The Human Mycobiome: Composition, Immune Interactions, and Impact on Disease

Abstract

The fungal component of microbiota, known as the mycobiome, inhabits different body niches such as the skin and the gastrointestinal, respiratory, and genitourinary tracts. Much information has been gained on the bacterial component of the human microbiota, but the mycobiome has remained somewhat elusive due to its sparsity, variability, susceptibility to environmental factors (e.g., early life colonization, diet, or pharmacological treatments), and the specific in vitro culture challenges. Functionally, the mycobiome is known to play a role in modulating innate and adaptive immune responses by interacting with microorganisms and immune cells. The latter elicits anti-fungal responses via the recognition of specific fungal cell-wall components (e.g., β-1,3-glucan, mannan, and chitin) by immune system receptors. These receptors then regulate the activation and differentiation of many innate and adaptive immune cells including mucocutaneous cell barriers, macrophages, neutrophils, dendritic cells, natural killer cells, innate-like lymphoid cells, and T and B lymphocytes. Mycobiome disruptions have been correlated with various diseases affecting mostly the brain, lungs, liver and pancreas. This work reviews our current knowledge on the mycobiome, focusing on its composition, research challenges, conditioning factors, interactions with the bacteriome and the immune system, and the known mycobiome alterations associated with disease.

Keywords: autoimmunity; cancer; fungal receptors; immune cells; infection; inflammation; mycobiome.

Figure 1

Immune cell receptors and cell-mediated responses contributing to fungal recognition and overgrowth control in the intestinal mucosa. (A) Structurally and functionally diverse families of pattern recognition receptors (PRRs) expressed by different innate and adoptive immune cell types well-represented in the intestinal mucosa and involved in fungal recognition (i.e., CLRs, TLRs, NKRs, and SRs). (B) Cell-mediated responses against fungi first involve different cell types from the intestinal mucosal barrier, including enterocytes, Goblet cells, Paneth cells, and M cells involved in alarmin release, mucin production, AMP production, and transcytosis processes (sample and transport antigens/pathogens from the luminal surface to the sub-epithelium), respectively. In the lamina propria, DCs and macrophages can engage in fungal antigen presentation to T cells and participate in the antifungal response via cytokine secretion and phagocytosis of harmful fungal particles. In this context, T_H17 and ILC3 responses can be triggered, ultimately leading to IL-22 release that can contribute to the integrity of the intestinal barrier. On the other hand, alarmins (e.g., IL-1β, IL-33) and DAMPs released in response to epithelial cell aggression or damage can trigger T_H2 and ILC2 responses. Additionally, exposure to whole fungal cells and or particles can engage antifungal responses involving neutrophil activation (NETs formation) as well as T cell-dependent and independent B cell activation (production of ASCAs and NAbs by conventional or innate-type B1a cells, respectively).