Biology subjects

Hepworth, O.

Publications and source records attributed to Hepworth, O..

3 recordsLinked to original sources

bioRxiv2025

Extracellular vesicles from diverse fungal pathogens induce species-specific and endocytosis-dependent immunomodulation

Microbial pathogens generate extracellular vesicles (EVs) for intercellular communication and quorum sensing. Microbial EVs also induce inflammatory pathways within host innate immune cells. We previously demonstrated that EVs secreted by Candida albicans trigger type I interferon signaling in host cells specifically via the cGAS-STING innate immune signaling pathway. Here, we show that despite sharing similar properties of morphology and internal DNA content, the interactions between EVs and the innate immune system differ according to the parental fungal species. EVs secreted by C. albicans, Saccharomyces cerevisiae, Cryptococcus neoformans, and Aspergillus fumigatus are endocytosed at different rates by murine macrophages triggering varied cytokine responses, innate immune signaling, and subsequent immune cell recruitment. Notably, cell wall constituents that decorate C. neoformans and A. fumigatus EVs inhibit efficient internalization by macrophages and dampen innate immune activation. Our data uncover the transcriptional and functional consequences of the internalization of diverse fungal EVs by immune cells and reveal novel insights into the early innate immune response to distinct clinically significant fungal pathogens.

microbiology↗

bioRxiv2023

EGR1 regulates oral epithelial cell responses to Candida albicans via the EGFR- ERK1/2 pathway

Candida albicans is a fungal pathobiont colonising mucosal surfaces of the human body, including the oral cavity. Under certain predisposing conditions, C. albicans invades 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 during C. albicans colonisation 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 to C. albicans. EGR1 expression increases in OECs when exposed to C. albicans independently of fungal viability, morphology, or candidalysin release, suggesting EGR1 is involved in the fundamental recognition of C. albicans, rather than in response to invasion or pathogenesis. Upregulation of EGR1 is mediated by EGFR via Raf1, ERK1/2 and NF-{kappa}B signalling but not PI3K/mTOR signalling. Notably, EGR1 mRNA silencing impacts on anti-C. albicans immunity, reducing GM-CSF, IL-1 and IL-1{beta} 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 by C. albicans and elucidate the regulation circuit of this transcription factor after contact.

immunology↗

bioRxiv2022

EGFR-MAPK adaptor proteins mediate the epithelial response to Candida albicans via the cytolytic peptide toxin, candidalysin

Candida albicans (C. albicans) is a dimorphic human fungal pathogen that can cause severe oropharyngeal candidiasis (OPC, oral thrush) in susceptible hosts. During invasive infection, C. albicans hyphae invade oral epithelial cells (OECs) and secrete candidalysin, a pore-forming cytolytic peptide that is required for fungal pathogenesis at mucosal surfaces. Candidalysin induces cell damage and activates multiple MAPK-based innate signaling events that collectively drive the production of downstream inflammatory mediators. The activities of candidalysin are also dependent on the epidermal growth factor receptor (EGFR), but how these signals are integrated is undefined. Here, we identified five essential adaptor proteins as key mediators of the epithelial response to C. albicans infection on cultured OECs, including growth factor receptor bound protein 2 (Grb2), Grb2-associated-binding protein 1 (Gab1), Src homology and collagen (Shc), SH2 containing protein tyrosine phosphatase-2 (Shp2) and casitas B-lineage lymphoma (c-Cbl). All these signaling effectors were inducibly phosphorylated in response to C. albicans, in a candidalysin-dependent mechanism but additionally required EGFR phosphorylation, matrix metalloproteinases (MMPs) and cellular calcium flux. Of these, Gab1, Grb2 and Shp2 were the dominant drivers of ERK1/2 signaling and production of downstream cytokines. Together, these results identify the key adaptor proteins that drive EGFR signaling mechanisms, which determine oral epithelial responses to C. albicans.

microbiology↗