In spite of the important role played by these risk factors, they do not explain all Candida infections, and only a minority of individuals at risk will eventually develop a fungal infection. It is therefore believed that also genetic factors must play an important role in determining the susceptibility to Candida infections. Indeed, mutations in single genes were found to be responsible for severe Candida infections in several primary immunodeficiencies that display the clinical picture of monogenetic disorders. However, these disorders are rare, and in the majority of patients no sole causative genetic factor can be found. In most patients a combination of gene polymorphisms and/or environmental factors will determine whether a patient will develop a Candida infection. The genetic susceptibility to more common Candida infections such as RVVC or candidemia is likely polygenic, but the understanding of the genetic factors that determine it is nevertheless crucial for future immunotherapeutic approaches in these patients.
Several monogenetic disorders have been described in the literature to be associated with an increased susceptibility to fungal infections. Glocker et al described that a homozygous mutation in the CARD9 gene, coding for a protein downstream of Dectin-1, results in an increased susceptibility to both mucosal and invasive Candida infections (Glocker et al, 2009; Lanternier et al, 2012). Disease severity in these patients is likely explained by the fact that CARD9 is also involved in the downstream signaling of several other CLR receptors, such as Dectin-2 and Mincle (Robinson et al, 2009; Saijo et al, 2010; Strasser et al, 2012; Yamasaki et al, 2008), implying that CARD9 is a central mediator of anti-Candida host defense.
Another monogenetic disorder that results in an important primary immunodeficiency associated with Candida infections is CMC. Both autosomal recessive and autosomal dominant variants of the disease have been described. Mutations in the CC-domain of STAT1, a signaling molecule downstream of the type I and type II IFN receptor (Darnell et al, 1994), but also IL-23 and IL-12 receptors (as heterodimer with STAT3 or STAT4), have recently been demonstrated to be the main cause of autosomal-dominant CMC (van de Veerdonk et al, 2011), and these findings were confirmed by several other research groups (Depner et al, 2012; Hirata et al, 2012; Liu et al, 2011; Martinez-Martinez et al, 2012; Moreira et al, 2012; Okada et al, 2012; Smeekens et al, 2011). In addition to STAT1 mutations, Puel et al demonstrated the presence of mutations in IL-17RA and IL-17F in some unexplained CMC cases (Puel et al, 2012). In contrast, patients with autosomal recessive autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) not only suffer from CMC, but also experience autoimmune phenomena (Lilic, 2002). APECED has been linked to mutations in the autoimmune regulator (AIRE) gene (Björses et al, 1998) that result in a loss-of-function phenotype, causing the production of neutralizing autoantibodies against important cytokines with antifungal properties such as IL-17E, IL-17F and IL-22 (Puel et al, 2010).
Another monogenetic defect resulting in a primary immunodeficiency syndrome associated with Candida infections of the skin is hyper-IgE syndrome (HIES). HIES was first described as Job's syndrome and is characterized by high serum IgE levels, eczema, recurrent mucosal infections with C. albicans, and skin and pulmonary infections with Staphylococcus aureus (Davis et al, 1966). There are a number of mutations known to be associated with HIES. Several mutations have been found in STAT3 (Holland et al, 2007; Minegishi et al, 2007), a signaling molecule downstream of the IL-23 receptor, resulting in absent IL-17 production (de Beaucoudrey et al, 2008; Ma et al, 2008; Milner et al, 2008; Sharfe et al, 1997). Other genes which have been associated with HIES include dedicator of cytokinesis (DOCK)8 that codes for a protein involved in Th17 polarization (Engelhardt et al, 2009) and TYK2 (Minegishi et al, 2006), coding for a Janus kinase (JAK) downstream of the IL-12 receptor (Shimoda et al, 2000). All in all, defective Th17 responses underlie both CMC and HIES, two immunodeficiencies associated with severe, chronic, mucosal Candida infections. This emphasizes the importance of the Th17 response in mucosal Candida immunity.
Also mutations in genes coding for cytokines and their receptors have been described to be associated with Candida infections. For example, IL-12Rb1 deficiency has been linked to mucocutaneous Candida infections, and these patients also have increased susceptibility for invasive candidiasis (Rodríguez-Gallego et al, 2012). Sharfe et al described a patient with a deletion in the CD25 gene, suffering from esophageal candidiasis. CD25 is the α-subunit of the IL-2 receptor, which is constitutively expressed on T regulatory cells (Sakaguchi et al, 1995). Furthermore, IL-2 is involved in the differentiation of effector T cells. Although Sharfe et al only described a single patient, this again emphasizes the importance of T cells in the anti-Candida host response. A complete overview of monogenetic disorders causing fungal infections is depicted in Table 1 and Fig 1.
Table 1. Monogenetic disorders
|Gene||Mutation||Mode of inheritance||Phenotype||Disease||Refs.|
|AIRE||R257X||Autosomal-dominant||Autoantibodies against IL-17 and IL-22||CMC|| |
|CARD9||Q295X||Autosomal-recessive||Reduced TNF-α production and Th17 cells||CMC||Glocker et al (2009)|
| ||Q289X R101C||Autosomal-recessive||Reduced Th17 responses||Invasive dermamtophytic disease||Lanternier et al (2012)|
|CD25||Deletion (60–64)||Autosomal recessive||Reduced number of CD4+ cells||Candida esophagitis||Sharfe et al (1997)|
|DOCK8||Multiple deletions and point mutations||Autosomal-recessive||Reduced Th17 cells||Hyper IgE syndrome||Engelhardt et al (2009)|
|IL-12Rb1||Multiple point mutations||Autosomal-recessive||Low levels of IFN-γ||Mucosal candidiasis||Rodríguez-Gallego et al (2012)|
|IL-17RA||Q284X||Autosomal-recessive||Absent IL-6 and GRO-a production||CMC||Puel et al (2011)|
|IL-17F||S65L||Autosomal-dominant||Reduced IL-6 and GRO-a production||CMC||Puel et al (2011)|
|STAT1||R274W A267V||Autosomal-dominant||Reduced IL-17, IL-22 and IFN-γ production||CMC||van de Veerdonk et al (2011)|
|STAT3||Multiple point mutations||Autosomal-dominant||Reduced IL-17 production||HIES||Holland et al (2007)|
|TYK2||Deletion (550–553)||Autosomal-recessive||Reduced Th1 and Type I IFN responses||HIES||Minegishi et al (2006)|
Common genetic variants and susceptibility to Candida infections
Despite the presence of primary immunodeficiency syndromes with fungal infections, the vast majority of fungal infections is not present in these individuals, but are common diseases with a polygenic pattern of increased susceptibility. Several studies have been published showing a link between genetic variation and an increased risk for Candida infections, with different genetic pattern being discerned between mucosal and systemic candidiasis. An example of this dichotomy is the role of a Dectin-1 polymorphism for susceptibility to mucosal, but not systemic, candidiasis. We have recently described a family in which its members suffered from recurrent vulvo-vaginal candidiasis (RVVC) and onychomycosis. Their symptoms could be explained by an early stop codon in Dectin-1 (Y238X) that resulted in defective β-glucan recognition and Th17 responses. Interestingly, this polymorphism is present in up to 8% of the Europeans and up to 40% of some sub-Saharan African populations (Ferwerda et al, 2009), being associated with mucosal Candida colonization and treatment in haematopoetic patients (Plantinga et al, 2009), but not with systemic candidiasis (Rosentul et al, 2011).
Genetic variation localized in other PRRs, such as the TLRs, has also been associated with an increased susceptibility to fungal infections. Three single nucleotide polymorphisms (SNPs) in the TLR1 gene have been shown to influence susceptibility to candidemia, presumably mediated by decreased levels of IL-8 and IFN-γ (Plantinga et al, 2012). However, these findings need to be replicated in independent studies, and it is unclear which component of Candida is recognized by TLR1. A similar observation has been made for TLR2 and TLR4, which recognize phospholipomannans and O-linked mannans, respectively. The R753Q TLR2 polymorphism increased the risk for candidemia in one small study through decreased IFN-γ and IL-8 levels (Woehrle et al, 2008), and two SNPs in the TLR4 gene were shown to be a risk factor for candidemia through increased IL-10 production (Van der Graaf et al, 2006), but these observations were not replicated in a larger study of patients (Plantinga et al, 2012). Nahum et al suggested that the L412F TLR3 polymorphism increases the risk for CMC, an effect mediated by decreased IFN-γ production (Nahum et al, 2011). Furthermore, variable number of tandem repeats in MBL2 gene that codes for the soluble PRR MBL has been linked to RVVC in two separate studies (Babula et al, 2003; Giraldo et al, 2007). Finally, length polymorphisms in the NLPR3 gene, coding for the receptor subunit of the NLRP3 inflammasome, can increase the risk for RVVC (Lev-Sagie et al, 2009).
In addition to the first step of pathogen recognition, genetic variation in several cytokines has been linked to an increased risk for Candida infections. Choi et al demonstrated that the −1089T/G, −589C/T and the −33C/T polymorphisms in IL-4 are associated with chronic disseminated candidiasis (Choi et al, 2003). Interestingly, the −589T/C SNP has also been demonstrated to pose a risk for RVVC (Babula et al, 2005). The −1082A/G polymorphism in the anti-inflammatory cytokine gene IL-10 and the 274INS/DEL polymorphism in IL-12b, are associated with persisting candidemia (Johnson et al, 2012). These data strongly suggest that the balance between pro- and anti-inflammatory cytokines represent an important component of host defense against both mucosal and systemic candidiasis.
The −44C/G polymorphism in DEFB1, coding for beta-defensin 1, is correlated with increased Candida carriage (Jurevic et al, 2003). The exact underlying mechanism is unclear, but in general beta-defensins are secreted by neutrophils and epithelial cells and contribute to epithelial immunity. The R620W polymorphism in PTPN22, a protein involved in T-cell and B-cell receptor signaling, was suggested to be associated with an increased risk for CMC. Although the potential mechanism of this association is unclear (Nahum et al, 2008). A complete overview of common genetic variants associated with fungal infection is depicted in Table 2 and Fig 1.
Table 2. Common genetic variants
|Dectin-1||Y238X (rs16910526)||Decreased IL-1β and Th17 responses||Candida colonization||Plantinga et al (2009)|
|DEFB1||−44C/G (rs1800972)||Unknown||Candida carriage||Jurevic et al (2003)|
|IL-4||−589T/C (rs2243250)||Increased vaginal IL-4, reduced NO and MBL levels||RVVC||Babula et al (2005)|
| ||−1098T/G (rs2243248), −589C/T (rs2243250), −33C/T (rs2070874)||Unknown||Chronic disseminated candidiasis||Choi et al (2003)|
|IL-10||−1082A/G (rs1800896)||Higher Candida-induced IL-10 production||Persisting candidemia||Johnson et al (2012)|
|IL-12B||2724INS/DEL (rs17860508)||Lower Candida-induced IFN-γ production||Persisting candidemia||Johnson et al (2012)|
|MBL2||Variable number of tandem repeats in intron 4||Reduced vaginal MBL levels||RVVC|| |
|NLPR3||Length polymorphism||Impaired IL-1β production||RVVC||Lev-Sagie et al (2009)|
|PTPN22||R620W (rs2476601)||Unknown||Increased risk for CMC||Nahum et al (2008)|
|TLR1||R80T (rs5743611), S248N (rs4833095), I602S (rs5743618)||Decreased production of IL-1β, IL-6 and IL-8 after TLR1-TLR2 stimulation||Increased susceptibility to candidemia||Plantinga et al (2012)|
|TLR2||R753Q (rs5743708)||Decreased levels of IFN-γ and IL-8||Increased susceptibility to candidemia||Woehrle et al (2008)|
|TLR3||L412F (rs3775291)||Decreased IFN-γ levels||Increased risk for CMC|| |
|TLR4||D299G (rs4986790), Y399I (rs4986791)||Increased IL-10 production||Increased susceptibility to candidemia||Van der Graaf et al (2006)|