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Host genetics and opportunistic fungal infections
REVIEW
10.1111/1469-0691.12800
Host genetics and opportunistic fungal infections Z.-D. Pana1, E. Farmaki2 and E. Roilides1 1) Infectious Diseases Unit, 3rd Department of Paediatrics, and 2) Laboratory of Clinical Immunology, 1st Department of Paediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Thessaloniki, Greece
Abstract Current knowledge on the human pathophysiology of fungal infections highlights the crucial role of genetic pitfalls in specific immunity pathways that determine, together with other risk factors, the predisposition to and clinical outcome of fungal disease. In several studies, associations between gene polymorphisms and genetic errors have been implicated in an immunodeficiency phenotype and an increased incidence of opportunistic fungal diseases. The major challenge is to fully understand the complex interactions between genetic variations and multiple factors, and their relative contributions to the final clinical fungal disease phenotype. The aim of this review is to present updated knowledge on immunity genetics and susceptibility to medically relevant fungal diseases, such as those caused by Candida, Aspergillus, and certain other more rare fungi. Keywords: Adaptive immunity, Aspergillus, Candida, fungi, immune markers, innate immunity Article published online: 10 October 2014 Clin Microbiol Infect 2014; 20: 1254–1264
Corresponding author: E. Roilides, Infectious Diseases Unit, 3rd Department of Paediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital Konstantinoupoleos 49, Thessaloniki, 54642 Greece E-mail: [email protected]
Introduction Fungal infections remain a major cause of significant morbidity and mortality among specific patient groups and of an increased financial burden to the healthcare economics. One major priority in the field is the extended identification of all possible fungal-specific and host-specific factors for fungal disease predisposition, which is crucial knowledge that could ‘refine’ the future management of these patients. A large panel of well-defined clinical and laboratory parameters has been implicated in the development, severity and outcome of certain invasive fungal diseases (IFDs) in the immunocompromised host. On the other hand, significant variability has been reported in the development and outcome of IFD among patients with the same predisposing factors, implying an individualized genetic pattern of susceptibility. Accumulating evidence has recently shown that immune system genetic variations leading to imbalances in both proinflammatory and anti-inflammatory
responses may predispose to fungal infections. Hence, it is reasonable to speculate that genetic variations involved in important pathways of the innate and adaptive immune systems may represent a potential source of variability in susceptibility to IFD. These genetic variations, known also as single-nucleotide polymorphisms (SNPs), refer to one of multiple alternative forms within a nucleic acid sequence that occurs with increased frequency (>1%) within a population and allows evolution by natural selection. SNPs are perceived as equally acceptable alternatives in a DNA sequence, and in most cases their impact on a gene may not significantly influence the activity of the encoded protein. Nevertheless, under certain circumstances, even these minor effects may significantly influence susceptibility to human disease. In contrast, mutations result from rare (<1%) genetic errors originating from unrepaired errors in the DNA replication process. These genetic errors can have an impact on the phenotype of an organism, especially if they occur within the pro-
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tein-coding sequence of a gene. Mutations can be also divided into hereditary or germline mutations, when the error exists in the reproductive cells and can be passed from generation to generation, and acquired or somatic mutations, when the error occurs in the DNA of individual cells that develop throughout a person’s life and is passed only to direct descendants of those cells. For many pathological conditions, there may even be different mutations in the gene, which may cause the same disease with variations in the phenotype. A few clinically relevant disorders may be the result of only a single defective gene mutation, and are called monogenetic disorders. These inherited diseases, controlled by a single pair of alleles, are passed on from one generation to another in a simple pattern according to Mendel’s laws. In recent years, variants in several immune-related SNPs and inborn genetic errors of immunity associated with monogenetic disorders have been proposed to affect immunity against Candida and Aspergillus species by influencing commensalism, symbiosis, latency and dissemination of the fungi. Selection of the appropriate candidate ‘key’ genes and their polymorphisms remains a great challenge, and metagenomic technologies hold promise for resolving questions regarding the functional effects of crucial genes in IFD predisposition. This review highlights the present knowledge on immunity genetics and susceptibility to IFD.
Immune Genetic Profile and Aspergillosis Innate immunity plays a significant role in the initial phase of ingestion, killing and elimination of Aspergillus conidia. Furthermore, the local production of cytokines by activated macrophages and neutrophils seems to regulate proinflammatory (Th1) and anti-inflammatory (Th2) immune reactions. Several cytokine gene polymorphisms are considered to be candidate prognostic biomarkers for Aspergillus infection (Table 1). Cytokine functional gene polymorphisms (interleukin (IL)-10, IL-15, transforming growth factor (TGF)-b1, tumour necrosis factor (TNF)-a, and interferon (IFN)-c) have been evaluated in patients with chronic cavitary pulmonary aspergillosis (CCPA) and allergic bronchopulmonary aspergillosis (ABPA) [1]. Specific alleles have been more frequently detected in patients suffering from invasive aspergillosis (IA), such as the IL-15 +13689A allele [1]. The presence of the IFN-c 874T>A polymorphism as a single SNP or as a combined deficiency with an SNP in Toll-the like receptor (TLR)-4 gene (1063A>G) has shown a trend to cause increased susceptibility to IA [1,2]. CCPA patients have been genetically determined produce less IL-10 and TGF-b1, owing to the frequent presence of the IL-10
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1082G and TGF-b1 +869T alleles [1]. In patients undergoing allogeneic stem cell transplantation (SCT), SNPs in the promoter region of the IL-10 gene and an ACC haplotype are independent protective markers for invasive pulmonary aspergillosis (IPA), suggesting that the genotypic variability of the IL-10 gene promoter region modulates the production of IL-10 and indirectly influences the risk of developing IPA [3,4]. In particular, for the IL-10 1082(AA) genotype, the results are rather controversial. According to Sainz et al., the IL-10 1082(AA) genotype is associated with resistance to the development of IPA, whereas in another study the genotype was associated with an increased risk of ABPA in patients with cystic fibrosis [5]. A polymorphism in the IL-4 receptor gene plays a role in the occurrence of ABPA [6]. Sainz et al. [7] evaluated the role of IL-1 gene cluster polymorphisms in the pathogenesis of, susceptibility to and resistance to IPA, and found that specific haplotypes (VNTR2/–889C/–511T) were significantly associated with the development of IPA, whereas others (VNTR2/–889C/–511C) were associated with resistance. In a recent study by Carvalho et al. [8], a prognostic role of IL-23 receptor gene polymorphism was found in patients undergoing SCT, implying that donors with the R381Q haplotype gave a protective effect against IA. In evaluation of the genetic risk for developing IPA, IL-6 gene polymorphisms (promoter at positions 174 (C/G) and 634 (G/C)) were not significantly associated with an increased predisposition to develop IPA [9]. As well as SNPs in other cytokine receptor genes, SNPs in the TNF receptor 1 and TNF receptor 2 genes have been associated with IPA predisposition in two studies, owing to decreased TNF expression [10,11]. SNPs in the gene encoding chemokine ligand 10, which enhances chemokine secretion after Aspergillus stimulation, seemed to influence susceptibility to IPA in alloSCT patients [12]. A non-synonymous SNP in the gene encoding plasminogen, a factor that binds to fungal cell wall of Aspergillus fumigatus, affected the risk of developing IA in patients after SCT [13]. An SNP in the gene encoding dectin-1 receptor, a major receptor for fungal b-glucans on myeloid cells, leads to a decreased Th17 response and seems to influence the presence of IA in non-SCT patients but not the clinical course of IA in SCT recipients [14]. However, in another study, this SNP increased the risk of IA, with the risk being highest when the SNP was detected simultaneously in both donor and recipient [15]. Finally, the carriage of several alleles of dectin-1 and DC-SIGN polymorphisms increases the risk of IPA [16]. The role of genetic variations of TLR genes in IA predisposition has been extensively evaluated, with partially contradictory results. TLR-2 gene polymorphism has not been associated with CCPA and IA in haematological patients after SCT [17,18].
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TABLE 1. Single-nucleotide polymorphisms (SNPs) and Aspergillus infection Gene Mannose-binding lectin (MBL)2
SNP
Aspergillus-related disease
Comments
Reference
10/82
CNPA
Mutant MBL2 higher in CNPA patients than in controls (70% vs. 25.6%) (p 0.004)
[23]
15/82
CCPA, ABPA
T allele (p 0.020) and CT genotype (p 0.05) associated with CCPA but not with ABPA
[22]
Codon 54 Allele B
23/52
IA
No difference in mutant MBL2 genotype between patients with aspergillosis and controls (44% vs. 34.8%) (p >0.05)
[21]
Intron –1011A/G
11/84
ABPA
Mutant SNP associated with allergic rhinitis in bronchial asthma and ABPA (p <0.01)
[24]
101C/T
51/49
IA after HSCT
SNP associated with an increased risk of IA development (p = 0.007 OR= 2.2 CI = 1.2–3.8)
[12]
1642C/G
39/46
IA after HSCT
SNP associated with an increased risk of IA development (p 0.003, OR 2.6. 95% CI 1.4–5.0)
[12]
52/44
IA after HSCT
SNP associated with an increased risk of IA development (p 0.001, OR 2.8, 95% CI 1.6–5.2)
[12]
22/105
IA after HSCT
Presence of both recipient SNPs associated with IA (p <0.001, OR 1.3, 95% CI 1.1–1.5)
[19]
22/105
IA after HSCT
SNP associated with IA (p <0.001, OR 1.3, 95% CI 1.1–1.5)
[19]
TLR-4 1063A/G
44/64
IA after HSCT
The combined presence of TLR-4 and IFN-c 874T>A SNPs associated with increased susceptibility to IA (p 0.04, OR 6.09, 95% CI 1.05–35.5)
[2]
TLR-4 1063A/G
103/263
IA after HSCT
Donor TLR-4 haplotype (S3) associated with increased risk of IA (p 0.020, OR 2.2, 95% CI 1.1–4.2)
[20]
TLR-4 1363C/T
103/263
IA after HSCT
Donor TLR-4 haplotype (S4) associated with increased risk of IA (p 0.002, OR 6.2, 95% CI 2.0–19.3)
[20]
TLR-4 1063A/G
40/80
CCPA
Recipient SNPs associated with CCPA (p 0.003, OR 3.5, 95% CI 1.5–8.1)
[17]
TLR-9 1237C/T
22/80
ABPA
SNP associated with ABPA (p 0.043, OR 2.5, 95% CI 1.0– 6.2)
[17]
Tumour necrosis factor (TNF)-a
TNF-a –308A/A
54/48
IA
Lower frequency of TNF-a –308A/A genotype in IA (p <0.01)
[1]
IPA in haematological patients
IPA associated with TNFR2 –322 SNP (p 0.029) but not with TNFR2 +676 SNP (p >0.05)
[10]
Interleukin (IL)
TNFR2 +676 322 IL-10 1082A/G 819C/T 592A/C
9/96
Increased IPA dependent on IL-10 haplotype (p 0.031)
[4]
IL-10 1082A/G
119 colonized/ 27 ABPA/232
Colonization with Aspergillus fumigatus or ABPA in CF
IL-10 –1082GG genotype associated with A. fumigatus colonization and ABPA in CF patients (p 0.020, OR 1.7, 95% CI 1.1–2.5)
[5]
IL-10 1082A/G
59/61
IPA in haematological patients
IL-10 –1082AA associated with resistance to IPA development (p 0.001)
[3]
Chemokine ligand 10 (C-X-C 10)
Codon 52 868C/T
Patients/ controls
1101A/G Toll-like receptors (TLRs)
TLR-4 239C/G 743A/G TLR-6 745C/T
IPA after HSCT
IL-10 promoter SNPs independent predictive factors for IPA (p 0.012, OR 9.3, 95% CI 1.6–52.8)
IL-10 –1082A allele weakly associated with IPA susceptibility (p 0.052, OR 1.7, 95% CI 1.0–2.9) IL-10 –1082A/G
24
CCPA
CCPA associated with lower frequency of IL-10 –1082G allele (OR 0.38, p 0.0006) and G/G genotype (p <0.001)
IL-1b 511C/T 889C/T IL-1Ra
59/51
IPA in haematological patients
IL-1 and IL-1Ra SNPs not associated with IPA (p 0.56 and p 0.68) VNTR2/889C/–511T haplotype associated with increased susceptibility to IPA (p 0.02); VNTR2/–889C/–511C haplotype associated with resistance to IPA (p 0.028)
[1]
[7]
IL-1Ra VNTR2/2 and IL1b(–511)T/T genotypes associated with higher positive serum galactomannan percentage than other genotypes (p 0.09) IL-15 +13689
IA
IA associated with higher frequency of IL-15 +13689A allele (OR 2.37, p 0.0028) and A/A genotype (p <0.001)
[1]
IL-23R IL-17A IL-17F
IA in SCT patients
IL-23R GA genotype improved overall survival (HR 0.48, p 0.028) and, in the donor, decreased the risk of fungal infections (p 0.05)
[8]
ABPA
IL-4Ra SNP associated with ABPA (p 0.008)
[6]
IL-4Ra 4679 A/C/G/T
40/56
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Primary Immunodeficiencies (monogenetic disorders) and Infections
(PIDs) Fungal
CMC
To date, several monogenetic disorders have been associated with an increased susceptibility to CMC [40–43]. Primary T-cell deficiencies, such as severe combined immunodeficiency (SCID) and certain combined immunodeficiencies, are variably associated with CMC in infancy, in addition to multiple infectious and autoimmune diseases (Table 3). Furthermore, CMC represents one of the main clinical presentations in several rare PIDs associated with defective Th17 responses [40–43]. Autosomal dominant hyper-IgE syndrome (HIES) was the first syndrome in which impaired IL-17 immunity was implicated in CMC susceptibility [44]. Autosomal dominant HIES is caused by mutations in the gene encoding STAT3, a signalling molecule downstream of the IL-23 receptor, resulting in markedly reduced or absent IL-17 production and increased susceptibility to CMC from the neonatal period, in addition to severe skin and lung staphylococcal infections [44,45].
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Recently, Glocker et al. [46] described a single large consanguineous family with autosomal recessive caspase recruitment domain-containing protein 9 (CARD9) deficiency and a history of recurrent CMC in addition to other fungal infections, such as dermatophytosis and central nervous system (CNS) candidiasis. All patients showed a significant defect in the Th17 response, probably because of impaired CARD9-dependent signalling downstream from several C-type lectin receptors, such as dectin-1, dectin-2, and MINCLE, which can recognize fungal pathogen-associated molecular patterns. However, the underlying mechanism remains to be elucidated [40,42]. Deep dermatophytosis was reported to be an important manifestation of CARD9 deficiency [47]. Patients with autosomal recessive IL-12Rb1 and IL-12p40 deficiencies typically present with Mendelian susceptibility to mycobacterial disease [48]. Approximately 25% of these patients also show mild CMC, which may be the first manifestation [49]. Some of these patients have low proportions of IL-17-producing and IL-22-producing T-cells, probably because of impaired IL-23 signalling [48,50]. CMC is the ‘signature’ disease and one of the earliest manifestations in patients with autosomal recessive autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy [51]. It is caused by
TABLE 3. Primary immunodeficiencies (PIDs) associated with chronic mucocutaneous candidiasis (CMC) CMC incidencea
PID Cellular and combined
PIDs with defective Th17 immunity
SCID (>30 genes) X-linked or AR
30–35%
CIDs: DOCK8 deficiency (AR HIES) NEMO or IKBa deficiency MST1/STK4 deficiency MHC class II deficiency CD25 deficiency TCR-a deficiency CRACM1 deficiency TYK2 deficiency (AR HIES) Idiopathic CD4 lymphopenia
Variable, depending on immune deficit High in DOCK8 (~80%)
STAT3 (AD HIES)
80%
CARD9 AR
Other fungal infections
Non-fungal infections
Variable, depending on immune deficit Variable, depending on immune deficit, mostly PCP, cryptococcosis, and histoplasmosis
Bacteria, viruses, and mycobacteria Viruses, bacteria, and mycobacteria (NEMO, CRACM1)
PCP Cryptococcosis Histoplasmosis
Viruses
Aspergillosis Cryptococcosis Histoplasmosis
Bacterial (mostly Staphylococcus aureus)
Dermatophytes CNS candidiasis
None
IL-12Rb1 and IL-12p40 (AR MSMD)
25–70%
Invasive candidiasis Histoplasmosis Coccidioidomycosis Paracoccidioidomycosis
Mycobacteria, Salmonella
AIRE (AR APECED)
90–100%
None
None
None
S. aureus
None
S. aureus
PCP Histoplasmosis Coccidioidomycosis
Viruses
CMCD: IL-17RA deficiency IL-17F deficiency STAT1 GOF mutation (AD)
Up to 100%
AD, autosomal dominant; AIRE, autoimmune regulator; APECED, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy; AR, autosomal recessive; CARD9, caspase recruitment domain-containing protein 9; CMCD, chronic mucocutaneous candidiasis disease; CNS, central nervous system; CRACM1, calcium release-activated calcium modulator 1; GOF, gain-of-function; HIES, hyper-IgE syndrome; IL, interleukin; MHC, major histocompatibility complex; MSMD, Mendelian susceptibility to mycobacterial disease; NEMO, nuclear factor-jB essential modulator; NK, natural killer; PCP, Pneumocystis pneumonia; SCID, severe combined immunodeficiency; STAT, signal transducer and activator of transcription; TCR, T-cell receptor. a Data on CMC incidence are presented for PIDs for which this information is available.
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TABLE 2. Single-nucleotide polymorphisms (SNPs) and Candida infection Gene Mannose-binding lectin (MBL)2
SNP Codon 54 Allele B Codon 54 Allele B
Patients/ controls
Candida-related disease
Comments
Reference
42/43
VVC
Allele B associated with increased risk of VVC (p <0.0001)
[38]
109
RVC
Variant allele B more frequent in patients with RVC than in controls (20% vs, 6.6%, OR 3.4, 95% CI 1.3–8.2, p 0.01)
[39]
B alleles in 25% of 36 patients not suffering from any recurrence during the maintenance therapy with decreasing doses of fluconazole vs. controls (OR 4.9, 95% CI 1.9–12.5, p 0.0007) B alleles in 20% of the 43 patients with sporadic recurrences vs. controls (OR 3.6, 95% CI 1.4–9.2, p 0.007) Allele D Allele B Allele C
88
Abdominal Candida infections
Variant MBL genotype not associated with abdominal yeast infection (53% vs. 38%, p 0.18)
[37]
Variant MBL genotype associated with yeast infection during early peritonitis (39% vs. 16%, p 0.012) 338/351
Candidaemia
Three TLR-1 SNPs (R80T, S248N, and I602S) associated with increased susceptibility to candidaemia (p 0.02; p 0.04; p 0.02)
[32]
325
Candidaemia in ICU patients
Heterozygous TLR-2 SNP patients showed elevated TNF-a plasma concentrations, but reduced IFN-c and IL-8 levels
[31]
TLR-4 D299G Y399I TLR-3 L412F
43/133
Candidaemia
TLR-4 Asp299Gly SNP more frequently detected in patients with candidaemia than in controls (26% vs. 10%; OR 3.0, 95% CI 1.3–6.9)
[30]
CMC
Variant SNP associated with reduced IFN-c and TNF-a secretion in response to stimulation with the TLR-3 ligand or Candida albicans
[29]
Dectin-1
Y238X
Candida colonization
Y238X SNP associated with increased risk of Candida colonization
[33]
CARD9
Y238X S12N
142 patients with HSCT 331/351
Candidaemia
No association between dectin-1 SNP, CARD9 SNP and prevalence of candidaemia (p >0.05)
[34]
Interleukin (IL)
IL-4 –589T/C IL-4 –1098T/G –589C/T –33C/T
42/43
VVC
Increased susceptibility to VVC in women with IL-4 SNP
[38]
40/43
CDC in leukaemia patients
IL-4 (–1098T/–589C/–33C) haplotype associated with increased risk of CDC development (p 0.01, OR 2.16)
[27]
IL-10 –1082A/G IL-12B 2724 INS/DEL –44C/G
338/351
Persistent candidaemia
Persistent candidaemia associated with SNPs in IL-10 (OR 3.45, 95% CI 1.33–8.93) and IL-12B (OR 5.36, 95% CI 1.51–19.0)
[26]
43/50
Candida carriage in diabetic patients
SNP associated with Candida carriage in both groups (diabetic and non-diabetic) (OR 25 for diabetic subjects and OR 8.5 for non-diabetic subjects)
[35]
Toll-like receptors (TLRs)
b-Defensin-1
TLR-1 R80T S248N I602S TLR-2 R753Q
IL-4 (–1098T/–589T/–33T) haplotype protective against CDC development (p 0.018, OR 0.47)
CARD9, caspase recruitment domain-containing protein 9; CDC, chronic disseminated candidiasis; CMC, chronic mucocutaneous candidiasis; HSCT, haematopoietic stem cell transplantation; ICU, intensive-care unit; IFN, interferon; RVC, recurrent vulvovaginal candidiasis; TNF, tumour necrosis factor; VVC, vulvolvaginal candidiasis.
predisposing role. Nahum et al. [29] observed that the TLR-3 receptor gene variant allele L412F seems to increase the risk of chronic mucocutaneous candidiasis (CMC). Increased susceptibility to invasive candidiasis (IC) and candidaemia has been also associated with the presence of specific SNPs in the TLR-2 and TLR-4 genes [30,31]. A multivariate analysis revealed that three TLR-1 gene SNPs (R80T, S248N, and I602S) were significantly associated with candidaemia susceptibility in Caucasians [32]. The C-type lectin receptor dectin-1 has been also implicated in the early recognition and elimination of Candida species. The dectin-1 Y238X early stop polymorphism was associated in one study with an increased risk of gastrointestinal colonization with Candida species in immunocompromised patients, whereas in another study the same SNP did not significantly influence the risk of candidaemia [33,34]. A
modulating effect on Candida colonization has also been associated with the presence of specific SNPs in the genes encoding b-defensins, which are cationic peptides of the epithelium that exert local antifungal activity. In particular, the C/G SNP at position –44 seemed to have a protective role against Candida colonization in diabetic and non-diabetic patients [35]. In one study, increased risks of CMC and recurrent vulvovaginal candidiasis were associated with the presence of one SNP in the gene encoding inflammasome component NALP3, which regulates IL-1b production [36]. Finally, patients with specific SNPs associated with a defective MBL2 gene showed an increased risk of developing abdominal Candida infections in secondary peritonitis, with recurrent vulvovaginal candidiasis and with response to fluconazole treatment [37– 39].
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Pana et al.
Primary Immunodeficiencies (monogenetic disorders) and Infections
(PIDs) Fungal
CMC
To date, several monogenetic disorders have been associated with an increased susceptibility to CMC [40–43]. Primary T-cell deficiencies, such as severe combined immunodeficiency (SCID) and certain combined immunodeficiencies, are variably associated with CMC in infancy, in addition to multiple infectious and autoimmune diseases (Table 3). Furthermore, CMC represents one of the main clinical presentations in several rare PIDs associated with defective Th17 responses [40–43]. Autosomal dominant hyper-IgE syndrome (HIES) was the first syndrome in which impaired IL-17 immunity was implicated in CMC susceptibility [44]. Autosomal dominant HIES is caused by mutations in the gene encoding STAT3, a signalling molecule downstream of the IL-23 receptor, resulting in markedly reduced or absent IL-17 production and increased susceptibility to CMC from the neonatal period, in addition to severe skin and lung staphylococcal infections [44,45].
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Recently, Glocker et al. [46] described a single large consanguineous family with autosomal recessive caspase recruitment domain-containing protein 9 (CARD9) deficiency and a history of recurrent CMC in addition to other fungal infections, such as dermatophytosis and central nervous system (CNS) candidiasis. All patients showed a significant defect in the Th17 response, probably because of impaired CARD9-dependent signalling downstream from several C-type lectin receptors, such as dectin-1, dectin-2, and MINCLE, which can recognize fungal pathogen-associated molecular patterns. However, the underlying mechanism remains to be elucidated [40,42]. Deep dermatophytosis was reported to be an important manifestation of CARD9 deficiency [47]. Patients with autosomal recessive IL-12Rb1 and IL-12p40 deficiencies typically present with Mendelian susceptibility to mycobacterial disease [48]. Approximately 25% of these patients also show mild CMC, which may be the first manifestation [49]. Some of these patients have low proportions of IL-17-producing and IL-22-producing T-cells, probably because of impaired IL-23 signalling [48,50]. CMC is the ‘signature’ disease and one of the earliest manifestations in patients with autosomal recessive autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy [51]. It is caused by
TABLE 3. Primary immunodeficiencies (PIDs) associated with chronic mucocutaneous candidiasis (CMC) CMC incidencea
PID Cellular and combined
PIDs with defective Th17 immunity
SCID (>30 genes) X-linked or AR
30–35%
CIDs: DOCK8 deficiency (AR HIES) NEMO or IKBa deficiency MST1/STK4 deficiency MHC class II deficiency CD25 deficiency TCR-a deficiency CRACM1 deficiency TYK2 deficiency (AR HIES) Idiopathic CD4 lymphopenia
Variable, depending on immune deficit High in DOCK8 (~80%)
STAT3 (AD HIES)
80%
CARD9 AR
Other fungal infections
Non-fungal infections
Variable, depending on immune deficit Variable, depending on immune deficit, mostly PCP, cryptococcosis, and histoplasmosis
Bacteria, viruses, and mycobacteria Viruses, bacteria, and mycobacteria (NEMO, CRACM1)
PCP Cryptococcosis Histoplasmosis
Viruses
Aspergillosis Cryptococcosis Histoplasmosis
Bacterial (mostly Staphylococcus aureus)
Dermatophytes CNS candidiasis
None
IL-12Rb1 and IL-12p40 (AR MSMD)
25–70%
Invasive candidiasis Histoplasmosis Coccidioidomycosis Paracoccidioidomycosis
Mycobacteria, Salmonella
AIRE (AR APECED)
90–100%
None
None
None
S. aureus
None
S. aureus
PCP Histoplasmosis Coccidioidomycosis
Viruses
CMCD: IL-17RA deficiency IL-17F deficiency STAT1 GOF mutation (AD)
Up to 100%
AD, autosomal dominant; AIRE, autoimmune regulator; APECED, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy; AR, autosomal recessive; CARD9, caspase recruitment domain-containing protein 9; CMCD, chronic mucocutaneous candidiasis disease; CNS, central nervous system; CRACM1, calcium release-activated calcium modulator 1; GOF, gain-of-function; HIES, hyper-IgE syndrome; IL, interleukin; MHC, major histocompatibility complex; MSMD, Mendelian susceptibility to mycobacterial disease; NEMO, nuclear factor-jB essential modulator; NK, natural killer; PCP, Pneumocystis pneumonia; SCID, severe combined immunodeficiency; STAT, signal transducer and activator of transcription; TCR, T-cell receptor. a Data on CMC incidence are presented for PIDs for which this information is available.
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a mutation in the autoimmune regulator gene, resulting in impaired T-cell tolerance. The associated CMC could not be explained by the underlying mutation in the context of autoimmunity until high levels of neutralizing autoantibodies against Th-17 cytokines (IL-17A, IL-17F, and IL-22) were detected in the sera of autoimmune polyendocrinopathy– candidiasis–ectodermal dystrophy patients [52]. These findings provided more evidence for the pivotal role of IL-17 immunity in protection against CMC. The pathogenesis of CMC was eventually deciphered in 2011, through investigations in patients suffering from CMC disease (CMCD), which had an unknown genetic cause until then [40]. The identification of complete autosomal recessive IL-17RA and partial autosomal dominant IL-17F deficiencies in pedigrees suffering from CMCD provided direct genetic evidence for the role of IL-17 immunity in human susceptibility to CMC [52]. Subsequently, gain-of-function mutations of STAT1 were demonstrated to be the main cause of autosomal dominant CMCD through genome-wide approaches [53,54]. These findings were confirmed by several other research groups in almost 100 patients with CMCD and markedly impaired IL-17 production, presumably as a result of impaired dephosphorylation of STAT1, a signalling molecule downstream of the IFN type I/II, IL-23 and IL-12 receptors [40,42,55]. Gain-of-function STAT1 mutations have also been reported to predispose to disseminated dimorphic yeast infections [55]. IFDs
Consistent with the immune mechanisms involved in human host defence against fungi, IFDs occur with increased frequency in patients with phagocytic, cellular and IFN-c–IL-12 axis immune defects [40,43,56]. Among PIDs, chronic granulomatous disease and HIES are most frequently associated with IFDs; variable susceptibility to IFDs is also seen in patients with SCID, X-linked hyper-IgM syndrome, and other rare PID syndromes (Table 4). Invasive aspergillosis. Chronic granulomatous disease (CGD) is the PID with the highest incidence of IFDs, mainly caused by Aspergillus species [56,57]. IA accounts for over one-third of all infections in CGD, and may be the presenting manifestation, frequently occurring during the first two decades of life [56,57]. An impaired respiratory burst in granulocytes and monocytes underlies pulmonary aspergillosis in CGD [58]. IA also occurs in approximately 25% of patients with autosomal dominant HIES, with 17% mortality. However, susceptibility to IA, which always arises secondarily to pneumatocyst formation or bronchiectasis resulting from repeated bacterial pneumonias, is probably related to defective
CMI
STAT3 functions in lung epithelia, and not to impaired phagocytosis [59]. Finally, IA has been occasionally encountered in autosomal recessive leukocyte adhesion deficiency type 1, and, to a lesser extent, in congenital neutropenia syndromes [40,41,56]. Invasive candidiasis. IC in PIDs is far less common than IA, and has occasionally been reported in patients with certain innate immune defects, such as CGD, severe congenital neutropenia, and autosomal recessive leukocyte adhesion deficiency type 1 [41,56]. CNS Candida infections have been reported in CGD patients and recently in three members of a consanguineous family with autosomal recessive CARD9 deficiency [40,46]. This is the only PID predisposing to IC of the CNS, possibly as a result of CARD9 expression predominantly on monocytes, affecting their function [40,43]. Other IFDs. Dimorphic fungal diseases such as disseminated histoplasmosis, coccidioidomycosis and paracoccidioidomycosis have been reported in patients with mutations affecting the IL-12–IFN-c axis and Mendelian susceptibility to mycobacterial disease, such as IL-12Rb1 and autosomal dominant partial IFN-cR1 deficiency [40,43,60]. In this patient group, fungal susceptibility is consistent with preclinical studies suggesting the important roles of IFN-c and IL-12 in host immune responses to these organisms [56,61]. Similarly, patients with gain-of-function STAT1 mutations have recently been reported with severe disseminated dimorphic yeast infections, probably because of aberrant regulation of IFN-c-mediated inflammation [55]. In addition, recent evidence suggests that genetic defects in the IFN-c and/or granulocyte–macrophage colony-stimulating factor signalling pathways may create a predisposition to cryptococcosis, as has been described in a few patients with neutralizing autoantibodies against IFN-c or granulocyte–macrophage colony-stimulating factor [62,63]. Disseminated histoplasmosis and cryptococcosis have also been reported in patients with idiopathic CD4 lymphopenia, X-linked CD40L deficiency, autosomal dominant HIES, DOCK8 deficiency associated with autosomal recessive HIES, and sporadic or autosomal dominant GATA2 deficiency related to the recently described syndrome of monocytopenia and susceptibility to mycobacteria, papillomaviruses, fungi, and myelodysplasia [40,41,64]. In addition to IA, Paecilomyces, and, to a lesser extent, Scedosporium and Trichosporon species have been occasionally implicated in infections in CGD patients [41,56]. Pneumocystis pneumonia (PCP) occurs with variable frequency in patients with profound T-cell deficiencies (SCID and certain combined immunodeficiencies, such as NEMO, DOCK8, caspase recruitment domain-containing protein 11
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– – Invasive CNS candidiasis –
– – Few cases
Autoantibodies against IFN-c or GM-CSF CARD9
MonoMAC syndrome
Occasionally (IL-12Rb1)
Occasionally
Occasionally Occasionally Occasionally Occasionally
–
High in patients with lung cavities –
High Occasionally Occasionally Occasionally
Invasive candidiasis
STAT1 GOF mutations
IL-12Rb1 and IFN-cR1 deficiency
AD HIES
CGD LAD Congenital neutropenia SCID, CIDs, ICL
Invasive aspergillosis
Histoplasmosis
–
Cryptococcal meningitis
–
Cryptococcosis
–
High –
–
–
–
–
–
– – –
Deep dermatophytosis
–
–
–
–
Occasionally –
Histoplasmosis Coccidioidomycosis Histoplasmosis Coccidioidomycosis Paracoccidioidomycosis Coccidioidomycosis Histoplasmosis –
– – – Variable, mostly in patients with SCID, NEMO, DOCK8, CARD11 and MHC class II deficiency High in patients with HIGM syndrome (50%) –
– – – Variable, mostly in patients with HIGM syndrome, DOCK8 deficiency, and ICL
– – – Variable susceptibility to histoplasmosis, mostly in patients with DOCK8 deficiency, HIGM syndrome, and ICL
PCP
Cryptococcosis
Dimorphic infections
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AD, autosomal dominant; CARD9, caspase recruitment domain-containing protein 9; CARD11, caspase recruitment domain-containing protein 11; CGD, chronic granulomatous disease; CID, combined immunodeficiency; CNS, central nervous system; GM-CSF, granulocyte–macrophage colony-stimulating factor; GOF, gain-of-function; HIES, hyper-IgE syndrome; HIGM, hyper-IgM; ICL, idiopathic CD4 lymphopenia; IFN, interferon; IL, interleukin; LAD, leukocyte adhesion deficiencies; MHC, major histocompatibility complex; MonoMAC, monocytopenia and susceptibility to mycobacteria, papillomaviruses, fungi, and myelodysplasia; NEMO, nuclear factor-jB essential modulator; PCP, Pneumocystis pneumonia; SCID, severe combined immunodeficiency; STAT1, signal transducer and activator of transcription 1 .
Other
Cellular and combined deficiencies
Phagocytic defects
PID
Fungal susceptibility
TABLE 4. Primary immunodeficiencies (PIDs) associated with invasive fungal diseases
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and major histocompatibility complex class II deficiency), as well as in patients with idiopathic CD4 lymphopenia, demonstrating the crucial role of CD4 T-cells [40,41]. PCP also occurs in approximately 50% of patients with X-linked hyper-IgM syndrome caused by mutations in CD40L (which is necessary for cooperation between T-lymphocytes and B-lymphocytes and immunoglobulin class switch). In these patients, PCP occurs at a median age of 1.3 years, and is often the defining syndrome for a diagnosis of X-linked hyper-IgM syndrome [65].
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to anticipate the discovery of more rare alleles that may have a greater effect size and thus help to bridge the gap between host genetics and clinics.
Transparency Declaration No conflict of interest of any of the authors is reported.
References
Comments
In the last few years, SNPs and inborn errors in distinct immunological axes mediating susceptibility to specific fungi have been recognized, providing valuable insights into human immunity to fungal diseases and a rationale for developing new approaches to their prevention and treatment. On the basis of current knowledge, certain fungal diseases are highly suggestive of specific PID types. Thus, CMC involves inborn errors in IL-17 immunity, IA involves defects in the phagocyte NADPH oxidase complex, disseminated endemic mycoses or cryptococosis involve defects in the IFN-c–IL-12 axis, and deep dermatophytosis and isolated CNS candidiasis have been associated with CARD9 deficiency. Furthermore, several SNPs have been associated with protection against IFD or a predisposition to IFD. In contrast, the true impact of human host genetics on the predisposition to IFDs and their complications, based on genetic association studies, is not yet established, and therefore host genetic data cannot yet be applied in everyday clinical practice [66,67]. From a clinical point of view, extended knowledge on host genetic polymorphisms associated with predisposition or severity may eventually contribute to a better understanding of the mechanism of disease, to the development of biomarkers, and to the prompt identification of high-risk individuals. Furthermore, the detection of accurate biomarkers could help to target individuals for prophylactic therapy, tailor supportive care according to individual risk profiles, in order to ultimately improve quality of life, reduce costs, and avoid unnecessary and sometimes toxic antifungal therapy. The question remains of what to do when one finds a genetic defect or a specific polymorphism. In the case of some main genetic defects, one can consider specific antifungal prophylaxis and have a high degree of suspicion for IFDs. In general, the transition from host genetics in IFDs to personalized medicine is a difficult issue, as data from both candidate gene studies and whole genome association studies need to be further validated with analytical and clinical sensitivity and specificity procedures. However, with the advent of new methods, such as next-generation sequencing, we may be able
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ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1254–1264
10.1111/1469-0691.12800
Host genetics and opportunistic fungal infections Z.-D. Pana1, E. Farmaki2 and E. Roilides1 1) Infectious Diseases Unit, 3rd Department of Paediatrics, and 2) Laboratory of Clinical Immunology, 1st Department of Paediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Thessaloniki, Greece
Abstract Current knowledge on the human pathophysiology of fungal infections highlights the crucial role of genetic pitfalls in specific immunity pathways that determine, together with other risk factors, the predisposition to and clinical outcome of fungal disease. In several studies, associations between gene polymorphisms and genetic errors have been implicated in an immunodeficiency phenotype and an increased incidence of opportunistic fungal diseases. The major challenge is to fully understand the complex interactions between genetic variations and multiple factors, and their relative contributions to the final clinical fungal disease phenotype. The aim of this review is to present updated knowledge on immunity genetics and susceptibility to medically relevant fungal diseases, such as those caused by Candida, Aspergillus, and certain other more rare fungi. Keywords: Adaptive immunity, Aspergillus, Candida, fungi, immune markers, innate immunity Article published online: 10 October 2014 Clin Microbiol Infect 2014; 20: 1254–1264
Corresponding author: E. Roilides, Infectious Diseases Unit, 3rd Department of Paediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital Konstantinoupoleos 49, Thessaloniki, 54642 Greece E-mail: [email protected]
Introduction Fungal infections remain a major cause of significant morbidity and mortality among specific patient groups and of an increased financial burden to the healthcare economics. One major priority in the field is the extended identification of all possible fungal-specific and host-specific factors for fungal disease predisposition, which is crucial knowledge that could ‘refine’ the future management of these patients. A large panel of well-defined clinical and laboratory parameters has been implicated in the development, severity and outcome of certain invasive fungal diseases (IFDs) in the immunocompromised host. On the other hand, significant variability has been reported in the development and outcome of IFD among patients with the same predisposing factors, implying an individualized genetic pattern of susceptibility. Accumulating evidence has recently shown that immune system genetic variations leading to imbalances in both proinflammatory and anti-inflammatory
responses may predispose to fungal infections. Hence, it is reasonable to speculate that genetic variations involved in important pathways of the innate and adaptive immune systems may represent a potential source of variability in susceptibility to IFD. These genetic variations, known also as single-nucleotide polymorphisms (SNPs), refer to one of multiple alternative forms within a nucleic acid sequence that occurs with increased frequency (>1%) within a population and allows evolution by natural selection. SNPs are perceived as equally acceptable alternatives in a DNA sequence, and in most cases their impact on a gene may not significantly influence the activity of the encoded protein. Nevertheless, under certain circumstances, even these minor effects may significantly influence susceptibility to human disease. In contrast, mutations result from rare (<1%) genetic errors originating from unrepaired errors in the DNA replication process. These genetic errors can have an impact on the phenotype of an organism, especially if they occur within the pro-
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tein-coding sequence of a gene. Mutations can be also divided into hereditary or germline mutations, when the error exists in the reproductive cells and can be passed from generation to generation, and acquired or somatic mutations, when the error occurs in the DNA of individual cells that develop throughout a person’s life and is passed only to direct descendants of those cells. For many pathological conditions, there may even be different mutations in the gene, which may cause the same disease with variations in the phenotype. A few clinically relevant disorders may be the result of only a single defective gene mutation, and are called monogenetic disorders. These inherited diseases, controlled by a single pair of alleles, are passed on from one generation to another in a simple pattern according to Mendel’s laws. In recent years, variants in several immune-related SNPs and inborn genetic errors of immunity associated with monogenetic disorders have been proposed to affect immunity against Candida and Aspergillus species by influencing commensalism, symbiosis, latency and dissemination of the fungi. Selection of the appropriate candidate ‘key’ genes and their polymorphisms remains a great challenge, and metagenomic technologies hold promise for resolving questions regarding the functional effects of crucial genes in IFD predisposition. This review highlights the present knowledge on immunity genetics and susceptibility to IFD.
Immune Genetic Profile and Aspergillosis Innate immunity plays a significant role in the initial phase of ingestion, killing and elimination of Aspergillus conidia. Furthermore, the local production of cytokines by activated macrophages and neutrophils seems to regulate proinflammatory (Th1) and anti-inflammatory (Th2) immune reactions. Several cytokine gene polymorphisms are considered to be candidate prognostic biomarkers for Aspergillus infection (Table 1). Cytokine functional gene polymorphisms (interleukin (IL)-10, IL-15, transforming growth factor (TGF)-b1, tumour necrosis factor (TNF)-a, and interferon (IFN)-c) have been evaluated in patients with chronic cavitary pulmonary aspergillosis (CCPA) and allergic bronchopulmonary aspergillosis (ABPA) [1]. Specific alleles have been more frequently detected in patients suffering from invasive aspergillosis (IA), such as the IL-15 +13689A allele [1]. The presence of the IFN-c 874T>A polymorphism as a single SNP or as a combined deficiency with an SNP in Toll-the like receptor (TLR)-4 gene (1063A>G) has shown a trend to cause increased susceptibility to IA [1,2]. CCPA patients have been genetically determined produce less IL-10 and TGF-b1, owing to the frequent presence of the IL-10
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1082G and TGF-b1 +869T alleles [1]. In patients undergoing allogeneic stem cell transplantation (SCT), SNPs in the promoter region of the IL-10 gene and an ACC haplotype are independent protective markers for invasive pulmonary aspergillosis (IPA), suggesting that the genotypic variability of the IL-10 gene promoter region modulates the production of IL-10 and indirectly influences the risk of developing IPA [3,4]. In particular, for the IL-10 1082(AA) genotype, the results are rather controversial. According to Sainz et al., the IL-10 1082(AA) genotype is associated with resistance to the development of IPA, whereas in another study the genotype was associated with an increased risk of ABPA in patients with cystic fibrosis [5]. A polymorphism in the IL-4 receptor gene plays a role in the occurrence of ABPA [6]. Sainz et al. [7] evaluated the role of IL-1 gene cluster polymorphisms in the pathogenesis of, susceptibility to and resistance to IPA, and found that specific haplotypes (VNTR2/–889C/–511T) were significantly associated with the development of IPA, whereas others (VNTR2/–889C/–511C) were associated with resistance. In a recent study by Carvalho et al. [8], a prognostic role of IL-23 receptor gene polymorphism was found in patients undergoing SCT, implying that donors with the R381Q haplotype gave a protective effect against IA. In evaluation of the genetic risk for developing IPA, IL-6 gene polymorphisms (promoter at positions 174 (C/G) and 634 (G/C)) were not significantly associated with an increased predisposition to develop IPA [9]. As well as SNPs in other cytokine receptor genes, SNPs in the TNF receptor 1 and TNF receptor 2 genes have been associated with IPA predisposition in two studies, owing to decreased TNF expression [10,11]. SNPs in the gene encoding chemokine ligand 10, which enhances chemokine secretion after Aspergillus stimulation, seemed to influence susceptibility to IPA in alloSCT patients [12]. A non-synonymous SNP in the gene encoding plasminogen, a factor that binds to fungal cell wall of Aspergillus fumigatus, affected the risk of developing IA in patients after SCT [13]. An SNP in the gene encoding dectin-1 receptor, a major receptor for fungal b-glucans on myeloid cells, leads to a decreased Th17 response and seems to influence the presence of IA in non-SCT patients but not the clinical course of IA in SCT recipients [14]. However, in another study, this SNP increased the risk of IA, with the risk being highest when the SNP was detected simultaneously in both donor and recipient [15]. Finally, the carriage of several alleles of dectin-1 and DC-SIGN polymorphisms increases the risk of IPA [16]. The role of genetic variations of TLR genes in IA predisposition has been extensively evaluated, with partially contradictory results. TLR-2 gene polymorphism has not been associated with CCPA and IA in haematological patients after SCT [17,18].
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TABLE 1. Single-nucleotide polymorphisms (SNPs) and Aspergillus infection Gene Mannose-binding lectin (MBL)2
SNP
Aspergillus-related disease
Comments
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10/82
CNPA
Mutant MBL2 higher in CNPA patients than in controls (70% vs. 25.6%) (p 0.004)
[23]
15/82
CCPA, ABPA
T allele (p 0.020) and CT genotype (p 0.05) associated with CCPA but not with ABPA
[22]
Codon 54 Allele B
23/52
IA
No difference in mutant MBL2 genotype between patients with aspergillosis and controls (44% vs. 34.8%) (p >0.05)
[21]
Intron –1011A/G
11/84
ABPA
Mutant SNP associated with allergic rhinitis in bronchial asthma and ABPA (p <0.01)
[24]
101C/T
51/49
IA after HSCT
SNP associated with an increased risk of IA development (p = 0.007 OR= 2.2 CI = 1.2–3.8)
[12]
1642C/G
39/46
IA after HSCT
SNP associated with an increased risk of IA development (p 0.003, OR 2.6. 95% CI 1.4–5.0)
[12]
52/44
IA after HSCT
SNP associated with an increased risk of IA development (p 0.001, OR 2.8, 95% CI 1.6–5.2)
[12]
22/105
IA after HSCT
Presence of both recipient SNPs associated with IA (p <0.001, OR 1.3, 95% CI 1.1–1.5)
[19]
22/105
IA after HSCT
SNP associated with IA (p <0.001, OR 1.3, 95% CI 1.1–1.5)
[19]
TLR-4 1063A/G
44/64
IA after HSCT
The combined presence of TLR-4 and IFN-c 874T>A SNPs associated with increased susceptibility to IA (p 0.04, OR 6.09, 95% CI 1.05–35.5)
[2]
TLR-4 1063A/G
103/263
IA after HSCT
Donor TLR-4 haplotype (S3) associated with increased risk of IA (p 0.020, OR 2.2, 95% CI 1.1–4.2)
[20]
TLR-4 1363C/T
103/263
IA after HSCT
Donor TLR-4 haplotype (S4) associated with increased risk of IA (p 0.002, OR 6.2, 95% CI 2.0–19.3)
[20]
TLR-4 1063A/G
40/80
CCPA
Recipient SNPs associated with CCPA (p 0.003, OR 3.5, 95% CI 1.5–8.1)
[17]
TLR-9 1237C/T
22/80
ABPA
SNP associated with ABPA (p 0.043, OR 2.5, 95% CI 1.0– 6.2)
[17]
Tumour necrosis factor (TNF)-a
TNF-a –308A/A
54/48
IA
Lower frequency of TNF-a –308A/A genotype in IA (p <0.01)
[1]
IPA in haematological patients
IPA associated with TNFR2 –322 SNP (p 0.029) but not with TNFR2 +676 SNP (p >0.05)
[10]
Interleukin (IL)
TNFR2 +676 322 IL-10 1082A/G 819C/T 592A/C
9/96
Increased IPA dependent on IL-10 haplotype (p 0.031)
[4]
IL-10 1082A/G
119 colonized/ 27 ABPA/232
Colonization with Aspergillus fumigatus or ABPA in CF
IL-10 –1082GG genotype associated with A. fumigatus colonization and ABPA in CF patients (p 0.020, OR 1.7, 95% CI 1.1–2.5)
[5]
IL-10 1082A/G
59/61
IPA in haematological patients
IL-10 –1082AA associated with resistance to IPA development (p 0.001)
[3]
Chemokine ligand 10 (C-X-C 10)
Codon 52 868C/T
Patients/ controls
1101A/G Toll-like receptors (TLRs)
TLR-4 239C/G 743A/G TLR-6 745C/T
IPA after HSCT
IL-10 promoter SNPs independent predictive factors for IPA (p 0.012, OR 9.3, 95% CI 1.6–52.8)
IL-10 –1082A allele weakly associated with IPA susceptibility (p 0.052, OR 1.7, 95% CI 1.0–2.9) IL-10 –1082A/G
24
CCPA
CCPA associated with lower frequency of IL-10 –1082G allele (OR 0.38, p 0.0006) and G/G genotype (p <0.001)
IL-1b 511C/T 889C/T IL-1Ra
59/51
IPA in haematological patients
IL-1 and IL-1Ra SNPs not associated with IPA (p 0.56 and p 0.68) VNTR2/889C/–511T haplotype associated with increased susceptibility to IPA (p 0.02); VNTR2/–889C/–511C haplotype associated with resistance to IPA (p 0.028)
[1]
[7]
IL-1Ra VNTR2/2 and IL1b(–511)T/T genotypes associated with higher positive serum galactomannan percentage than other genotypes (p 0.09) IL-15 +13689
IA
IA associated with higher frequency of IL-15 +13689A allele (OR 2.37, p 0.0028) and A/A genotype (p <0.001)
[1]
IL-23R IL-17A IL-17F
IA in SCT patients
IL-23R GA genotype improved overall survival (HR 0.48, p 0.028) and, in the donor, decreased the risk of fungal infections (p 0.05)
[8]
ABPA
IL-4Ra SNP associated with ABPA (p 0.008)
[6]
IL-4Ra 4679 A/C/G/T
40/56
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1254–1264
CMI
Pana et al.
Primary Immunodeficiencies (monogenetic disorders) and Infections
(PIDs) Fungal
CMC
To date, several monogenetic disorders have been associated with an increased susceptibility to CMC [40–43]. Primary T-cell deficiencies, such as severe combined immunodeficiency (SCID) and certain combined immunodeficiencies, are variably associated with CMC in infancy, in addition to multiple infectious and autoimmune diseases (Table 3). Furthermore, CMC represents one of the main clinical presentations in several rare PIDs associated with defective Th17 responses [40–43]. Autosomal dominant hyper-IgE syndrome (HIES) was the first syndrome in which impaired IL-17 immunity was implicated in CMC susceptibility [44]. Autosomal dominant HIES is caused by mutations in the gene encoding STAT3, a signalling molecule downstream of the IL-23 receptor, resulting in markedly reduced or absent IL-17 production and increased susceptibility to CMC from the neonatal period, in addition to severe skin and lung staphylococcal infections [44,45].
Host genetics and opportunistic fungal infections
1259
Recently, Glocker et al. [46] described a single large consanguineous family with autosomal recessive caspase recruitment domain-containing protein 9 (CARD9) deficiency and a history of recurrent CMC in addition to other fungal infections, such as dermatophytosis and central nervous system (CNS) candidiasis. All patients showed a significant defect in the Th17 response, probably because of impaired CARD9-dependent signalling downstream from several C-type lectin receptors, such as dectin-1, dectin-2, and MINCLE, which can recognize fungal pathogen-associated molecular patterns. However, the underlying mechanism remains to be elucidated [40,42]. Deep dermatophytosis was reported to be an important manifestation of CARD9 deficiency [47]. Patients with autosomal recessive IL-12Rb1 and IL-12p40 deficiencies typically present with Mendelian susceptibility to mycobacterial disease [48]. Approximately 25% of these patients also show mild CMC, which may be the first manifestation [49]. Some of these patients have low proportions of IL-17-producing and IL-22-producing T-cells, probably because of impaired IL-23 signalling [48,50]. CMC is the ‘signature’ disease and one of the earliest manifestations in patients with autosomal recessive autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy [51]. It is caused by
TABLE 3. Primary immunodeficiencies (PIDs) associated with chronic mucocutaneous candidiasis (CMC) CMC incidencea
PID Cellular and combined
PIDs with defective Th17 immunity
SCID (>30 genes) X-linked or AR
30–35%
CIDs: DOCK8 deficiency (AR HIES) NEMO or IKBa deficiency MST1/STK4 deficiency MHC class II deficiency CD25 deficiency TCR-a deficiency CRACM1 deficiency TYK2 deficiency (AR HIES) Idiopathic CD4 lymphopenia
Variable, depending on immune deficit High in DOCK8 (~80%)
STAT3 (AD HIES)
80%
CARD9 AR
Other fungal infections
Non-fungal infections
Variable, depending on immune deficit Variable, depending on immune deficit, mostly PCP, cryptococcosis, and histoplasmosis
Bacteria, viruses, and mycobacteria Viruses, bacteria, and mycobacteria (NEMO, CRACM1)
PCP Cryptococcosis Histoplasmosis
Viruses
Aspergillosis Cryptococcosis Histoplasmosis
Bacterial (mostly Staphylococcus aureus)
Dermatophytes CNS candidiasis
None
IL-12Rb1 and IL-12p40 (AR MSMD)
25–70%
Invasive candidiasis Histoplasmosis Coccidioidomycosis Paracoccidioidomycosis
Mycobacteria, Salmonella
AIRE (AR APECED)
90–100%
None
None
None
S. aureus
None
S. aureus
PCP Histoplasmosis Coccidioidomycosis
Viruses
CMCD: IL-17RA deficiency IL-17F deficiency STAT1 GOF mutation (AD)
Up to 100%
AD, autosomal dominant; AIRE, autoimmune regulator; APECED, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy; AR, autosomal recessive; CARD9, caspase recruitment domain-containing protein 9; CMCD, chronic mucocutaneous candidiasis disease; CNS, central nervous system; CRACM1, calcium release-activated calcium modulator 1; GOF, gain-of-function; HIES, hyper-IgE syndrome; IL, interleukin; MHC, major histocompatibility complex; MSMD, Mendelian susceptibility to mycobacterial disease; NEMO, nuclear factor-jB essential modulator; NK, natural killer; PCP, Pneumocystis pneumonia; SCID, severe combined immunodeficiency; STAT, signal transducer and activator of transcription; TCR, T-cell receptor. a Data on CMC incidence are presented for PIDs for which this information is available.
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1254–1264
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Clinical Microbiology and Infection, Volume 20 Number 12, December 2014
TABLE 2. Single-nucleotide polymorphisms (SNPs) and Candida infection Gene Mannose-binding lectin (MBL)2
SNP Codon 54 Allele B Codon 54 Allele B
Patients/ controls
Candida-related disease
Comments
Reference
42/43
VVC
Allele B associated with increased risk of VVC (p <0.0001)
[38]
109
RVC
Variant allele B more frequent in patients with RVC than in controls (20% vs, 6.6%, OR 3.4, 95% CI 1.3–8.2, p 0.01)
[39]
B alleles in 25% of 36 patients not suffering from any recurrence during the maintenance therapy with decreasing doses of fluconazole vs. controls (OR 4.9, 95% CI 1.9–12.5, p 0.0007) B alleles in 20% of the 43 patients with sporadic recurrences vs. controls (OR 3.6, 95% CI 1.4–9.2, p 0.007) Allele D Allele B Allele C
88
Abdominal Candida infections
Variant MBL genotype not associated with abdominal yeast infection (53% vs. 38%, p 0.18)
[37]
Variant MBL genotype associated with yeast infection during early peritonitis (39% vs. 16%, p 0.012) 338/351
Candidaemia
Three TLR-1 SNPs (R80T, S248N, and I602S) associated with increased susceptibility to candidaemia (p 0.02; p 0.04; p 0.02)
[32]
325
Candidaemia in ICU patients
Heterozygous TLR-2 SNP patients showed elevated TNF-a plasma concentrations, but reduced IFN-c and IL-8 levels
[31]
TLR-4 D299G Y399I TLR-3 L412F
43/133
Candidaemia
TLR-4 Asp299Gly SNP more frequently detected in patients with candidaemia than in controls (26% vs. 10%; OR 3.0, 95% CI 1.3–6.9)
[30]
CMC
Variant SNP associated with reduced IFN-c and TNF-a secretion in response to stimulation with the TLR-3 ligand or Candida albicans
[29]
Dectin-1
Y238X
Candida colonization
Y238X SNP associated with increased risk of Candida colonization
[33]
CARD9
Y238X S12N
142 patients with HSCT 331/351
Candidaemia
No association between dectin-1 SNP, CARD9 SNP and prevalence of candidaemia (p >0.05)
[34]
Interleukin (IL)
IL-4 –589T/C IL-4 –1098T/G –589C/T –33C/T
42/43
VVC
Increased susceptibility to VVC in women with IL-4 SNP
[38]
40/43
CDC in leukaemia patients
IL-4 (–1098T/–589C/–33C) haplotype associated with increased risk of CDC development (p 0.01, OR 2.16)
[27]
IL-10 –1082A/G IL-12B 2724 INS/DEL –44C/G
338/351
Persistent candidaemia
Persistent candidaemia associated with SNPs in IL-10 (OR 3.45, 95% CI 1.33–8.93) and IL-12B (OR 5.36, 95% CI 1.51–19.0)
[26]
43/50
Candida carriage in diabetic patients
SNP associated with Candida carriage in both groups (diabetic and non-diabetic) (OR 25 for diabetic subjects and OR 8.5 for non-diabetic subjects)
[35]
Toll-like receptors (TLRs)
b-Defensin-1
TLR-1 R80T S248N I602S TLR-2 R753Q
IL-4 (–1098T/–589T/–33T) haplotype protective against CDC development (p 0.018, OR 0.47)
CARD9, caspase recruitment domain-containing protein 9; CDC, chronic disseminated candidiasis; CMC, chronic mucocutaneous candidiasis; HSCT, haematopoietic stem cell transplantation; ICU, intensive-care unit; IFN, interferon; RVC, recurrent vulvovaginal candidiasis; TNF, tumour necrosis factor; VVC, vulvolvaginal candidiasis.
predisposing role. Nahum et al. [29] observed that the TLR-3 receptor gene variant allele L412F seems to increase the risk of chronic mucocutaneous candidiasis (CMC). Increased susceptibility to invasive candidiasis (IC) and candidaemia has been also associated with the presence of specific SNPs in the TLR-2 and TLR-4 genes [30,31]. A multivariate analysis revealed that three TLR-1 gene SNPs (R80T, S248N, and I602S) were significantly associated with candidaemia susceptibility in Caucasians [32]. The C-type lectin receptor dectin-1 has been also implicated in the early recognition and elimination of Candida species. The dectin-1 Y238X early stop polymorphism was associated in one study with an increased risk of gastrointestinal colonization with Candida species in immunocompromised patients, whereas in another study the same SNP did not significantly influence the risk of candidaemia [33,34]. A
modulating effect on Candida colonization has also been associated with the presence of specific SNPs in the genes encoding b-defensins, which are cationic peptides of the epithelium that exert local antifungal activity. In particular, the C/G SNP at position –44 seemed to have a protective role against Candida colonization in diabetic and non-diabetic patients [35]. In one study, increased risks of CMC and recurrent vulvovaginal candidiasis were associated with the presence of one SNP in the gene encoding inflammasome component NALP3, which regulates IL-1b production [36]. Finally, patients with specific SNPs associated with a defective MBL2 gene showed an increased risk of developing abdominal Candida infections in secondary peritonitis, with recurrent vulvovaginal candidiasis and with response to fluconazole treatment [37– 39].
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1254–1264
CMI
Pana et al.
Primary Immunodeficiencies (monogenetic disorders) and Infections
(PIDs) Fungal
CMC
To date, several monogenetic disorders have been associated with an increased susceptibility to CMC [40–43]. Primary T-cell deficiencies, such as severe combined immunodeficiency (SCID) and certain combined immunodeficiencies, are variably associated with CMC in infancy, in addition to multiple infectious and autoimmune diseases (Table 3). Furthermore, CMC represents one of the main clinical presentations in several rare PIDs associated with defective Th17 responses [40–43]. Autosomal dominant hyper-IgE syndrome (HIES) was the first syndrome in which impaired IL-17 immunity was implicated in CMC susceptibility [44]. Autosomal dominant HIES is caused by mutations in the gene encoding STAT3, a signalling molecule downstream of the IL-23 receptor, resulting in markedly reduced or absent IL-17 production and increased susceptibility to CMC from the neonatal period, in addition to severe skin and lung staphylococcal infections [44,45].
Host genetics and opportunistic fungal infections
1259
Recently, Glocker et al. [46] described a single large consanguineous family with autosomal recessive caspase recruitment domain-containing protein 9 (CARD9) deficiency and a history of recurrent CMC in addition to other fungal infections, such as dermatophytosis and central nervous system (CNS) candidiasis. All patients showed a significant defect in the Th17 response, probably because of impaired CARD9-dependent signalling downstream from several C-type lectin receptors, such as dectin-1, dectin-2, and MINCLE, which can recognize fungal pathogen-associated molecular patterns. However, the underlying mechanism remains to be elucidated [40,42]. Deep dermatophytosis was reported to be an important manifestation of CARD9 deficiency [47]. Patients with autosomal recessive IL-12Rb1 and IL-12p40 deficiencies typically present with Mendelian susceptibility to mycobacterial disease [48]. Approximately 25% of these patients also show mild CMC, which may be the first manifestation [49]. Some of these patients have low proportions of IL-17-producing and IL-22-producing T-cells, probably because of impaired IL-23 signalling [48,50]. CMC is the ‘signature’ disease and one of the earliest manifestations in patients with autosomal recessive autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy [51]. It is caused by
TABLE 3. Primary immunodeficiencies (PIDs) associated with chronic mucocutaneous candidiasis (CMC) CMC incidencea
PID Cellular and combined
PIDs with defective Th17 immunity
SCID (>30 genes) X-linked or AR
30–35%
CIDs: DOCK8 deficiency (AR HIES) NEMO or IKBa deficiency MST1/STK4 deficiency MHC class II deficiency CD25 deficiency TCR-a deficiency CRACM1 deficiency TYK2 deficiency (AR HIES) Idiopathic CD4 lymphopenia
Variable, depending on immune deficit High in DOCK8 (~80%)
STAT3 (AD HIES)
80%
CARD9 AR
Other fungal infections
Non-fungal infections
Variable, depending on immune deficit Variable, depending on immune deficit, mostly PCP, cryptococcosis, and histoplasmosis
Bacteria, viruses, and mycobacteria Viruses, bacteria, and mycobacteria (NEMO, CRACM1)
PCP Cryptococcosis Histoplasmosis
Viruses
Aspergillosis Cryptococcosis Histoplasmosis
Bacterial (mostly Staphylococcus aureus)
Dermatophytes CNS candidiasis
None
IL-12Rb1 and IL-12p40 (AR MSMD)
25–70%
Invasive candidiasis Histoplasmosis Coccidioidomycosis Paracoccidioidomycosis
Mycobacteria, Salmonella
AIRE (AR APECED)
90–100%
None
None
None
S. aureus
None
S. aureus
PCP Histoplasmosis Coccidioidomycosis
Viruses
CMCD: IL-17RA deficiency IL-17F deficiency STAT1 GOF mutation (AD)
Up to 100%
AD, autosomal dominant; AIRE, autoimmune regulator; APECED, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy; AR, autosomal recessive; CARD9, caspase recruitment domain-containing protein 9; CMCD, chronic mucocutaneous candidiasis disease; CNS, central nervous system; CRACM1, calcium release-activated calcium modulator 1; GOF, gain-of-function; HIES, hyper-IgE syndrome; IL, interleukin; MHC, major histocompatibility complex; MSMD, Mendelian susceptibility to mycobacterial disease; NEMO, nuclear factor-jB essential modulator; NK, natural killer; PCP, Pneumocystis pneumonia; SCID, severe combined immunodeficiency; STAT, signal transducer and activator of transcription; TCR, T-cell receptor. a Data on CMC incidence are presented for PIDs for which this information is available.
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1254–1264
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Clinical Microbiology and Infection, Volume 20 Number 12, December 2014
a mutation in the autoimmune regulator gene, resulting in impaired T-cell tolerance. The associated CMC could not be explained by the underlying mutation in the context of autoimmunity until high levels of neutralizing autoantibodies against Th-17 cytokines (IL-17A, IL-17F, and IL-22) were detected in the sera of autoimmune polyendocrinopathy– candidiasis–ectodermal dystrophy patients [52]. These findings provided more evidence for the pivotal role of IL-17 immunity in protection against CMC. The pathogenesis of CMC was eventually deciphered in 2011, through investigations in patients suffering from CMC disease (CMCD), which had an unknown genetic cause until then [40]. The identification of complete autosomal recessive IL-17RA and partial autosomal dominant IL-17F deficiencies in pedigrees suffering from CMCD provided direct genetic evidence for the role of IL-17 immunity in human susceptibility to CMC [52]. Subsequently, gain-of-function mutations of STAT1 were demonstrated to be the main cause of autosomal dominant CMCD through genome-wide approaches [53,54]. These findings were confirmed by several other research groups in almost 100 patients with CMCD and markedly impaired IL-17 production, presumably as a result of impaired dephosphorylation of STAT1, a signalling molecule downstream of the IFN type I/II, IL-23 and IL-12 receptors [40,42,55]. Gain-of-function STAT1 mutations have also been reported to predispose to disseminated dimorphic yeast infections [55]. IFDs
Consistent with the immune mechanisms involved in human host defence against fungi, IFDs occur with increased frequency in patients with phagocytic, cellular and IFN-c–IL-12 axis immune defects [40,43,56]. Among PIDs, chronic granulomatous disease and HIES are most frequently associated with IFDs; variable susceptibility to IFDs is also seen in patients with SCID, X-linked hyper-IgM syndrome, and other rare PID syndromes (Table 4). Invasive aspergillosis. Chronic granulomatous disease (CGD) is the PID with the highest incidence of IFDs, mainly caused by Aspergillus species [56,57]. IA accounts for over one-third of all infections in CGD, and may be the presenting manifestation, frequently occurring during the first two decades of life [56,57]. An impaired respiratory burst in granulocytes and monocytes underlies pulmonary aspergillosis in CGD [58]. IA also occurs in approximately 25% of patients with autosomal dominant HIES, with 17% mortality. However, susceptibility to IA, which always arises secondarily to pneumatocyst formation or bronchiectasis resulting from repeated bacterial pneumonias, is probably related to defective
CMI
STAT3 functions in lung epithelia, and not to impaired phagocytosis [59]. Finally, IA has been occasionally encountered in autosomal recessive leukocyte adhesion deficiency type 1, and, to a lesser extent, in congenital neutropenia syndromes [40,41,56]. Invasive candidiasis. IC in PIDs is far less common than IA, and has occasionally been reported in patients with certain innate immune defects, such as CGD, severe congenital neutropenia, and autosomal recessive leukocyte adhesion deficiency type 1 [41,56]. CNS Candida infections have been reported in CGD patients and recently in three members of a consanguineous family with autosomal recessive CARD9 deficiency [40,46]. This is the only PID predisposing to IC of the CNS, possibly as a result of CARD9 expression predominantly on monocytes, affecting their function [40,43]. Other IFDs. Dimorphic fungal diseases such as disseminated histoplasmosis, coccidioidomycosis and paracoccidioidomycosis have been reported in patients with mutations affecting the IL-12–IFN-c axis and Mendelian susceptibility to mycobacterial disease, such as IL-12Rb1 and autosomal dominant partial IFN-cR1 deficiency [40,43,60]. In this patient group, fungal susceptibility is consistent with preclinical studies suggesting the important roles of IFN-c and IL-12 in host immune responses to these organisms [56,61]. Similarly, patients with gain-of-function STAT1 mutations have recently been reported with severe disseminated dimorphic yeast infections, probably because of aberrant regulation of IFN-c-mediated inflammation [55]. In addition, recent evidence suggests that genetic defects in the IFN-c and/or granulocyte–macrophage colony-stimulating factor signalling pathways may create a predisposition to cryptococcosis, as has been described in a few patients with neutralizing autoantibodies against IFN-c or granulocyte–macrophage colony-stimulating factor [62,63]. Disseminated histoplasmosis and cryptococcosis have also been reported in patients with idiopathic CD4 lymphopenia, X-linked CD40L deficiency, autosomal dominant HIES, DOCK8 deficiency associated with autosomal recessive HIES, and sporadic or autosomal dominant GATA2 deficiency related to the recently described syndrome of monocytopenia and susceptibility to mycobacteria, papillomaviruses, fungi, and myelodysplasia [40,41,64]. In addition to IA, Paecilomyces, and, to a lesser extent, Scedosporium and Trichosporon species have been occasionally implicated in infections in CGD patients [41,56]. Pneumocystis pneumonia (PCP) occurs with variable frequency in patients with profound T-cell deficiencies (SCID and certain combined immunodeficiencies, such as NEMO, DOCK8, caspase recruitment domain-containing protein 11
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1254–1264
– – Invasive CNS candidiasis –
– – Few cases
Autoantibodies against IFN-c or GM-CSF CARD9
MonoMAC syndrome
Occasionally (IL-12Rb1)
Occasionally
Occasionally Occasionally Occasionally Occasionally
–
High in patients with lung cavities –
High Occasionally Occasionally Occasionally
Invasive candidiasis
STAT1 GOF mutations
IL-12Rb1 and IFN-cR1 deficiency
AD HIES
CGD LAD Congenital neutropenia SCID, CIDs, ICL
Invasive aspergillosis
Histoplasmosis
–
Cryptococcal meningitis
–
Cryptococcosis
–
High –
–
–
–
–
–
– – –
Deep dermatophytosis
–
–
–
–
Occasionally –
Histoplasmosis Coccidioidomycosis Histoplasmosis Coccidioidomycosis Paracoccidioidomycosis Coccidioidomycosis Histoplasmosis –
– – – Variable, mostly in patients with SCID, NEMO, DOCK8, CARD11 and MHC class II deficiency High in patients with HIGM syndrome (50%) –
– – – Variable, mostly in patients with HIGM syndrome, DOCK8 deficiency, and ICL
– – – Variable susceptibility to histoplasmosis, mostly in patients with DOCK8 deficiency, HIGM syndrome, and ICL
PCP
Cryptococcosis
Dimorphic infections
Pana et al.
AD, autosomal dominant; CARD9, caspase recruitment domain-containing protein 9; CARD11, caspase recruitment domain-containing protein 11; CGD, chronic granulomatous disease; CID, combined immunodeficiency; CNS, central nervous system; GM-CSF, granulocyte–macrophage colony-stimulating factor; GOF, gain-of-function; HIES, hyper-IgE syndrome; HIGM, hyper-IgM; ICL, idiopathic CD4 lymphopenia; IFN, interferon; IL, interleukin; LAD, leukocyte adhesion deficiencies; MHC, major histocompatibility complex; MonoMAC, monocytopenia and susceptibility to mycobacteria, papillomaviruses, fungi, and myelodysplasia; NEMO, nuclear factor-jB essential modulator; PCP, Pneumocystis pneumonia; SCID, severe combined immunodeficiency; STAT1, signal transducer and activator of transcription 1 .
Other
Cellular and combined deficiencies
Phagocytic defects
PID
Fungal susceptibility
TABLE 4. Primary immunodeficiencies (PIDs) associated with invasive fungal diseases
CMI Host genetics and opportunistic fungal infections 1261
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1254–1264
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Clinical Microbiology and Infection, Volume 20 Number 12, December 2014
and major histocompatibility complex class II deficiency), as well as in patients with idiopathic CD4 lymphopenia, demonstrating the crucial role of CD4 T-cells [40,41]. PCP also occurs in approximately 50% of patients with X-linked hyper-IgM syndrome caused by mutations in CD40L (which is necessary for cooperation between T-lymphocytes and B-lymphocytes and immunoglobulin class switch). In these patients, PCP occurs at a median age of 1.3 years, and is often the defining syndrome for a diagnosis of X-linked hyper-IgM syndrome [65].
CMI
to anticipate the discovery of more rare alleles that may have a greater effect size and thus help to bridge the gap between host genetics and clinics.
Transparency Declaration No conflict of interest of any of the authors is reported.
References
Comments
In the last few years, SNPs and inborn errors in distinct immunological axes mediating susceptibility to specific fungi have been recognized, providing valuable insights into human immunity to fungal diseases and a rationale for developing new approaches to their prevention and treatment. On the basis of current knowledge, certain fungal diseases are highly suggestive of specific PID types. Thus, CMC involves inborn errors in IL-17 immunity, IA involves defects in the phagocyte NADPH oxidase complex, disseminated endemic mycoses or cryptococosis involve defects in the IFN-c–IL-12 axis, and deep dermatophytosis and isolated CNS candidiasis have been associated with CARD9 deficiency. Furthermore, several SNPs have been associated with protection against IFD or a predisposition to IFD. In contrast, the true impact of human host genetics on the predisposition to IFDs and their complications, based on genetic association studies, is not yet established, and therefore host genetic data cannot yet be applied in everyday clinical practice [66,67]. From a clinical point of view, extended knowledge on host genetic polymorphisms associated with predisposition or severity may eventually contribute to a better understanding of the mechanism of disease, to the development of biomarkers, and to the prompt identification of high-risk individuals. Furthermore, the detection of accurate biomarkers could help to target individuals for prophylactic therapy, tailor supportive care according to individual risk profiles, in order to ultimately improve quality of life, reduce costs, and avoid unnecessary and sometimes toxic antifungal therapy. The question remains of what to do when one finds a genetic defect or a specific polymorphism. In the case of some main genetic defects, one can consider specific antifungal prophylaxis and have a high degree of suspicion for IFDs. In general, the transition from host genetics in IFDs to personalized medicine is a difficult issue, as data from both candidate gene studies and whole genome association studies need to be further validated with analytical and clinical sensitivity and specificity procedures. However, with the advent of new methods, such as next-generation sequencing, we may be able
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