IL-1α released from oral epithelial cells upon candidalysin exposure initiates an early innate epithelial response

Abstract

Candida albicans is a commensal fungus that predominantly resides on mucosal surfaces and can cause lethal systemic infection when the host defense is compromised. Candidalysin is a cytolytic peptide toxin produced by C. albicans hyphae that is essential for mucosal tissue damage and is believed to contribute to the establishment of systemic infection and mortality. Candidalysin is also required for the epithelial innate response in which proinflammatory cytokines and chemokines are produced and neutrophil recruitment is initiated. It was recently reported that epidermal growth factor receptor (EGFR) was essential for the candidalysin-triggered epithelial response. The present study identified interleukin (IL)-1α as another component of candidalysin-mediated initial epithelial activation. We found that human oral epithelial cells released IL-1α rapidly after candidalysin exposure. Blockade of IL-1α/IL-1 receptor (IL-1R) signaling in candidalysin-exposed cells resulted in decreased phosphorylation of IκBα, decreased induction of IκBζ, and decreased production of granulocyte macrophage-colony stimulating factor and IL-8. Expression of c-Fos, which is induced downstream of EGFR signaling in candidalysin-treated cells, is less affected by IL-1R blockade. Inversely, blockade of EGFR signaling does not affect candidalysin-mediated phosphorylation of IκBα and induction of IκBζ, suggesting that independent signaling pathways contribute to the induction of NF-κB and c-Fos downstream of candidalysin pore formation site. Consistently, antibody inhibition of both EGFR and IL-1R enhanced the suppressive effect of cytokine production in candidalysin-treated cells. Thus, we identified the immediate release of IL-1α and its synergistic role with EGFR ligands on the initial activation of oral epithelial cells in response to candidalysin.

Candida albicans—The Virulence Factors and Clinical Manifestations of Infection

“…Polymorphism implies the transition of C. albicans from a commensal form to a pathological one, which depends on changes in the environment in which it is located. It is characterized by the morphological transition of blastospores into hyphae, and the transitional form between are pseudohyphae [ 18 , 19 ]. Asexual spores, chlamydospores, are formed under adverse conditions and are three to four times bigger than blastospores [ 12 ].…”

“…It has been shown that a hypha-specific toxin, candidalysin, is crucial for the occurrence of candidiasis [ 19 , 27 ]. Candidalysin is a cytolytic 31-amino acid α-helical amphipathic peptide [ 19 , 28 ]. It is produced by the C. albicans hyphae, and it is crucial in damaging the host cells.…”

“…The most important is cAMP-dependent protein kinase A (cyclic adenosine monophosphate PKA) [3,26]. It has been shown that a hypha-specific toxin, candidalysin, is crucial for the occurrence of candidiasis [19,27]. Candidalysin is a cytolytic 31-amino acid α-helical amphipathic peptide [19,28].…”

Divergent EGFR/MAPK-Mediated Immune Responses to Clinical Candida Pathogens in Vulvovaginal Candidiasis

“…The heat map shows most up-regulated genes including CSF2, CSF3, FOS, IL-1, GADD45 (Figure 1A). Since numerous studies have shown that phosphorylation of EGFR and MAPK signaling are critical for the activation of oral epithelial cells in response to C. albicans (20,25,41,42), we next investigated the phosphorylation of EGFR, MAPK (p38, ERK1/2, JNK), c-Fos and NF-kB(p65) in VK2/E6E7 vaginal epithelial cells at different time points post co-culture with SC5314 at 5 of multiplicity of infection (MOI). The phosphorylation level of EGFR on tyrosine residue 1068 immediately increased after1 h post infection and sharply increased at 4-6 h and then remained high levels until 10 h post infection (Figure 1B).…”

LncRNA: A Potential Target for Host-Directed Therapy of Candida Infection

“…The MAPK1 and Fos signaling pathways in epithelial cells can be activated by Candida hyphae, while NF-κB-signaling pathways can be activated in a TLR4-dependent way by both Candida hyphae and yeast [ 69 ]. The release of IL-1α upon candidalysin exposure and its ligand epidermal growth factor receptor could also play a synergistic role in initiating an early innate epithelial response [ 70 ]. Under the stimulation of these signals, epithelial cells may secrete AMPs, including β-defensins, cathelicidin LL-37, and S-100 protein [ 71 ], suggesting epithelial cells exert a direct antifungal effect.…”