Over the last decades, fungal infections have emerged as a growing threat to human health. Although the human body is at potential risk, various body sites host several commensal fungal species, including Candida albicans. In healthy individuals, C. albicans colonizes different mucosal surfaces without causing harm, while under diverse circumstances the fungus can proliferate and cause disease. In this context, the understanding of host⁻C. albicans interactions in health and during infection may lead to novel therapeutic approaches. Importantly, host cells express pattern recognition receptors (PRRs), which sense conserved fungal structures and orchestrate innate immune responses. Herein, important findings on the topic of the recognition of C. albicans at host barrier sites are discussed. This review briefly summarizes the importance and functions of myeloid PRRs, reviews the fungal recognition and biology of stromal cells, and highlights important C. albicans virulence attributes during site-specific proliferation and invasion.

The fungal microbiota (mycobiota) is an integral part of the microbial community colonizing the body surfaces and is involved in many key aspects of human physiology, while an imbalance of the fungal communities, termed fungal dysbiosis, has been described in pathologies ranging from infections to inflammatory bowel disease. Commensal organisms, such as the fungus Candida albicans, induce antigen-specific immune responses that maintain immune homeostasis. Adaptive immune mechanisms are vital in this process, while deficiencies in adaptive immunity are linked to fungal infections. We start to understand the mechanisms by which a shift in mycobiota composition, in particular in C. albicans abundance, is linked to immunopathological conditions. This review discusses the mechanisms that ensure continuous immunosurveillance of C. albicans during mucosal colonization, how these protective adaptive immune responses can also promote immunopathology, and highlight therapeutic advances against C. albicans-associated disease.

The fungus Candida albicans colonizes the oral mucosal surface of 30-70% of healthy individuals. Due to local or systemic immunosuppression, this commensal fungus is able to proliferate resulting in oral disease, called oropharyngeal candidiasis (OPC). However, in healthy individuals C. albicans causes no harm. Unlike humans mice do not host C. albicans in their mycobiome. Thus, oral fungal challenge generates an acute immune response in a naive host. Therefore, we utilized C. albicans clinical isolates which are able to persist in the oral cavity without causing disease to analyze adaptive responses to oral fungal commensalism. We performed RNA sequencing to determine the transcriptional host response landscape during C. albicans colonization. Pathway analysis revealed an upregulation of adaptive host responses due to C. albicans oral persistence, including the upregulation of the immune network for IgA production. Fungal colonization increased cross-specific IgA levels in the saliva and the tongue, and IgA⁺ cells migrated to foci of fungal colonization. Binding of IgA prevented fungal epithelial adhesion and invasion resulting in a dampened proinflammatory epithelial response. Besides CD19⁺ CD138^- B cells, plasmablasts, and plasma cells were enriched in the tongue of mice colonized with C. albicans suggesting a potential role of B lymphocytes during oral fungal colonization. B cell deficiency increased the oral fungal load without causing severe OPC. Thus, in the oral cavity B lymphocytes contribute to control commensal C. albicans carriage by secreting IgA at foci of colonization thereby preventing fungal dysbiosis.

Mucosal epithelial tissues are exposed to high numbers of microbes, including commensal fungi, and are able to distinguish between those that are avirulent and those that cause disease. Epithelial cells have evolved multiple mechanisms to defend against colonization and invasion by Candida species. The interplay between mucosal epithelial tissues and immune cells is key for control and clearance of fungal infections. Our understanding of the mucosal innate host defense system has expanded recently with new studies bringing to light the importance of epithelial cell responses, innate T cells, neutrophils, and other phagocytes during Candida infections. Epithelial tissues release cytokines, host defense peptides, and alarmins during Candida invasion that act in concert to limit fungal proliferation and recruit immune effector cells. The innate T cell/IL-17 axis and recruitment of neutrophils are of central importance in controlling mucosal fungal infections. Here, we review current knowledge of the innate immunity at sites of mucosal Candida infection, with a focus on infections caused by C. albicans.

Oral epithelial cells discriminate between pathogenic and non-pathogenic stimuli, and only induce an inflammatory response when they are exposed to high levels of a potentially harmful microorganism. The pattern recognition receptors (PRRs) in epithelial cells that mediate this differential response are poorly understood. Here, we demonstrate that the ephrin type-A receptor 2 (EphA2) is an oral epithelial cell PRR that binds to exposed β-glucans on the surface of the fungal pathogen Candida albicans. Binding of C. albicans to EphA2 on oral epithelial cells activates signal transducer and activator of transcription 3 and mitogen-activated protein kinase signalling in an inoculum-dependent manner, and is required for induction of a proinflammatory and antifungal response. EphA2 ^-/- mice have impaired inflammatory responses and reduced interleukin-17 signalling during oropharyngeal candidiasis, resulting in more severe disease. Our study reveals that EphA2 functions as a PRR for β-glucans that senses epithelial cell fungal burden and is required for the maximal mucosal inflammatory response to C. albicans.

In the version of this Article originally published, the authors described the ANT compound used in their study as 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-hydroxybenzoic acid (ANT). The authors now wish to clarify that the ANT compound used was actually a 2,5-dimethylpyrrolyl benzoic acid derivative¹ that has been shown to inhibit not only the enzymatic activity of EphA2, but also several unrelated enzymes². The description of the compound in the Article has now been changed to 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-hydroxybenzoic acid derivative (ANT) to reflect this.

The capacity of Candida albicans to switch reversibly between the white phenotype and the opaque phenotype is required for the fungus to mate. It also influences virulence during hematogenously disseminated candidiasis. We investigated the roles of the mating type loci (MTL) and white-opaque switching in the capacity of C. albicans to mate in the oropharynx and cause oropharyngeal candidiasis (OPC). When immunosuppressed mice were orally infected with mating-competent opaque a/a and α/α cells either alone or mixed with white cells, no detectable mating occurred, indicating that the mating frequency was less than 1.6 × 10^-6 Opaque cells were also highly attenuated in virulence; they either were cleared from the oropharynx or switched to the white phenotype during OPC. Although there were strain-to-strain differences in the virulence of white cells, they were consistently more virulent than opaque cells. In vitro studies indicated that relative to white cells, opaque cells had decreased capacity to invade and damage oral epithelial cells. The reduced invasion of at least one opaque strain was due to reduced surface expression of the Als3 invasin and inability to activate the epidermal growth factor receptor, which is required to stimulate the epithelial cell endocytic machinery. These results suggest that mating is a rare event during OPC because opaque cells have reduced capacity to invade and damage the epithelial cells of the oral mucosa.

Oropharyngeal candidiasis (OPC), caused predominantly by Candida albicans, is a prevalent infection in patients with advanced AIDS, defects in Th17 immunity, and head and neck cancer. A characteristic feature of OPC is fungal invasion of the oral epithelial cells. One mechanism by which C. albicans hyphae can invade oral epithelial cells is by expressing the Als3 and Ssa1 invasins that interact with the epidermal growth factor receptor (EGFR) on epithelial cells and stimulate endocytosis of the organism. However, the signaling pathways that function downstream of EGFR and mediate C. albicans endocytosis are poorly defined. Here, we report that C. albicans infection activates the aryl hydrocarbon receptor (AhR), leading to activation of Src family kinases (SFKs), which in turn phosphorylate EGFR and induce endocytosis of the fungus. Furthermore, treatment of oral epithelial cells with interferon gamma inhibits fungal endocytosis by inducing the synthesis of kynurenines, which cause prolonged activation of AhR and SFKs, thereby interfering with C. albicans-induced EGFR signaling. Treatment of both immunosuppressed and immunocompetent mice with an AhR inhibitor decreases phosphorylation of SFKs and EGFR in the oral mucosa, reduces fungal invasion, and lessens the severity of OPC. Thus, our data indicate that AhR plays a central role in governing the pathogenic interactions of C. albicans with oral epithelial cells during OPC and suggest that this receptor is a potential therapeutic target.IMPORTANCE OPC is caused predominantly by the fungus C. albicans, which can invade the oral epithelium by several mechanisms. One of these mechanisms is induced endocytosis, which is stimulated when fungal invasins bind to epithelial cell receptors such as EGFR. Receptor binding causes rearrangement of epithelial cell microfilaments, leading to the formation of pseudopods that engulf the fungus and pull it into the epithelial cell. We discovered AhR acts via SFKs to phosphorylate EGFR and induce the endocytosis of C. albicans Our finding that a small molecule inhibitor of AhR ameliorates OPC in mice suggests that a strategy of targeting host cell signaling pathways that govern epithelial cell endocytosis of C. albicans holds promise as a new approach to preventing or treating OPC.