Primary immunodeficiencies underlying fungal infections

Abstract

Purpose of review

We review the primary immunodeficiencies underlying an increasing variety of superficial and invasive fungal infections. We also stress that the occurrence of such fungal infections should lead physicians to search for the corresponding single-gene inborn errors of immunity. Finally, we suggest that other fungal infections may also result from hitherto unknown inborn errors of immunity, at least in some patients with no known risk factors.

Recent findings

An increasing number of primary immunodeficiencies are being shown to underlie fungal infectious diseases in children and young adults. Inborn errors of the phagocyte NADPH oxidase complex (chronic granulomatous disease), severe congenital neutropenia and leukocyte adhesion deficiency type I confer a predisposition to invasive aspergillosis and candidiasis. More rarely, inborn errors of IFN-γ immunity underlie endemic mycoses. Inborn errors of IL-17 immunity have recently been shown to underlie chronic mucocutaneous candidiasis, whereas inborn errors of CARD9 immunity underlie deep dermatophytosis and invasive candidiasis.

Summary

Chronic mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, deep dermatophytosis, pneumocystosis, and endemic mycoses can all be caused by primary immunodeficiencies. Each type of infection is highly suggestive of a specific type of primary immunodeficiency. In the absence of overt risk factors, single-gene inborn errors of immunity should be sought in children and young adults with these and other fungal diseases.

Introduction

Saprophytic and commensal fungi infect billions of people each year [1,2]. Medically important fungi include yeast Candida spp., mold Aspergillus spp., the atypical fungus Pneumocystis jirovecii, dimorphic (Coccidioides, Paracoccidioides and Histoplasmosma spp.) fungi, dermatophytes (e.g. Trichophyton spp.), and encapsulated yeast Cryptococcus spp. Invasive fungal diseases (IFDs), such as candidiasis, aspergillosis, pneumocytosis and cryptococcosis in particular, have become a major health problem [3,4]. The acquired immunodeficiency syndrome (AIDS) epidemic, the more widespread use of immunosuppressive therapies, the longer survival of immunosuppressed patients, the increased use of intravenous lines and increased movements of patients at risk are the main acquired risk factors contributing to IFDs. Despite advances in treatment, mortality rates for IFDs remain high, at 30 to 50% [5–7]. Superficial fungal diseases, although less severe, can also lead to significant morbidity and mortality [8]. In any case, a number of superficial and invasive fungal diseases are not explained by any of the known risk factors.

It is important to understand the pathogenesis of fungal infections in patients without known risk factors. It is also timely to decipher the cellular and molecular mechanisms of anti-fungal immunity, with a view to developing new tools for treating fungal infections [7,9] and new preventive measures, including vaccines [10]. The study of primary immunodeficiencies (PIDs) conferring a predisposition to fungal infections can serve both purposes, as the elucidation of genetic etiologies of unexplained fungal diseases also improves our understanding of antifungal immunity in other settings [11–14]. In recent years, the genetic dissection of chronic mucocutaneous candidiasis disease (CMCD) has revealed a role for IL-17 in mucocutaneous immunity to C. albicans [7,15–18]. Other examples include the role played by CARD9 in IFDs caused by dermatophytes and Candida spp., that of IFN-γ in immunity to dimorphic fungi, and that of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in immunity to Aspergillus spp. We review here the PIDs known to confer a predisposition to fungal infections.

Primary immunodeficiencies underlying chronic mucocutaneous candidiasis

Candida spp. are cosmopolite commensal yeasts colonizing the skin (C. parapsilosis) and digestive tract (C. albicans) of healthy individuals. However, they can lead to superficial mucocutaneous infections, which can occasionally become chronic (chronic mucocutaneous candidiasis or CMC). CMC is characterized by persistent or recurrent infections of the mouth, esophagus, digestive and genital mucosae, nails and/or skin, mostly with C. albicans. CMC is frequent, and associated with other infections caused by a broad spectrum of microorganisms, in the context of acquired conditions (HIV infection, immunosuppressive therapies, prolonged antibiotic therapies, diabetes mellitus) or various inherited primary T-cell immunodeficiencies. Patients with severe combined immunodeficiencies (SCID) and patients with combined immunodeficiencies (CID) develop CMC in infancy due to T-cell deficiency [13,16]. Patients with idiopathic CD4 lymphopenia are also susceptible to CMC. All (n=6) known patients with an autosomal dominant (AD) IκBα gain-of-function mutation [19,20] and impaired NF-κB signaling have developed CMC and other fungal infections [19]. Two thirds of patients with CID and low T-cell counts, such as those with autosomal recessive (AR) DOCK8 deficiency, display CMC [21,22]. Those with CID and impaired T-cell function, caused by AR TCR-α, AR ORAI1, AR MST1/STK4, AR RFXANK or AR CD25 deficiencies, for example, have also been reported to display susceptibility to CMC [19,21–31].

In other PIDs, CMC is one of the main clinical presentations [15,16]. Approximately 85% of patients with AD STAT3 deficiency and hyper-IgE syndrome (AD-HIES) display CMC in addition to severe staphylococcal skin and pulmonary disease [26,32–36], with 64% of these patients displaying oral candidiasis from the neonatal period onwards. CMC has also been reported in 25% of patients with AR IL-12Rβ1 or IL-12p40 deficiency, both of which are genetic etiologies of Mendelian susceptibility to mycobacterial disease (MSMD) [37,38]. Six of the seven patients reported in one large consanguineous multiplex kindred with AR CARD9 deficiency displayed CMC in addition to other fungal diseases [39]. In these three PIDs, patients have been shown to have a deficit of IL-17A- and IL-22-producing T cells [36,40–46]. This deficit probably results from impaired STAT3-dependent signaling downstream from IL-6, IL-21 and IL-23, impaired IL-12Rβ1-dependent signaling downstream from IL-23 or impaired CARD9-dependent signaling downstream from C-type lectin receptors, respectively, these signaling pathways being involved in IL-17 T-cell development and maintenance [47,48]. Finally, in AR autoimmune polyendocrinopathy syndrome type 1 (APS-1 or APECED), caused by AIRE deficiency [49–51] and resulting in impaired T-cell tolerance, 88% of patients develop CMC at a mean age of 3.7 years [52]. High levels of neutralizing autoantibodies against IL-17A, IL-17F and/or IL-22 have been detected in the sera of APS-1 patients [41,52]. Overall, these studies strongly suggest that human IL-17 immunity plays a critical role in defense against CMC [15–17,53–57], and they paved the way for the identification of the first genetic etiologies of CMC disease (CMCD) [7].

CMCD is defined as CMC in patients with no other prominent clinical signs and with none of the genetic defects mentioned above. Complete AR IL-17RA and partial AD IL17F deficiencies, resulting in impaired IL-17 immunity, were first reported in one CMCD family each [58]. Subsequently, genome-wide approaches led to the discovery of heterozygous STAT1 missense mutations in patients with CMCD [59,60]. These mutations, unlike the previously reported mono- or biallelic STAT1 loss-of-function mutations associated with susceptibility to mycobacterial, intracellular bacterial and viral infections [61–63], were shown to be gain-of-function (GOF). Almost 100 patients with STAT1 GOF mutations have been reported to date [59,60,64–72]. These patients developed CMCD at a mean age of 1.4 years, mostly affecting the oropharynx (98%), nails (58%), skin (46%) and esophagus (20%). CMCD-causing STAT1 mutations increase STAT1 responses to IFN-α/β, IFN-γ and IL-27, which repress IL-17 T-cell development, probably accounting for the small numbers of IL-17- producing T cells in these patients and the resulting CMCD [59]. Accordingly, GM-CSF, followed by G-CSF treatment, in one of these patients improved candidiasis and resulted, in parallel, in the restoration of normal IL17-producing T-cell counts and an increase in STAT3 levels [73], confirming the role of IL-17 cytokines in mucosal cutaneous immunity to Candida infections. Primary immunodeficiencies associated with chronic mucocutaneous candidiasis are summarized in Table 1. Other extensive superficial fungal infections, such as dermatophytosis [60,65] and recurrent skin fusariosis [81] (caused by an environmental hyalohyphomycete and leading to disseminated infections in neutropenic individuals [82–84]) have been observed in a few patients with STAT1 GOF mutations.

Table 1.

Primary immunodeficiencies associated with chronic mucocutaneous candidiasis

Disease	Associated infections	Immunological phenotype	Gene, transmission
CMC
SCID	Bacteria, viruses, fungi, mycobacteria	No T cells, with or without B and/or NK cell lymphopenia	>30 genes[74]: IL2RG, XL; JAK3, AR; RAG1, AR; RAG2, AR; ARTEMIS, AR; ADA, AR; CD3, AR…
CID		T-cell defect
CD25 deficiency	Viruses and bacteria		IL2RA, AR[23]
NEMO or IKBG deficiency	Pyogenic bacteria, mycobacteria, viruses		NEMO, or IKBG X-linked [19]
IKBA GOF mutation			IKBA, AD[19,20]
DOCK8 deficiency	Viruses, bacteria and fungi		DOCK8, AR[21,22,25]
TCR-α deficiency	Viruses and bacteria		TCRA, AR[27]
ORAI1 deficiency	Viruses, mycobacteria, bacteria and fungi		ORAI1, AR[75]
MST1/STK4 deficiency	Viruses and bacteria		MST1/STK4, AR[28,29]
MHC class II deficiency	Viruses, bacteria and fungi		CIITA, RFXANK, RFXC, RFXAP, all AR[30]
Idiopathic CD4 lymphopenia	Pneumocystis, Cryptococcus, virus	CD4 T cells<300/mm3	UNC119, AD[76], MAGT1, X-linked[77] RAG1, AR[78]
Syndromic CMC
IL-12Rβ 1 and IL-12p40 deficiencies	Mycobacteria, Salmonella	Deficit of IL-17 producing T cells	IL12RB1, AR[37] IL12B, AR[38]
STAT3 deficiency (AD-HIES)	Staphylococcus aureus, Aspergillus	Hyper IgE, deficit of IL- 17-producing T cells	STAT3, AD[33,34,35,36]
APECED/APS-1	No	Neutralizing anti-IL- 17A, IL-17F and/or IL- 22 autoantibodies	AIRE, AR[41,52]
CARD9 deficiency	Dermatophytes, Candida brain abscess	Deficit of IL-17- producing T cells	CARD9, AR[39,79,80]
CMCD
Complete IL-17RA deficiency	S. aureus	No IL-17 response	IL17RA, AR[16]
Partial IL-17F deficiency	S. aureus	Impaired IL-17F, IL- 17A/F function	IL17F, AD[16]
STAT1 GOF mutations	Bacteria, viruses, fungi, mycobacteria	Low IL-17 producing T cells	STAT1, AD[59,60,64,65,67- 72,81]

Primary immunodeficiencies underlying invasive aspergillosis

Aspergillus spp. are present in soils and decaying plant material. Spores are inhaled, and hyphae can grow in the lungs, leading to pulmonary aspergillosis, the most frequent (90%) clinical presentation. Invasive aspergillosis is a life-threatening disease with an incidence of 0.27/10³ admissions and a global mortality rate at 3 months close to 45% [5]. The underlying diseases are mostly hematological malignancies and particularly acute myeloblastic leukemia (78%), with prolonged neutropenia, solid organ transplant, solid tumors, systemic inflammatory diseases and chronic respiratory diseases [5]. The prevalence of invasive aspergillosis is particularly high in patients with chronic granulomatous disease (CGD), 17% of whom develop invasive aspergillosis. A. fumigatus is the Aspergillus spp. most frequently associated with disease, found in approximately 40% of the CGD cases [85,86]. A. nidulans, which is encountered almost exclusively in CGD patients, is associated with a high mortality rate [87]. Invasive aspergillosis is mostly pulmonary in CGD patients [85,86]. This disease results from an NADPH oxidase complex defect in phagocytes, mostly due to X-linked (CYBB) mutations [88] or biallelic mutations in autosomal (NCF1, NCF2, NCF4, CYBA) genes [54–56,85,86,89–94]. Tissue susceptibility to bacteria and fungi is due to a defect in reactive oxygen (ROS) species production by phagocytes, resulting in an inability to kill microorganisms. Studies of patients with mycobacterial but not fungal disease and CYBB mutations impairing the respiratory burst in macrophages but not in monocytes or granulocytes [88] have suggested that disruption of the respiratory burst in granulocytes and monocytes underlies pulmonary aspergillosis in CGD patients.

Approximately 20% of AD-HIES patients develop invasive aspergillosis, always secondary to lung lesions (pneumatocyst formation or bronchiectasis), with 17% mortality [36,95]. AD-HIES patients display a normal inhibition of A. fumigatus growth by phagocytosis, unlike CGD patients [95]. The susceptibility of AD-HIES patients to IFD therefore results from the presence of pneumatocysts due to repeated bacterial infections of the lungs and defective STAT3-dependent epithelial immunity [95]. The incidence of invasive aspergillosis is also high, at 17%, in patients with AD GATA2 deficiency [55,96], as are the incidences of mycobacterial, papillomavirus and other fungal infections [97,98]. Consistent with the role of GATA2 as a transcription factor involved in hematopoiesis and maintenance of the stem cell compartment, patients with GATA2 deficiency present a complex phenotype, with monocytopenia, B and NK lymphopenia, low counts of dendritic cells and myelodysplasia [96,97,99–101]. Finally, invasive aspergillosis has been reported in rare cases of AD or AR severe congenital neutropenia (SCN) [102–106] or AR type I leukocyte adhesion deficiency (CD18 deficiency) [107–109].

Primary immunodeficiencies underlying invasive candidiasis

Candida spp. also causes candidiasis, the most frequent presentation of which is as fungemia [110]. Candidiasis is the fourth most important cause of nosocomial blood stream infection [111,112] and the most frequent IFD in Western countries [113], with a mortality rate of 40% [110]. Candidiasis is classically described in neutropenic patients, intensive care unit patients with catheters, treated with broad-spectrum antibiotics and with parenteral nutrition. Invasive candidiasis has occasionally been reported in patients with PIDs: 2% (n=486) of the patients from the French SCN registry developed invasive candidiasis, for example [109]. Despite the scarcity of data, AR type 1 leukocyte adhesion deficiency with CD18 deficiency is also known to be complicated with invasive candidiasis [108]. Candida spp. infection of the central nervous system (CNS) is mostly reported after neurosurgery or in premature infants [114,115]. It has also been reported in CGD patients [92] and, recently, in patients with AR CARD9 deficiency. So far, at least three (probably four — three from an Iranian kindred and one of Korean origin) individuals have developed Candida infections of the CNS, at a mean age of 13 years [39,79], with Candida spp. meningoencephalitis reported in three cases. CARD9 is an adaptor molecule expressed in myeloid cells downstream from the C-type lectin receptors (CLR) Dectin-1, Dectin-2 and MINCLE [116–123], which recognize fungal pathogen-associated molecular patterns (PAMPs) [94,124,125]. After coil-coiled domain phosphorylation by PKC-δ [126], activated CARD9 couples with BCL10 and MALT1, resulting in NF-κB activation, leading to the secretion of proinflammatory cytokines [126–129]. CARD9-deficient peripheral blood mononuclear cells (PBMCs) contain a smaller than normal proportion of IL-17 T cells, but the role of IL-17 immunity in human defense against Candida invasive infection remains unclear [39]. In addition, PBMCs and neutrophils display impaired proinflammatory cytokine release in response to Candida stimulation [79]. Moreover, an impairment of neutrophil killing of unopsonized Candida yeasts has been observed, despite normal levels of NADPH oxidase activity in response to Candida stimulation in the patient tested. Nonetheless, it was suggested that the patient’s neutrophils displayed an abnormal phagolysosome function in contact with C. albicans, on the basis of electron microscopy [79]. The preferential CNS location of Candida infection in CARD9- deficient patients may also result from the inability of monocytes, macrophages and/or microglial cells to eliminate Candida efficiently at the blood brain barrier [54].

Primary immunodeficiencies underlying deep dermatophytosis

Dermatophytes are cosmopolite filamentous fungi that frequently cause benign infections, such as tinea capitis and corporis and onychomycosis [130]. By contrast, deep dermatophytosis is a rare condition defined by the invasion of the dermis and hypodermis by dermatophytes, sometimes associated with lymph node, brain, digestive tract or bone involvement [131,132]. Deep dermatophytosis has been reported in immunocompromised patients with HIV infection (n=3) or on immunosuppressive therapy (n=16) [133]. Sixty-nine cases have been reported in patients without known immunodeficiency [134–144], 45 of whom originated from North Africa. Twenty-four of these patients were from consanguineous families, with 19 familial cases from eight multiplex families. This strongly suggests that predisposition to idiopathic deep dermatophytosis is inherited as an AR trait. Recently, 17 patients from eight kindreds with idiopathic deep dermatophytosis from North Africa (11 previously reported [134,141,145–149]) were shown to display AR CARD9 deficiency [80]. Fifteen Algerian and Tunisian patients carried the same homozygous Q289X allele inherited from a common ancestor living approximately 975 years ago. Whole blood from the patients displayed impaired IL-6 production in response to stimulation with heat-killed C. albicans and S. cerevisiae, and PBMCs were found to contain a particularly small proportion of circulating IL-17-producing T cells. The only other infectious condition observed was thrush, in 35% of the patients [80]. These data provided evidence for a role of CARD9 in antifungal defense against dermatophytes, broadening the spectrum of IFDs associated with CARD9 deficiency. However, the underlying mechanism remains to be elucidated.

Primary immunodeficiencies underlying dimorphic fungal infections (endemic mycoses)

Dimorphic fungi are present as hyphae in the environment and as yeasts in tissues, the transition between these two forms being triggered by temperature changes. They have a limited geographic distribution. Coccidioides immitis or posadii is endemic to the South West United States, Paracoccidioides brasiliensis is endemic to Latin America and Histoplasmosma capsulatum is endemic to the Midwestern United States [150,151]. Infection occurs by spore inhalation. Disseminated histoplasmosis occurs in patients with immunodeficiency, mostly AIDS, and involves the lymph nodes, liver, spleen, mucosae, bone marrow and brain [152]. Disseminated coccidioidomycosis involves the lungs, central nervous system and bones and occurs in patients without known risk factors in 55% of cases [153]. Patients with mutations affecting the IL-12/IFN-γ circuit and MSMD [37] have been reported with dimorphic fungal infections. Indeed, IL-12Rβ1-deficient patients from Arizona, India and Brazil with coccidioidomycosis, (n=2) histoplasmosis (n=1), and paracoccidioidomycosis (n=1) have been reported [37,154,155]. Similarly, two IFN-γR1- deficient patients, one from Arizona and one from Texas, with disseminated coccidioidomycosis and histoplasmosis, respectively, have been described [156,157]. Salmonellosis and mycobacterial infections were associated with these infections in all but one patient. Patients with disseminated dimorphic infections should therefore be explored for defects of the IFN-γ/IL-12 circuit and patients with deficiencies in the IFN-γ/IL-12 axis should be considered at risk of infection with endemic fungi. Five patients with heterozygous STAT1 GOF mutations have recently been reported, two with disseminated coccidioidomycosis and three with histoplasmosis [65]. Endemic mycosis occurred in these patients at a mean age of 13 years. Finally, disseminated histoplasmosis has also been reported in patients with AD GATA2 deficiency [96,98], AR-DOCK8 deficiency [25], idiopathic CD4 lymphopenia [158–161], and X-linked CD40L deficiency [162,163].

Primary immunodeficiencies underlying cryptococcosis

Cryptococcosis is a fungal infection mostly caused by the encapsulated yeast Cryptococcus neoformans. The burden of cryptococcosis is high: one million cases are reported each year in Sub-Saharan Africa, with more than 600,000 deaths/year in human immunodeficiency virus (HIV)-infected patients, in whom such infections are the fourth leading cause of death [164]. Cryptococcus neoformans is present in the soil. The major route of infection is probably inhalation. The main clinical presentation for C. neoformans infections is meningoencephalitis (90% in HIV-positive and 70% in HIV-negative individuals) [165]. Other risk factors include solid organ transplantation, hematological malignancies, diabetes mellitus, cirrhosis, sarcoidosis, CD4 T-cell lymphopenia, prolonged corticosteroid or immunosuppressive treatment. Cryptococcosis has been reported in patients with idiopathic CD4 lymphopenia [166,167], with AD GATA2 deficiency [96], and in a few patients with X-linked CD40L deficiency [168,169]. In addition, cryptococcosis was found in eight patients with neutralizing autoantibodies against IFN- γ [170] and seven patients with neutralizing autoantibodies against GM-CSF [171]. These data suggest, in addition to CD4⁺ T cells, a role for GM-CSF and IFN-γ in defenses against cryptococcosis, at the level of pulmonary macrophages. In patients of East Asian descents with disseminated nontuberculous mycobacterial infections, a genetic origin has recently been demonstrated for the presence of autoantibodies against IFN-γ [172,173]. Genetic defects of the IFN-γ and/or GM-CSF signaling pathways may, therefore, create a predisposition to cryptococcosis. No genetic etiology has yet been identified in patients with unexplained and isolated cryptococcosis.

Primary immunodeficiencies underlying Pneumocystis jirovecii pneumonia

P. jirovecii is an obligate extracellular fungus [174]. Pneumocystis spp. are host-specific and P. jirovecii is an exclusively human pathogen [175,176]. This fungus is ubiquitous and seroconversion occurs early in life. P. jirovecii is transmitted from individual to individual, through the air. It causes a severe form of interstitial pneumonia in patients with acquired or inherited IDs. Pneumocystosis was the first infection reported in patients with AIDS in the USA, in 1981 [177,178]. Pneumocystis pneumonia remains one of the leading causes of mortality and morbidity in AIDS patients [179], and develops when CD4⁺ T-cell count falls below 200 cell/μl [178]. P. jirovecii pneumonia is also frequent in patients with severe combined immunodeficiency (SCID), and in patients with idiopathic CD4 lymphopenia [31,158,167], demonstrating the crucial role of CD4 T cells. Patients with impaired NF-κB signaling, AD IκB-α gain-of-function mutations [19,20] and X-linked NEMO deficiency [19], AR MHC class II deficiency [180], AR DOCK8 deficiency and X-linked Wiskott-Aldrich syndrome [25,181] also develop pneumocystosis. Finally, P. jirovecii pneumonia is common in patients with X-linked CD40L deficiency, associated with recurrent bacterial and cryptosporidium infections. In a series of 79 XHIGM patients, 48% developed P. jirovecii pneumonia at a median age of 1.26 years, and this infection was often the revelatory symptom for XHIGM diagnosis [168]. XHIGM is caused by mutations of CD40L, encoding the CD40 ligand, which is expressed on T cells and necessary for cooperation between T and B lymphocytes and immunoglobulin class switch. Affected patients therefore have deficiencies of IgG, IgA and IgE and high levels of IgM antibodies. CD40L is also required for the maturation of antigen-presenting cells, the stimulation of macrophage effector functions and the antigen priming of T lymphocytes [168]. The T-cell defect is probably the main cause of pneumocystosis in this PID. Primary immunodeficiencies associated with invasive fungal diseases are summarized in Table 2. Main PIDs associated with fungal infections are presented in Table 3.

Table 2.

Primary immunodeficiencies associated with invasive fungal diseases

Fungal susceptibility	Disease	Associated infections	Immunological phenotype	Gene, transmission
Deep dermatophytosis	CARD9 deficiency	CMC	Deficit of IL-17- producing T cells	CARD9, AR[80]
Aspergillosis	Chronic granulomatous disease	Bacteria, Scedosporium	NADPH oxidase complex defect in phagocytes	CYBB, X-linked or CYBA, NCF1, NCF2, NCF4, AR [54–56,85,86,89–94]
	STAT3 deficiency (AD- HIES) with lung cavities	S. aureus	STAT3 deficiency, epithelial lung dysfunction	STAT3, AD[35,182]
	MonoMAC syndrome	Environmental mycobacteria, viruses, fungi, bacteria	Monocytopenia, deficit of dendritic cells, B and NK cell lymphopenia,	GATA2, AD[96,97,99–101]
	Leukocyte adhesion deficiency type 1	Bacteria	Impaired neutrophil adhesion	CD18, AR
	Severe congenital neutropenia	Bacteria, invasive candidiasis	Neutropenia	ELA2, AD[106] HAX1, AR[104]
Invasive candidiasis	Severe congenital neutropenia	Bacteria, invasive candidiasis	Neutropenia	ELA2, AD[106] HAX1, AR[104]
	Leukocyte adhesion deficiency type 1	Bacteria	Impaired neutrophil adhesion	CD18, AR[108]
Candida CNS infection	Chronic granulomatous disease	Bacteria, Scedosporium	NADPH oxidase complex defect in phagocytes	CYBB, X-linked or autosomal CYBA, NCF1, NCF2, NCF4, AR [54–56,85,86,89–94]
	CARD9 deficiency	Dermatophytes, CMC	Impaired Candida killing by PMN	CARD9, AR[39,79]
Cryptococcosis	Autoantibodies against GM-CSF	No	Neutralizing anti-GM- CSF autoantibodies	Unknown[171]
	Autoantibodies against IFN-γ	Mycobacteria	Neutralizing anti-IFN-γ autoantibodies
	CD40 ligand deficiency	Pneumocystis, bacteria	Hypo IgG, IgA, High IgM levels, T/B cell cooperation defect	CD40L, X- linked[168,169]
	MonoMAC syndrome	Environmental mycobacteria, viruses, fungi	Monocytopenia, deficit of dendritic cells, B and NK cell lymphopenia,	GATA2, AD[96]
Dimorphic fungal infection
Coccidioidomycosis	IL-12Rβ1 deficiency	Mycobacteria, Salmonella		IL12RB1, AR[155]
	IFN-γR1 deficiency	Mycobacteria, Salmonella		IFNGR1, AD[156]
	STAT1 GOF mutation	CMC, viruses		STAT1, AD[65]
Histoplasmosis	IFN-γR1 deficiency	Mycobacteria, Salmonella		IFNGR1, AD[157]
	IL-12Rβ1 deficiency	Mycobacteria, Salmonella CMC		IL12RB1, AR[37]
	STAT1 GOF mutation	CMC, viruses	Deficit of IL-17- producing T cells, impaired response to IFN-γ restimulation	STAT1, AD[65]
	Idiopathic CD4 lymphopenia	Pneumocystis, Cryptococcus, viruses	CD4 T cells<300/mm3	UNC119, AD[76] MAGT1, X-linked[77] RAG1, AR[78]
	DOCK8 deficiency	Viruses and bacteria	T-cell defect	DOCK8, AR[21,22,25]
	X-linked CD40L deficiency	Pneumocystis, bacteria	Hypo IgG, IgA, high IgM levels, T/B cell cooperation defect	CD40L, X- linked[168,169]
	MonoMAC syndrome	Mycobacteria, viruses, fungi	Monocytopenia, deficit of dendritic cells, B and NK cell lymphopenia	GATA2, AD[96]
PCC	IL-12Rβ1 deficiency	Mycobacteria, Salmonella		IL-12RB1, AR[154]
Pneumocystosis	SCID	Bacteria, viruses, fungi, mycobacteria	No T cells, with or without B and NK cell lymphopenia	>30 genes[74]:IL2RG, XL JAK3, AR, RAG1, AR, RAG2, AR, ARTEMIS, AR, ADA, AR, CD3, AR…
	X-linked CD40 ligand deficiency	Pneumocystis, bacteria	Hypo IgG, IgA, high IgM levels, T/B cell cooperation defect	CD40L, X- linked[168,169]
	MHC class II deficiency	Bacteria, viruses, fungi,	T-cell defect	CIITA, RFXANK, RFXC, RFXAP, AR[30]
	NEMO deficiency	Pyogenic bacteria, mycobacteria, viruses	T-cell defect	NEMO, X-linked [19]
	DOCK8 deficiency	Viruses, bacteria	T-cell defect	DOCK8, AR[21,22,25]
	X-linked recessive Wiskott-Aldrich syndrome	Bacteria, viruses	T-cell defect	WASP, X-linked recessive[181,183]

PCC: paracoccidioidomycosis, GOF, gain of function, AR: autosomal recessive, AD: autosomal dominant, CMC: chronic mucocutaneous candidiasis

Table 3.

Main genetic etiologies of fungal infections

Fungal susceptibility	Disease
CMC	STAT1 GOF mutation (CMCD), STAT3 deficiency (AD-HIES), APECED/APS-1
Deep dermatophytosis	CARD9 deficiency
Aspergillosis	Chronic granulomatous disease, STAT3 deficiency (AD-HIES) with lung cavities
Candida CNS infection	Chronic granulomatous disease, CARD9 deficiency
Cryptococcosis	Autoantibodies against GM-CSF or against IFN-γ
Dimorphic fungal infection	IL-12Rβ1 deficiency, IFN-γR1 deficiency, STAT1 GOF mutation
Pneumocystosis	SCID, X-linked CD40 ligand deficiency

Conclusion

If the last few years are anything to go by, the near future will bear witness to the discovery of single-gene inborn errors of immunity underlying fungal infections. Progress in this area will be facilitated by technological progress, in deep sequencing in particular, making it possible to decipher genetic etiologies of infectious diseases, including IFDs in particular. The genetic dissection of both superficial and invasive fungal diseases should progressively lead to elucidation of the molecular and cellular mechanisms underlying protective immunity to fungal pathogens. Genetic dissection of the pathogenesis of inherited IFD will shed new light on the pathogenesis of IFD in other settings. The further genetic dissection of patients with no known risk factor displaying IFD should lead to the identification of new genetic etiologies of IFD. These discoveries will improve our knowledge of human antifungal immunity and should pave the way for the development of new, more appropriate treatments.

Key bullets points.

• Chronic mucocutaneous candidiasis diagnosis should lead to the exploration of IL-17 immunity defects, such as STAT1 mutations in particular.

• Candida CNS infection diagnosis should lead to explorations of possible chronic granulomatous disease or CARD9 deficiency.

• Deep dermatophytosis diagnosis should lead to explorations of possible CARD9 deficiency.

• Endemic mycoses and cryptococcosis diagnosis should lead to explorations of the IL-12/IFN- γ axis and evaluations of the presence of plasma autoantibodies against IFN-γ or GM-CSF.

• Pneumocystosis diagnosis should lead to the exploration of T-cell disorders, such as SCID and CD40 ligand deficiency in particular.