Candida albicans yeast and hyphae are discriminated by MAPK signaling in vaginal epithelial cells.

David L Moyes,Manohursingh Runglall,Celia Murciano,Ayesha Islam,Julian R Naglik,Selvam Thavaraj,Alexandra Carolyn Brand

doi:10.1371/journal.pone.0026580

Abstract

We previously reported that a bi-phasic innate immune MAPK response, constituting activation of the mitogen-activated protein kinase (MAPK) phosphatase MKP1 and c-Fos transcription factor, discriminates between the yeast and hyphal forms of Candida albicans in oral epithelial cells (ECs). Since the vast majority of mucosal Candida infections are vaginal, we sought to determine whether a similar bi-phasic MAPK-based immune response was activated by C. albicans in vaginal ECs. Here, we demonstrate that vaginal ECs orchestrate an innate response to C. albicans via NF-κB and MAPK signaling pathways. However, unlike in oral ECs, the first MAPK response, defined by c-Jun transcription factor activation, is delayed until 2 h in vaginal ECs but is still independent of hypha formation. The ‘second’ or ‘late’ MAPK response, constituting MKP1 and c-Fos transcription factor activation, is identical to oral ECs and is dependent upon both hypha formation and fungal burdens. NF-κB activation is immediate but independent of morphology. Furthermore, the proinflammatory response in vaginal ECs is different to oral ECs, with an absence of G-CSF and CCL20 and low level IL-6 production. Therefore, differences exist in how C. albicans activates signaling mechanisms in oral and vaginal ECs; however, the activation of MAPK-based pathways that discriminate between yeast and hyphal forms is retained between these mucosal sites. We conclude that this MAPK-based signaling pathway is a common mechanism enabling different human epithelial tissues to orchestrate innate immune responses specifically against C. albicans hyphae.

Highlights

The mucosal epithelium is of immense importance in host defense and immune surveillance, as it is the initial tissue encountered by the majority of infecting microorganisms
We report that differences exist in how vaginal epithelial cells (ECs) initially respond to C. albicans as compared with oral ECs, but that a near-identical mitogen-activated protein kinase (MAPK)-based mechanism discriminates between the yeast and hyphal form of C. albicans
We propose that this MAPK/MKP1/c-Fos-based signaling system identifies a common mechanism playing a central role in enabling different human epithelial tissues to recognize C. albicans hyphae and initiate innate immune responses

Summary

Introduction

The mucosal epithelium is of immense importance in host defense and immune surveillance, as it is the initial tissue encountered by the majority of infecting microorganisms. Vaginal epithelium provides a physical barrier, which recognizes commensal and pathogenic microbes, as well as regulating the influx of immune cells to prevent inflammatory tissue destruction. This specialized interaction between microbes, epithelial cells (ECs) and local immune cells results in either a degree of mutualism between microbe and host, as in the case of commensal microbes, or a breach of the mucosal barrier and subsequent cell injury, as in the case of pathogenic microbes. The polymorphic fungus Candida albicans is one such opportunistic microbe, being a constituent of the normal vaginal microbiota but commonly causing mucosal disease in healthy women of fertile age [1]

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