The mycobiota of the human body: a spark can start a prairie fire

Figures & data

Figure 1. Time line of clinical progress of mycobiota and related diseases in various parts of the human body.

Table 1. Genetic polymorphisms related diseases.

Gene	Immunity impairment	Response to Diseases	References
CYBA/CYBB NCF1,2,4	Damage to NADPH oxidase	CGD	^Citation45
Dectin-1	Reduce the effect of IL-1β and Th17	CMC Candida colonization Invasive aspergillosis	^Citation46,Citation47
DEFB1	Unknown	Resistance to Candida carriage	^Citation48
IL-4	Increase vaginal IL-4, reduce NO and MBL levels	RVVC	^Citation49
IL-10	Reduce the production of IL-10	Resistance to invasive aspergillosis	^Citation50
	Increase the production of IL-10	Persisting candidemia	^Citation51
IL-12B	Reduce the production of IFN-γ	Persisting candidemia
IL-12Rβ1	Reduce the response to IL-12 and IL-23	CMC	^Citation52
IL-17RA IL-17 F	Reduce the axis of IL-17	CMC	^Citation45
IL-22	Increase the production of IL-22	Resistance to VVC and RVVC
MBL2	Reduced MBL levels	RVVC Chronic necrotizing pulmonary aspergillosis	^Citation53
CARD9	Impair the response of dectin-1/dectin-2 Reduce the response of Th17 cell and TNF	CMC Onychomycosis Deep dermatophytosis	^Citation54,Citation55
	Reduce the production of IL-1β	IBD	^Citation56
NLPR3	Reduce the production of IL-1β	RVVC	^Citation57
TLR1	Reduce the production of IL-1β, IL-6 and IL-8	Candidemia Invasive aspergillosis	^Citation58
TLR3	Reduce the production of IFN-γ and TNF-α	CMC	^Citation59
TLR4		Invasive aspergillosis	^Citation60
TLR9	Increase NF-kB signal	ABPA	^Citation61
AIRE	Autoimmunity reduce the production of IL-17A, IL-17 F and IL-22 Impair the response of T cells	Autoimmune polyendocrine syndrome type I APECED CMC	^Citation62
DOCK8	Impair the response of Th17 cell	Hyper-IgE syndrome(HIES) CMC	^Citation63,Citation64
STAT3	Impair the response of T cell(Th17 cell and memory T cell)	HIES CMC	^Citation65,Citation66
CX3CR1-M280	CX3CR1 functional decline	Systemic candidiasis	^Citation67
STAT1	Reduce the production of IL-17, IL-22 and IFNγ (the response of Th1 and Th17 cells)	CMC	^Citation68
SFTPA2	Increase the production of IgE and eosinophilia	ABPA, CCPA	^Citation69

Abbreviation: CMC: Chronic mucocutaneous candidiasis; CGD: Chronic Granulomatous Disease; VVC: Vulvovaginal candidiasis; RVVC: Recurrent vulvovaginal candidiasis; APECED: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; CCPA: chronic cavitary pulmonary aspergillosis; ABPA: allergic bronchopulmonary aspergillosis; IBD: Inflammatory bowel disease

Figure 2. The influence of mycobiota on IBD and colorectal carcinogenesis.

Table

Box 1: ABPM Patients with ABPM usually have severe asthma, elevated IgE levels, and bronchiectasis. Many factors such as a humid environment and climate change can affect the sensitivity of the airway to mycobiota. Skin prick test and IgE serological tests are commonly used to diagnose allergic reactions to mycobiota in patients.^Citation96 Allergic bronchopulmonary aspergillosis (ABPA), the major form of ABPM, is caused by Aspergillus fumigatus. Colonization of the airway mucus by this fungal species promotes the responses of CD4^+Th2 cells, eosinophils and mast cells in patients.^Citation88,Citation97 A recent study found that the Geno variation of ZNF77 is beneficial to fungal colonization in ABPA, which can be regarded as a diagnostic marker for fungal infection.^Citation98 Further study discovered that most patients with ABPA have a Card9 S12 N mutation;^Citation99 the infection of Aspergillus fumigatus activates the RelB signaling pathway (nonclassical NF-κB), which mediates the production of IL-5 by pulmonary macrophages. After that, Th2 cells begin to differentiate and trigger allergic reactions, leading to ABPA. Epidemiological evidence of an association between asthma and fungal allergies is accumulating.^Citation100 SAFS may be complicated by pulmonary-infiltrating inflammation, bronchial mucus clogging, and proximal bronchiectasis, and then degenerate into pulmonary fibrosis.^Citation95 Studies have shown that corticosteroids can increase the airway fungal burden in patients with SAFS.^Citation101 In addition, the mechanism of fungal exacerbation of asthma depends on the immunomodulatory function of β-glucans (component of fungal cell wall) rather than the antigenicity of fungal spores.^Citation102

Figure 3. Gut-lung axis.

Figure 4. The reaction between mycobiota and immune system.

Table 2. Other contributors of anti-fungal immunity.

Immunity		Effect
Cells	Epithelial cells	·Barrier ·Control growth ·Let pathogens expose to anti-fungal drugs obviously.
	NK cells (rely on IL-17,IL-23)^Citation149	·NKp30 activating receptor is used for recognition and defense. ·Produce GM-CSF to instruct neutrophils ·Control systemic fungal infection
	Dendritic cells	·Produce IL-23p19 depend on Syk promote NK cells to secrete GM-CSF ·Control the inflammation ·Activate T cells
	ILCs	·Produce IL-17 against Candida and IL-23 against Aspergillus
	Treg cells^Citation150	·Product IL-10 and TGF-β to down-regulate the inflammation ·Promote the tolerance and inhibition of immune system to mitigate tissue damage caused by immune overload
	mAbs^Citation151	·Target β-glucan, mannan and Cryptococcus to provide protection ·Regulate the response of T cells.
Molecules	Complements	·C3b promotes phagocytosis of neutrophils and macrophages ·C3a and C5a promote inflammation
	Chemokines and Chemokine receptors	·CXCR2: recruit monocytes ·CXC type: recruit neutrophils ·IL-22:acting on epithelial cells, anti-fungal in the case of anti–inflammatory.
	CBLB^Citation152	Ubiquitin dectin-1 and dectin-2 to restrict the signal of Syk thus reduce the innate immunity.

Abbreviation: NK cells: Natural killer cells; ILCs: Innate lymphoid cells; mAbs: Monoclonal antibodies; CBLB: Casitas B lymphoma-b

Table

Box 2: Trained immunity People have always held the view that, among the immune responses, including nonspecific (innate) and specific (adaptive) responses, only the latter can preserve memory to provide a stronger protection against reinfection. However, several studies have shown that plants and invertebrates, which only have innate immunity, are on-alert when they reencounter the same or different pathogens. This phenomenon is named systemic acquired resistance. Targeted in-depth studies have deepened our understanding of this phenomenon. Previous invasion trained the innate immune system to offer better protection when reinfection occurred. Thus, the concept of ‘trained immunity’ is widely known. According to a study on vertebrates, we also found the existence of trained immunity in their bodies, which has the characteristic of adaptability, but not specificity.^Citation170 On the basis of experimental studies, β-glucan (mycobiota), peptidoglycan or lipopolysaccharide (bacteria) and other microbial pathogens could trigger responses targeted on innate immune cells, mainly macrophages, monocytes and natural killer cells. Compared with adaptive immunity, trained innate immunity contains many differences such as temporal and nonspecific characteristics, which are attributed to the dependence on epigenetic or transcriptional changes rather than genetic variation. However, there are still some adverse effects and labile factors exist.^Citation171

Figure 5. Fungal detected methods.

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