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

Key Points

  • The fungal microbiota, or 'mycobiota', is an understudied component of the microflora that is found on all mucosal surfaces and on the skin.

  • Like other microorganisms, fungi interact with the immune system at these surfaces in ways that are important both for host defence and for regulating the immune system.

  • Investigators who study the mycobiota face both biological and bioinformatic challenges.

  • The study of human genetic disorders and genetic polymorphisms teaches us about the mechanisms by which commensal and pathogenic fungi interact with the 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.

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Figure 1: The human mycobiota.
Figure 2: Immune receptors and signalling pathways involved in recognition of fungi.
Figure 3: Mucosal immune responses involved in interacting with fungi at different body sites.

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Acknowledgements

The authors' work relating to this manuscript was funded by the US National Institutes of Health (grant DK098310 to I.D.I. and DK093426 to D.M.U.), as well as the Crohn's and Colitis Foundation of America.

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Correspondence to David M. Underhill or Iliyan D. Iliev.

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Glossary

Inflammatory bowel disease

(IBD). A group of chronic inflammatory conditions that affect the large and small intestine. The major types are Crohn's disease and ulcerative colitis.

Dysbiosis

A term that was originally coined by the 1908 Nobel laureate Eli Metchnikoff to refer to pathogenic alterations of the bacterial microflora in the gut. Now used more generally to refer to any microbial imbalance in or on the body at sites including the gastrointestinal tract, the skin and exposed mucosal surfaces such as the lungs, vagina or mouth.

Shotgun sequencing

A sequencing approach in which a complex pool of DNA is broken up into random small segments that are sequenced en masse. Computational tools are then used to reassemble and characterize the DNA fragments.

Uncultured

A term that is used in mycobiome sequencing studies to refer to sequences that are identified in the National Center for Biotechnology Information GenBank database as fungal but that are currently of uncharacterized origin.

Candida

A genus of yeasts that includes common species such as Candida albicans, C. tropicalis, C. glabrata, C. parapsilosis and C. krusei. Candida species are normal inhabitants of the skin and mucous membranes and primarily cause disease in immunocompromised individuals. Candidiasis (disease caused by Candida) of the mouth or throat is called thrush or oropharyngeal candidiasis.

Anti-Saccharomyces cerevisiae antibodies

(ASCAs). Antibodies that are commonly found in serum from patients with inflammatory bowel disease. These antibodies are more common in individuals with Crohn's disease than in patients with ulcerative colitis. ASCAs cross-react with mannans from the cell walls of many fungi (including Candida species), which suggests that the name might be misleading.

Caspase recruitment domain-containing protein 9

(CARD9). A signalling adaptor molecule that functions downstream of many immunoreceptor tyrosine- based activation motif (ITAM) receptors that are present in phagocytes, including macrophages and dendritic cells. CARD9 associates with B cell lymphoma 10 (BCL-10) and the paracaspase MALT1 to facilitate signalling through nuclear factor-κB and to promote acute inflammatory responses and the initiation of adaptive immunity.

T helper 1 (TH1) cell-mediated immunity

An immune response that is characterized by T cells that produce IFNγ. This is generally associated with effective host defence against intracellular bacteria and protozoa.

Malassezia

A genus of basidiomycetous fungi that includes species such as Malassezia dermatis, M. furfur and M. restricta. These yeasts are specifically adapted for growth on mammalian skin and they are associated with conditions such as dandruff, atopic eczema and dermatitis, pityriasis versicolor, seborrheic dermatitis and folliculitis.

Chronic mucocutaneous candidiasis

(CMC). A condition that is characterized by recurrent Candida infections of the mouth, skin and other mucosal surfaces.

Onychomycosis

A fungal infection of the toenails or fingernails. These infections are most commonly caused by dermatophytes (Microsporum, Epidermophyton and Trichophyton) but can also be caused by Candida species and non-dermatophytic moulds.

C-type lectin receptor

(CLR). A member of a large family of receptors that bind to carbohydrates, typically in a calcium-dependent manner. Here, we use the term to refer to the set of CLRs that act as 'pattern recognition receptors' in the detection of microbial threats and that activate immune responses. The CLR family includes membrane receptors, such as CLEC6A, CLEC7A and the mannose receptor, and also soluble receptors, such as mannose-binding lectin (MBL). The binding activity of these receptors is mediated by conserved carbohydrate-recognition domains.

a–α mating type

This refers to two haploid sexual forms of yeast. The a-type yeast cells secret an 'a-factor', which is a pheromone that attracts the α-mating type, which, in turn, secretes 'α-factor'. The a-type cells respond to the α-factor by growing a projection (shmoo) towards the α-cells. Haploid cells respond only to a pheromone of the opposite cell type, which allows for mating to only occur between a-type and α-type cells.

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Underhill, D., Iliev, I. The mycobiota: interactions between commensal fungi and the host immune system. Nat Rev Immunol 14, 405–416 (2014). https://doi.org/10.1038/nri3684

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