The mycobiota: interactions between commensal fungi and the host immune system

Abstract

The body is host to a wide variety of microbial communities from which the immune system protects us and that are important for the normal development of the immune system and for the maintenance of healthy tissues and physiological processes. Investigators have mostly focused on the bacterial members of these communities, but fungi are increasingly being recognized to have a role in defining these communities and to interact with immune cells. In this Review, we discuss what is currently known about the makeup of fungal communities in the body and the features of the immune system that are particularly important for interacting with fungi at these sites.

Figure 1. The human mycobiota

Complex populations of fungi have been found associated with all mucosal surfaces and the skin on the healthy human body. The pie charts indicate the relative proportions of fungal genera reported in representative fungal deep sequencing studies. The legend indicates particularly common fungi associated with the respective sites. Mucosal surfaces tend to be more diverse compared to skin. Healthy lung, as in the reported study, likely reflects largely environmental fungi, and are mostly not included in the legend. “Others” in the legend refers to sequences representing less than 1% of the total recovered sequences at each site. “Uncultured” in the legend refers to sequences identified in GenBank as fungal, but of uncharacterized origin. Pie charts were derived from the following studies: Oral, Lung, Colon, Vagina, Skin.

Figure 2. Immune receptors and signalling pathways involved in recognition of fungi

Innate immune cells utilize a wide variety of membrane-bound and soluble receptors to recognize fungi. Membrane-bound receptors such as lectin receptors (that recognize fungal polysaccharides), Toll-like receptors (TLRs), and scavenger receptor family members can directly recognize a wide variety of fungi or soluble products released from fungi. These receptors trigger phagocytosis, respiratory burst via the NADPH phagocyte oxidase, and killing of fungi, as well as trigger intracellular signaling via pathways leading to activation of transcription factors such as NF-κB that mediate production of many inflammatory cytokines and chemokines that are important for host defence against fungi. Fungi may also be recognized by soluble receptors such as the mannose-binding lectin (MBL) that can direct complement activation for killing and release of inflammatory mediators as well as opsonize fungi for recognition by additional membrane-bound receptors such as complement receptors.

Figure 3. Mucosal immune responses involved in interaction with fungi at different sites

Different body sites are colonized by diverse groups of fungi, and the communities are shaped by the characteristics of each environment. Epithelial cells at these surfaces produce antimicrobial peptides that directly modulate fungal survival. In response to fungi, cytokines and chemokines that recruit immune cells are also produced. Fungi may also be directly sensed by dendritic cells and γδT cells at epithelial surfaces. When epithelial barriers are breached, macrophages, dendritic cells, and neutrophils kill fungi and produce cytokines that promote adaptive immune responses. Innate lymphoid cells may also respond directly to fungi by producing cytokines. Genetic studies in humans have revealed proteins (indicated in red) that are particularly important for antifungal defence and implicate a crucial role for the IL-17 pathway in this process.