What is a fungus?
Fungi are eukaryotic, heterotrophic, mainly aerobic organisms, possessing chitin in their cell walls, ergosterol in their plasma membranes, typical eukaryotic 80S ribosomes, and can produce lysine, for some of them, exhibiting a dual state as either yeast or mold (13). Regarding microscopic fungi, yeasts are unicellular forms that reproduce through budding, while molds are multicellular forms displaying hyphae in a mycelium (13). Fungi that present as yeast-like or molds, depending on physicochemical conditions and nutrient availability, are called “dimorphic” (13).
Before 2011, the taxonomy of fungi was blurred by the co-existence of distinct names for the sexual (teleomorph) and asexual (anamorph) states of the same fungus. This dual nomenclature of fungi has hampered research on fungi for decades. Since 2011, and as a fortunate sequel to the advent of DNA-base taxonomy genome, an initiative explicitly called “One fungus, one name” of the International Mycological Association resolved to use only one name per species (14). To date, the fungal taxonomy is still in progress and remains relatively unstable.
As stressed above, fungi are ubiquitous in the environment. Humans are exposed to fungi via inhalation in indoor and outdoor environments; they are also exposed via ingestion through the digestive tract and via contact with the skin and eyes. Exposure to fungi may cause a vast variety of diseases, mainly allergic (such as conjunctivitis, asthma, hypersensitivity pneumonitis, rhinitis, and allergic broncho-pulmonary aspergillosis) or infectious (e.g., mucormycoses, invasive aspergillosis, or fusariosis). Fungal hypersensitivity is often found in patients with asthma, chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis, ranking among the most prevalent diseases worldwide (4,15). Fungal infections develop predominantly in immunocompromised hosts and may exceed 50% case-fatality rates (4,16). Hypersensitivity pneumonitis (HSP) may occur in subjects without a previous condition (17).
Moreover, fungi release mycotoxins and volatile organic compounds (VOC). Mycotoxin production aims to secure fungal nutrients, while VOC is defined as small molecules containing carbon and able to evaporate under ambient conditions, such as 0.01 kPa and 20°C (18–20). Exposure to mycotoxins may occur through inhalation of airborne mycotoxins or ingestion of contaminated foods, giving rise to mycotoxicosis (19,21).
Fungal VOC are produced by primary and/or secondary metabolism pathways as a species-specific profile subject to environmental changes. To date, more than 400 fungal VOC have been described encompassing a wide variety of chemical compounds: simple hydrocarbons, heterocycles, aldehydes, ketones, alcohols, phenols, thioalcohols, thioesters and their derivatives, benzene derivatives, and cyclohexanes (20,21). Although some fungal VOC have been shown to induce symptoms (fatigue, lethargy, headache, irritation of ocular and upper airway mucosae, wheezing) and upregulate biomarkers of inflammation in healthy volunteers (20,22) their impact on human health is still controversial (18–20). Given their characteristics mentioned above, fungi are key constituents of the human exposome and further research is needed to evaluate and characterize the impact of fungal exposome on human health and use the data for risk assessment.
Fungal exposome
Worldwide, molds are an increasingly acknowledged part of the human exposome, both external (23) and internal as microbiome components collectively named mycobiota (24) (Figure 1) . The external, or environmental, part of the fungal exposome may be divided into outdoor and indoor categories, with many shared features but also with many differences in terms of composition, variation, and potential interventions.
Indoor and outdoor mold exposure shows geographical, seasonal, and urbanversus rural variability (25–27) and induces immune responses and health effects, often respiratory and allergic, that may start in infancy (28–31). In fact, human-fungus interactions extend from medicine and pharmacy to leisure activities, agriculture, food processing, industry, and even interplanetary travels (13,32,33).
Currently, allergenic molecules from more than 40 fungal genera have been characterized (www.allergen.org, accessed March 8th, 2022), but molecular data are still lacking for many environmental fungi (Table 2) . Cross-reactivity between fungal allergens may help to identify some, but not all, fungal sensitization outside of the available extracts and molecules (34,35).