A Biphasic Innate Immune MAPK Response Discriminates between the Yeast and Hyphal Forms of Candida albicans in Epithelial Cells

Abstract

SummaryDiscriminating between commensal and pathogenic states of opportunistic pathogens is critical for host mucosal defense and homeostasis. The opportunistic human fungal pathogen Candida albicans is also a constituent of the normal oral flora and grows either as yeasts or hyphae. We demonstrate that oral epithelial cells orchestrate an innate response to C. albicans via NF-κB and a biphasic MAPK response. Activation of NF-κB and the first MAPK phase, constituting c-Jun activation, is independent of morphology and due to fungal cell wall recognition. Activation of the second MAPK phase, constituting MKP1 and c-Fos activation, is dependent upon hypha formation and fungal burdens and correlates with proinflammatory responses. Such biphasic response may allow epithelial tissues to remain quiescent under low fungal burdens while responding specifically and strongly to damage-inducing hyphae when burdens increase. MAPK/MKP1/c-Fos activation may represent a “danger response” pathway that is critical for identifying and responding to the pathogenic switch of commensal microbes.

Candida albicansdimorphism as a therapeutic target

“…Activation of NF-kB and c-Jun Yes Yes [58] Activation of c-Fos and MKP1 No Yes, dose dependent [58] Proinflammatory cytokines No Yes, dose dependent [58] Review Candida albicans dimorphism as a therapeutic target competition assays, Keppler-Ross et al observed higher uptake of yeast than hyphae by macrophages [64]. Thus, more research is needed to fully elucidate the role of fungal morphology in the interaction with macrophages.…”

“…So how do epithelial cells discriminate between C. albicans colonization and infection? Recently, Moyes et al have begun to shed light on the molecular mechanisms for this discriminatory process, and their data indicates that both the morphological form of C. albicans and the fungal burden are crucial [58]. Oral epithelial cells appear to orchestrate responses to C. albicans via NF-kB and a biphasic MAPK signaling mechanism.…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…17 MAPK pathway is revealed to identify the invasive C. albicans, while NF-kB pathway is in charge of anti-fungal responses. 17 The activation of the pathways would lead to series of biological effects, and the effects can be divided into 2 categories. One is to activate weak but direct anti-fungal defense by secreting antimicrobial peptides (such as b-defensins and LL-37).…”

“…MAPK/MKP1/c-Fos activation may be critical for identifying and responding to the pathogenic switch of commensal microbes. 17 An open question is what exact PAMPs on different forms of C. albicans are presented to immune cells. To date, this question is partly answered.…”

“…8,16 In accordance, the yeast form is tolerated by the host immune system, while the invasive hyphal form may induce robust immune responses. 17 The cell wall of C. albicans provides targets for host immune system to sense the pathogen and trigger immune response. The cell wall is a matrix of 3 components: chitin, glucans, and mannans.…”