Characterisation of EGFR signalling events induced by Candida albicans and the cytolytic peptide toxin, candidalysin

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Fungal infections contribute significantly to morbidity and mortality in humans. Of these, the Candida species are the most predominant species causing superficial to life threatening infections in humans, with Candida albicans (C. albicans) the most prevalent. Though normally a harmless member of the oral, vaginal and gut microbiota, disturbances caused by environmental cues and a compromised immune system results in overgrowth of C. albicans and the superficial infection of mucous membranes. Such superficial mucosal infections affect millions of individuals annually, with C. albicans also causing life threatening invasive infections in those who are immunocompromised, with mortality rates exceeding 40%.As a polymorphic fungus, the transition between yeast and hypha is critical for pathogenesis. At mucosal surfaces, the growth of C. albicans as unicellular yeast is generally associated with commensalism, while hyphal growth is associated with invasion, damage of epithelial cells, and immune induction. During infection, C. albicans hyphae secrete candidalysin, a cytolytic peptide that is critical for pathogenesis at mucosal surfaces. Candidalysin secretion is closely associated with epithelial damage, as well as the activation of a MAPK-based innate signalling mechanism that is crucial in producing inflammatory mediators and cell survival signals in epithelial cells. This activation of epithelial immunity is mediated by the epidermal growth factor receptor (EGFR); however, early EGFR signalling events in response to this toxin, and thus C. albicans, remain unknown.This study investigated the early molecular events of EGFR and adaptor activation in response to candidalysin and C. albicans. The results show that infection of oral epithelial cells with C. albicans or stimulation with candidalysin induces activation of Gab1, Grb2, Shc, Shp2 and cCbl adaptors, with their activation reliant on candidalysin-induced calcium flux and activation of matrix metalloproteinases (MMPs). Adaptors activation mediated the release of IL-1α, IL-1β, IL-6, GM-CSF and G-CSF via ERK1/2-MAPK from oral epithelial cells, with Gab1, Grb2 and Shp2 adaptors being the main drivers of ERK1/2 signalling and cytokine responses.Overall, this study identifies the key signalling adaptor molecules activated downstream of EGFR in response to C. albicans, with vital roles for Gab1, Grb2 and Shp2 in mediating epithelial immunity in response to candidalysin.
Date of Award1 Jul 2021
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJulian Naglik (Supervisor) & Dave Moyes (Supervisor)

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