Fungal dysbiosis: immunity and interactions at mucosal barriers

Abstract

Fungi and mammals share a co-evolutionary history and are involved in a complex web of interactions. Studies focused on commensal bacteria suggest that pathological changes in the microbiota, historically known as dysbiosis, are at the root of many inflammatory diseases of non-infectious origin. However, the importance of dysbiosis in the fungal community - the mycobiota - was only recently acknowledged to have a pathological role, as novel findings have suggested that mycobiota disruption can have detrimental effects on host immunity. Fungal dysbiosis and homeostasis are dynamic processes that are probably more common than actual fungal infections, and therefore constantly shape the immune response. In this Review, we summarize specific mycobiota patterns that are associated with fungal dysbiosis, and discuss how mucosal immunity has evolved to distinguish fungal infections from dysbiosis and how it responds to these different conditions. We propose that gut microbiota dysbiosis is a collective feature of complex interactions between prokaryotic and eukaryotic microbial communities that can affect immunity and that can influence health and disease.

Figure 1. The mycobiota during health and in dysbiosis

A) During homeostasis, diverse fungal communities reside all human barrier surfaces during homeostasis, such as the mouth; lung; skin, gut and vagina (left hand side). The pie charts represent the relative abundance of the observed taxa at the phylum and genus levels (inner and outer circles, respectively). Of note, the data for the vagina are estimates that are based on culture-dependent studies, due to a lack of sequencing-based studies related to disease conditions (indicated with an asterisk). ‘Other’ refers to sequences with <5% relative abundance. During diseases, those communities are perturbed (right hand side). Dysbiotic fungal communities are observed in the oral cavity and the vagina of HIV patients; in the lung of cystic fibrosis patients; on the skin of primary immunodeficiency and chronic wounds patients; in the gut of Crohn’s disease patients. B) Factors contributing to fungal dysbiosis at different barrier surfaces. AF, antecubital fossa; HF, hind foot; STAT3, signal transducer and activator of transcription 3.

Figure 2. Examples of mucosal immune responses to fungal infection and dysbiosis

The host barrier surfaces are inhabited by mycobiota. Several sites, such as the skin, lung, oral cavity and the vagina are prone to fungal infections and fungal dysbiosis upon compromised host immunity, whereas the gastrointestinal tract is resistant to fungal infections, but susceptible to fungal dysbiosis. Host mucosal immunity has evolved to distinguish fungal infection from fungal dysbiosis. A) Fungal infection leads to breaches in the epithelial surfaces due to fungal activity, which in turn leads to rapid infiltration of neutrophils and monocytes at the site of infection. The production of cytokines and chemokines by epithelial and innate immune cells leads to further influx and recruitment monocytes, neutrophils and T cells among others. Resident phagocytes such as macrophages and dendritic cells (DCs) recognize and process fungal antigens and promote fungal specific T cell responses and polarization. Innate lymphoid cells (ILC3) can respond directly to fungi or to the inflammatory environment during infection with production of IL-22 and IL-17. Epithelial cells produce antimicrobial peptides that directly affect fungal survival. B) By contrast, fungal dysbiosis is characterized by alterations in the mycobiota composition that might be both the cause and/or consequence of changes in the tissue environment or changes in the intestinal lumen. Fungal dysbiosis can influence both local and systemic immunity through several mechanisms including the modulation of cytokine milieu, the activation of different cell types and the release of metabolites. Fungal dysbiosis in the gut can influence immunity at distant sites such as the lung and contribute to allergy. Intestinal inflammation and breaches of the intestinal epithelial barrier caused by non-fungal triggers can lead to direct exposure to fungal antigens coming from the intestinal lumen and development of systemic IgG and IgA anti-Saccharomyces cerevisiae antibodies (ASCA). Mucosal immunity to gut fungi during dysbiosis is poorly explored and only a few molecules have been studied in this context. At the barrier surfaces, fungi and bacteria can affect each other; thus, microbiota dysbiosis is probably a collective feature of the complex crosstalk between the fungal and bacterial microbiota, and the host. CCR2, CC-chemokine receptor 2; CXCL2, CXC-chemokine ligand 2; IDO1, indoleamine 2,3-dioxygenase 1; IFNγ, interferon-γ; iTreg, induced T regulatory; NK, natural killer; PGE2, prostaglandin E2; TNF, tumour necrosis factor; TH, T helper.

Figure 3. C-type lectin receptor (CLR) recognition and signaling

Fungal polysaccharides are recognized by C type lectin receptors (CLRs) such as macrophage-inducible C-type lectin (MINCLE), dectin 1, dectin 2and dectin 2, resulting in the activation of spleen tyrosine kinase (SYK). The E3 ubiquitin ligase CBLB, which ubiquitylates SYK, regulates antifungal immune responses downstream of dectin 1 and dectin 2. CLRs trigger phagocytosis and respiratory burst (reactive oxygen species production, ROS) through the SYK-dependent phospholipase Cγ2 (PLCγ2) activation of NADPH phagocyte oxidase and killing of fungi. Engagement of protein kinase Cδ (PKCδ) followed by activation of the CARD9–BCL-10–MALT1 complex leads to nuclear factor-κB (NF κB) activation, caspase 1 activity and the production of cytokines and other mediators that are crucial for host defence against fungi. Dectin-SYK induction promotes IRF5-dependent IFN-γ production. CD23 is a newly identified CLR that is upregulated upon dectin 1 activation and that leads to the production of ROS. The signaling events downstream of CD23 and the mannose receptor (MR) remain unknown (indicated by a question mark). ASC, apoptosis- associated speck-like protein containing a CARD; CARD9, caspase recruitment domain-containing protein 9; CBLB, casitas B-lineage lymphoma-b; COX2, cyclooxygenase 2;FcRγ, Fc receptor common γ-chain; IFNβ, interferon-β; IRF5, interferon-regulatory factor 5; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; NFAT, nuclear factor of activated T cells; NLRP3, NOD, LRR and Pyrin domain-containing protein 3; PGE2, prostaglandin E2; TNF, tumor necrosis factor.