription factor c-Fos. In mice, p38, but not c-Fos, was required for early clearance of the pathogen. Thus, different MAPK pathways mediate discrete host cell responses to candidalysin and Candida infection. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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