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Keywords:

  • Candida albicans;
  • primary immunodeficiencies;
  • interferon gamma;
  • interleukin-17;
  • disease susceptibility

Abstract

  1. Top of page
  2. Abstract
  3. Infections with Candida species
  4. Candida albicans host defense
  5. General risk factors for Candida infections
  6. Genetic risk factors for Candida infections
  7. Future developments
  8. Acknowledgements
  9. References

Candida spp. are medically important fungi causing severe mucosal and life-threatening invasive infections, especially in immunocompromised hosts. However, not all individuals at risk develop Candida infections, and it is believed that genetic variation plays an important role in host susceptibility. On the one hand, severe fungal infections are associated with monogenic primary immunodeficiencies such as defects in STAT1, STAT3 or CARD9, recently discovered as novel clinical entities. On the other hand, more common polymorphisms in genes of the immune system have also been associated with fungal infections such as recurrent vulvovaginal candidiasis and candidemia. The discovery of the genetic susceptibility to Candida infections can lead to a better understanding of the pathogenesis of the disease, as well as to the design of novel immunotherapeutic strategies. This review is part of the review series on host-pathogen interactions. See more reviews from this series.


Infections with Candida species

  1. Top of page
  2. Abstract
  3. Infections with Candida species
  4. Candida albicans host defense
  5. General risk factors for Candida infections
  6. Genetic risk factors for Candida infections
  7. Future developments
  8. Acknowledgements
  9. References

Candida spp, especially Candida albicans, are commensal fungi that reside on the skin, mucosa and gastrointestinal tract of 30 to 50% of healthy individuals at any given time, with everyone being colonized at a certain moment of his/her lifetime (Brown & Netea, 2007). Although C. albicans is not pathogenic under normal host conditions, it can cause severe mucosal or systemic infections when host defense is compromised.

Mucosal infections

Mucosal infections affect the skin and mucous membranes. Common sites for these superficial infections are the mouth, vagina, external ear, skin and nails, of which oral candidiasis is the most common (Odds, 1988). Mucosal infections are usually sporadic, but some patients experience severe and recurrent infections of the skin and oropharyngeal cavities termed chronic mucocutaneous candidiasis (CMC). In addition, most women suffer at least once in their lifetime from vulvovaginal candidiasis, while up to 8% of them have recurrent infections (Sobel, 2007).

Systemic infections

In contrast to mucosal candidiasis which is highly prevalent but does not cause high mortality, systemic infections are life threatening, with mortality rates reaching up to 26–60% (Das et al, 2011). When the organisms enter the blood stream they can invade deep tissues and organs such as brain, heart and kidneys. Considering the number of patients diagnosed each year, Candida has emerged in the recent decades as one of the most important pathogens in sepsis, causing significant morbidity and mortality. Moreover, mortality due to these severe infections has not been significantly changed in the last decade, despite the introduction of potent antifungals such as azoles and echinocandins (Fortún et al, 2012). It is currently believed that only a combination of standard antimycotic treatment with adjuvant immunotherapy may significantly improve the outcome of fungal infections, and both immunological and genetic studies are needed to accomplish the necessary understanding of the pathogenesis of these infections.

Candida albicans host defense

  1. Top of page
  2. Abstract
  3. Infections with Candida species
  4. Candida albicans host defense
  5. General risk factors for Candida infections
  6. Genetic risk factors for Candida infections
  7. Future developments
  8. Acknowledgements
  9. References

The C. albicans cell wall can be divided into two distinct layers: the inner layer consisting mainly of polysaccharides like chitin, 1,3-β-glucans and 1,6-β-glucans, and the outer layer consisting mainly of proteins that are heavily mannosylated with mannan side-chains. These pathogen-associated molecular patterns (PAMPs) can be recognized by several pathogen recognition receptors (PRRs), such as the Toll-like receptors (TLRs) and C-type lectins (CLRs) on the surface of antigen presenting cells (APCs). TLR2 recognizes phospholipomannans (Jouault et al, 2003), and TLR4 recognizes O-linked mannans (Netea et al, 2006). N-linked mannans are recognized by the macrophage mannose receptor (MMR) (Netea et al, 2006), with other CLRs which can recognize mannose residues being Dectin-2 (McGreal et al, 2006), Mincle (Wells et al, 2008), DC-specific ICAM-grapping non-integrin (DC-SIGN) (Cambi et al, 2003) and the soluble receptor mannose-binding lectin (MBL) (Brouwer et al, 2008). The CLR Dectin-1 recognizes β-glucan (Brown & Gordon, 2001) (Fig 1)

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Figure 1. Schematic overview of the anti-Candida albicans immune response. When Candida is recognized by Toll-like receptors (TLRs) and C-type lectin receptors, the production of cytokines is initiated through activation of transcription factors like NF-κB. IL-1β and IL-18 first need to be cleaved by the NLRP3 inflammasome before they can be secreted. IL-2 is involved in the differentiation of all effector T-cells. The IL-2 receptor is highly expressed on regulatory T-cells (Treg). IL-12 and IL-18 promote the differentiation of T helper 1 (Th1) cells, with IFN-γ being their main product. IL-4 and IL-10 promote the differentiation of Th2 cells, while IL-10 can also suppress Th1 cells. IL-1β, IL-6 and IL-23 drive the development of Th17 cells. DOCK8 is involved in the maintenance of Th17 cells. IL-17 promotes the recruitment of neutrophils, which have tissue protective effects by the production of beta-defensins. Cytokines are recognized by cytokine receptors, which use several adaptor molecules like STAT1, STAT3 and TYK2. PTPN22 is involved in B- and T-cell receptor signaling. Components with mutations and/or genetic variation known to be associated with Candida infection are shown in color. APC: antigen presenting cell, BCR: B-cell receptor, CARD9: caspase recruitment domain 9, DC-SIGN: dendritic cell-specific ICAM-grapping non-integrin, MBL: mannose binding lectin, MMR: macrophage mannose receptor, NLRP3: NACHT, LRR and PYD domains-containing protein 3, TCR: T-cell receptor, TLR: Toll-like receptor.

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When a PRR recognizes its corresponding ligand, adaptor molecules engage with the receptor. Different types of PRRs use different adaptor molecules, which transduce a signal by activating a kinase cascade, in order to induce the transcription of proinflammatory cytokines. Dectin-1 signals through Syk (Rogers et al, 2005) and caspase recruitment domain 9 (CARD9) (Gross et al, 2006). Dectin-1 can induce cytokine production independently of other receptors, as well as synergize with TLRs for an optimal stimulation of the cell. When ligands are recognized by TLRs, signals are transduced intracellularily through adaptor proteins like myeloid differentiation factor (MYD)88. Subsequently, a mitogen-activated protein kinase (MAPK) response is activated leading to the nuclear translocation of transcription factors like NF-κB and c-Jun, inducing the transcription of cytokines and chemokines (Akira et al, 2006). Interestingly, depending on the fungal burden and amount of hyphae formation a second MAPK phase, consisting of MKP1 and c-Fos activation, can be initiated, further promoting proinflammatory responses (Moyes et al, 2010).

The recognition of C. albicans by cells of the innate immune system will lead to phagocytosis (Heinsbroek et al, 2008) and killing of the invading pathogen. At the same time, the production of cytokines is induced that on the one hand activate inflammation, and on the other hand engage and direct the adaptive immune response. Activation of the caspase-1 component of the inflammasome, mediated by the intracellular activation of the NOD-like receptor NLRP3, is a central event leading to the processing of pro-IL-1β and pro-IL-18 into their respective bioactive cytokines, directing the induction of Th17 and Th1 responses, respectively (Cheng et al, 2011; Lalor et al, 2011). IFN-γ production by Th1 cells, and IL-17 production by Th17 cells are important characteristics of the Candida-induced immune response (Netea et al, 2008). Inflammasome and Th17 activation is considered to be a central event for the discrimination of colonization versus invasion with C. albicans at the level of the mucosa (Gow et al, 2011).

General risk factors for Candida infections

  1. Top of page
  2. Abstract
  3. Infections with Candida species
  4. Candida albicans host defense
  5. General risk factors for Candida infections
  6. Genetic risk factors for Candida infections
  7. Future developments
  8. Acknowledgements
  9. References

C. albicans is an opportunistic fungal pathogen. In healthy individuals, the immune response will usually clear infections, but an immunocompromised immune system causes a significant increase in the risk for Candida infections. Das et al demonstrated that 92% of Candida bloodstream infections are preceded by a course of broad-spectrum antibiotics (Das et al, 2011), which suppress the growth of the normal bacterial flora and eliminates natural antagonism of fungal colonization of the mucosa. There are several other examples in which Candida acts as an opportunistic pathogen. For example, almost all AIDS and oncologic patients with neutropenia suffer from oropharyngeal candidiasis (Grabar et al, 2008; Viscoli et al, 1999). Furthermore, 41% of patients undergoing hematopoietic stem cell transplantation, for which the immune system is destroyed beforehand, suffer from one or more bloodstream infections within the first ten years after transplantation, 4% of which are caused by Candida spp. The crude mortality rate associated with these Candida-infections is 42% (Ortega et al, 2005). Also patients with systemic lupus erythematosus (SLE), which are treated with glucocorticoids and other immunosuppressive agents, have an increased risk for invasive fungal infections (IFI), which are predominantly caused by Candida spp. (Fan et al, 2012).

Not only a weakened immune system increases the risk for Candida infections, also the extent to which individuals are colonized with pathogens plays a significant role in the development of candidiasis. Candidiasis typically affects patients with prolonged hospitalization. Fifty-one percent of Candida blood-stream infections is associated with being admitted to the ICU (Das et al, 2011). The mean time of onset of systemic Candida infections is 22 days after hospitalization (Wisplinghoff et al, 2004). Furthermore, when barriers to the outside world are damaged or breached by medical devices or surgery, this creates a portal of entry for pathogens like C. albicans. For instance, major abdominal surgery poses an increased risk for systemic Candida infections, which is underlined by the observation that in a cohort of 107 patients with candidemia, 50% underwent recent surgery (Das et al, 2011). Another factor contributing to systemic candidiasis is the fact that Candida spp. can form biofilms on many medical devices like central venous catheters (CVC), contact lenses, intrauterine devices (IUDs) (Donlan & Costerton, 2002) and pacemakers (Glöckner, 2011). Candida can even cause prosthetic joint infections, although they are considered to be rare (Springer & Chatterjee, 2012). Indeed, neonates on the intensive care unit (ICU) with a central line often suffer from infections, with the third most causative pathogen being Candida spp. Fortunately this incidence is decreasing due to the use of anti-fungal prophylaxis (Chitnis et al, 2012).

Genetic risk factors for Candida infections

  1. Top of page
  2. Abstract
  3. Infections with Candida species
  4. Candida albicans host defense
  5. General risk factors for Candida infections
  6. Genetic risk factors for Candida infections
  7. Future developments
  8. Acknowledgements
  9. References

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.

Monogenetic disorders

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
GeneMutationMode of inheritancePhenotypeDiseaseRefs.
AIRER257XAutosomal-dominantAutoantibodies against IL-17 and IL-22CMC

Nagamine et al (1997

), Pearce et al (1998)

CARD9Q295XAutosomal-recessiveReduced TNF-α production and Th17 cellsCMCGlocker et al (2009)
 Q289X R101CAutosomal-recessiveReduced Th17 responsesInvasive dermamtophytic diseaseLanternier et al (2012)
CD25Deletion (60–64)Autosomal recessiveReduced number of CD4+ cellsCandida esophagitisSharfe et al (1997)
DOCK8Multiple deletions and point mutationsAutosomal-recessiveReduced Th17 cellsHyper IgE syndromeEngelhardt et al (2009)
IL-12Rb1Multiple point mutationsAutosomal-recessiveLow levels of IFN-γMucosal candidiasisRodríguez-Gallego et al (2012)
IL-17RAQ284XAutosomal-recessiveAbsent IL-6 and GRO-a productionCMCPuel et al (2011)
IL-17FS65LAutosomal-dominantReduced IL-6 and GRO-a productionCMCPuel et al (2011)
STAT1R274W A267VAutosomal-dominantReduced IL-17, IL-22 and IFN-γ productionCMCvan de Veerdonk et al (2011)
STAT3Multiple point mutationsAutosomal-dominantReduced IL-17 productionHIESHolland et al (2007)
TYK2Deletion (550–553)Autosomal-recessiveReduced Th1 and Type I IFN responsesHIESMinegishi 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
GeneSNP (rs-number)PhenotypeDiseaseRefs.
Dectin-1Y238X (rs16910526)Decreased IL-1β and Th17 responsesCandida colonizationPlantinga et al (2009)
DEFB1−44C/G (rs1800972)UnknownCandida carriageJurevic et al (2003)
IL-4−589T/C (rs2243250)Increased vaginal IL-4, reduced NO and MBL levelsRVVCBabula et al (2005)
 −1098T/G (rs2243248), −589C/T (rs2243250), −33C/T (rs2070874)UnknownChronic disseminated candidiasisChoi et al (2003)
IL-10−1082A/G (rs1800896)Higher Candida-induced IL-10 productionPersisting candidemiaJohnson et al (2012)
IL-12B2724INS/DEL (rs17860508)Lower Candida-induced IFN-γ productionPersisting candidemiaJohnson et al (2012)
MBL2Variable number of tandem repeats in intron 4Reduced vaginal MBL levelsRVVC

Babula et al (2003

), Giraldo et al (2007)

NLPR3Length polymorphismImpaired IL-1β productionRVVCLev-Sagie et al (2009)
PTPN22R620W (rs2476601)UnknownIncreased risk for CMCNahum et al (2008)
TLR1R80T (rs5743611), S248N (rs4833095), I602S (rs5743618)Decreased production of IL-1β, IL-6 and IL-8 after TLR1-TLR2 stimulationIncreased susceptibility to candidemiaPlantinga et al (2012)
TLR2R753Q (rs5743708)Decreased levels of IFN-γ and IL-8Increased susceptibility to candidemiaWoehrle et al (2008)
TLR3L412F (rs3775291)Decreased IFN-γ levelsIncreased risk for CMC

Nahum et al (2011

, 2012)

TLR4D299G (rs4986790), Y399I (rs4986791)Increased IL-10 productionIncreased susceptibility to candidemiaVan der Graaf et al (2006)

Future developments

  1. Top of page
  2. Abstract
  3. Infections with Candida species
  4. Candida albicans host defense
  5. General risk factors for Candida infections
  6. Genetic risk factors for Candida infections
  7. Future developments
  8. Acknowledgements
  9. References

The current body of evidence has provided many new insights into the working mechanism of the anti-Candida immune response. These new insights can pinpoint novel potential targets for immunotherapy. For example, several studies have demonstrated a correlation between decreased IFN-γ levels and an increased risk for systemic Candidiasis (Johnson et al, 2012; Woehrle et al, 2008). A double-blind, randomized, placebo-controlled study is currently being performed using adjuvant IFN-γ therapy in sepsis. It would be also very relevant to try and reverse the immunoparalysis (Leentjens et al, 2012). This suggests that IFN-γ is a promising treatment option in sepsis-induced immune paralysis. We are currently investigating the efficacy of recombinant IFN-γ in patients with Candida sepsis.

Despite the significant progress of the last few years for uncovering susceptibility to fungal infections, there are still a significant number of Candida infections for which the environmental and/or genetic risk factors are not yet deciphered. Even more importantly, in spite of current treatment regimens, mortality rates associated with systemic infections are still very high, and in order to improve diagnostic- and treatment options, future efforts should be directed towards gaining more insight into the anti-Candida host immune response. This can be achieved in several ways. Discovering novel mutations that underlie monogenetic disorders associated with Candida infections can generate crucial information about a particular gene or protein, and the pathway in which this protein is involved. For example, the use of next generation sequencing and whole exome sequencing to discover STAT1 mutations as a cause of CMC (van de Veerdonk et al, 2011), has also led in the understanding of its role for the generation of Th1 and Th17 responses and the anti-Candida host defense (Smeekens et al, 2011). This discovery can lead to novel approaches to the therapy of CMC, some of them being currently tested.

Of course, the list of existing monogenetic disorders is relatively small, as the majority of Candida cases are likely polygenic and/or multifactorial. In order to investigate this type of disorders other methods will have to be employed such as genome-wide association studies (GWAS), deep sequencing, and systems biology. We have recently used a combination of transcriptional analysis and functional genomics to demonstrate that type I IFNs play an important role in the anti-Candida host defense (Smeekens et al, 2013). Stimulation of circulating leukocytes with C. albicans led to a transcription profile with overrepresentation of genes from the type I IFN pathway. Subsequently, we showed that polymorphisms in these genes modify Candida-induced cytokine production and influence susceptibility to systemic Candida infections. Furthermore, validation studies showed that type I IFNs skew Candida-induced cytokine responses from Th17 toward Th1, while STAT1-deficient CMC patients display defective expression of genes in the type I IFN pathway. This ‘systems approach’, that integrates the information on anti-Candida host defense from several types of studies, provides information with respect to potential novel anti-Candida immune responses that may represent targets for immunotherapy. It is to be expected that an integration of efforts from immunology, genetics, microbiology and systems biology will represent the novel level of understanding of host defense against fungal (and other) pathogens, improving the outcome of these severe infections.

Pending issues

Integration efforts from immunology, genetics, microbiology and systems biology to increase the level of understanding of the host defense against fungal (and other) pathogens.

Design of novel immunotherapeutic strategies for an improved treatment.

Discovering novel mutations that underlie monogenetic disorders associated with Candida infections by GWAS or deep sequencing.

The authors declare that they have no conflict of interest.

Glossary

Autosomal-dominant

Mode of inheritance in which the presence of only one copy of a gene on one of the 22 autosomal–non-sex chromosomes, will result in the phenotypic expression of that gene.

Candidemia

The presence of Candida species in the blood.

Candidiasis

Fungal infection with any of the Candida species. Includes candidemia (in case of systemic infection).

Chronic mucocutaneous candidiasis (CMC)

An immune disorder characterized by chronic infections with Candida that are limited to mucosal surfaces, skin and nails.

Genetic variation

Variations of genomes between members of species or between groups of species. Includes SNP (in case it is a common genetic variant), mutation (in case it is a rare genetic variant) and copy-number variation.

Immunocompromised

State in which the immune system is not functioning properly, increasing susceptibility to infection.

Immunodeficiency

A state in which the immune system's ability to fight infectious disease is compromised or entirely absent.

Immune paralysis

A state in which induction of tolerance is due to injection of large amounts of antigen that remains poorly metabolized.

Neutropenia

An immune disorder characterized by an abnormally low level of neutrophils.

Pathogenesis

The mechanism by which the disease is caused.

Pathogen recognition receptors (PRRs)

Proteins expressed by cells of the innate immune system, which recognize pathogen-associated molecular patterns (PAMPs) from microbial pathogens.

Polymorphism

Having multiple alleles of a gene within a population, usually linked to different phenotypes.

Single nucleotide polymorphism (SNP)

DNA sequence variation occurring when a single nucleotide in the genome differs between members of a biological species or paired chromosomes in an individual.

References

  1. Top of page
  2. Abstract
  3. Infections with Candida species
  4. Candida albicans host defense
  5. General risk factors for Candida infections
  6. Genetic risk factors for Candida infections
  7. Future developments
  8. Acknowledgements
  9. References
  • Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124: 783- 801
  • Babula O, Lazdāne G, Kroica J, Ledger WJ, Witkin SS (2003) Relation between recurrent vulvovaginal candidiasis, vaginal concentrations of mannose-binding lectin, and a mannose-binding lectin gene polymorphism in Latvian women. Clin Infect Dis 37: 733- 737
  • Babula O, Lazdāne G, Kroica J, Linhares IM, Ledger WJ, Witkin SS (2005) Frequency of interleukin-4 (IL-4) −589 gene polymorphism and vaginal concentrations of IL-4, nitric oxide, and mannose-binding lectin in women with recurrent vulvovaginal candidiasis. Clin Infect Dis 40: 1258- 1262
  • Björses P, Aaltonen J, Horelli-Kuitunen N, Yaspo ML, Peltonen L (1998) Gene defect behind APECED: a new clue to autoimmunity. Hum Mol Genet 7: 1547- 1553
  • Brouwer N, Dolman KM, van Houdt M, Sta M, Roos D, Kuijpers TW (2008) Mannose-binding lectin (MBL) facilitates opsonophagocytosis of yeasts but not of bacteria despite MBL binding. J Immunol 180: 4124- 4132
  • Brown GD, Gordon S (2001) Immune recognition. A new receptor for beta-glucans. Nature 413: 36- 37
  • Brown GD, Netea MG (2007) Immunology of Fungal Infections. Dordrecht: Springer
  • Cambi A, Gijzen K, de Vries LJM, Torensma R, Joosten B, Adema GJ, Netea MG, Kullberg BJ, Romani L, Figdor CG (2003) The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur J Immunol 33: 532- 538
  • Cheng S-C, van de Veerdonk FL, Lenardon M, Stoffels M, Plantinga T, Smeekens S, Rizzetto L, Mukaremera L, Preechasuth K, Cavalieri D, et al (2011) The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans. J Leukoc Biol 90: 357- 366
  • Chitnis AS, Magill SS, Edwards JR, Chiller TM, Fridkin SK, Lessa FC (2012) Trends in Candida central line-associated bloodstream infections among NICUs, 1999–2009. Pediatrics 130: e46- e52
  • Choi EH, Foster CB, Taylor JG, Erichsen HC, Chen RA, Walsh TJ, Anttila V-J, Ruutu T, Palotie A, Chanock SJ (2003) Association between chronic disseminated candidiasis in adult acute leukemia and common IL4 promoter haplotypes. J Infect Dis 187: 1153- 1156
  • Darnell JE, Kerr LM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellularsignaling proteins. Science 264: 1415- 1421
  • Das I, Nightingale P, Patel M, Jumaa P (2011) Epidemiology, clinical characteristics, and outcome of candidemia: experience in a tertiary referral center in the UK. Int J Infect Dis 15: e759- e763
  • Davis SD, Schaller J, Wedgwood RJ (1966) Job's syndrome. Recurrent, “cold”, staphylococcal abscesses. Lancet 1: 1013- 1015
  • de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, Feinberg J, Bernuth von H, Samarina A, Jannière L, et al (2008) Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med 205: 1543- 1550
  • Depner M, van de Veerdonk F, Wanders J, Stauss H, Raabe J, Atkinson TP, Schroeder HW Jr, Niehues T, Duckers G, Puck J, et al (2012) Mutation screening in STAT1, CARD9 and PKC-delta in patients with chronic mucocutaneous candidiasis. J Clin Immunol 32: S334- S335
  • Donlan RM, Costerton JW (2002) Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 15: 167- 193
  • Engelhardt KR, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herrera G, Chen A, Kim HS, Lloret MG, Schulze I, et al (2009) Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol 124: 1289.e4- 1302.e4
  • Fan Y-C, Li W-G, Zheng M-H, Gao W, Zhang Y-Y, Song L-J (2012) Invasive fungal infection in patients with systemic lupus erythematosus: experience from a single institute of Northern China. Gene 506: 184- 187
  • Ferwerda B, Ferwerda G, Plantinga TS, Willment JA, van Spriel AB, Venselaar H, Elbers CC, Johnson MD, Cambi A, Huysamen C, et al (2009) Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med 361: 1760- 1767
  • Fortún J, Martín-Dávila P, Gómez-García de la Pedrosa E, Pintado V, Cobo J, Fresco G, Meije Y, Ros L, Alvarez ME, Luengo J, et al (2012) Emerging trends in candidemia: a higher incidence but a similar outcome. J Infect 65: 64- 70
  • Giraldo PC, Babula O, Gonçalves AKS, Linhares IM, Amaral RL, Ledger WJ, Witkin SS (2007) Mannose-binding lectin gene polymorphism, vulvovaginal candidiasis, and bacterial vaginosis. Obstet Gynecol 109: 1123- 1128
  • Glocker E-O, Hennigs A, Nabavi M, Schäffer AA, Woellner C, Salzer U, Pfeifer D, Veelken H, Warnatz K, Tahami F, et al (2009) A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med 361: 1727- 1735
  • Glöckner A (2011) Recurrent candidaemia and pacemaker wire infection with Candida albicans. Mycoses 54: 20- 23
  • Gow NAR, van de Veerdonk FL, Brown AJP, Netea MG (2011) Candida albicans morphogenesis and host defence: discriminating invasion from colonization. Nat Rev Microbiol 10: 112- 122
  • Grabar S, Lanoy E, Allavena C, Mary-Krause M, Bentata M, Fischer P, Mahamat A, Rabaud C, Costagliola D, Clinical Epidemiology Group of the French Hospital Database on HIV. (2008) Causes of the first AIDS-defining illness and subsequent survival before and after the advent of combined antiretroviral therapy. HIV Med 9: 246- 256
  • Gross O, Gewies A, Finger K, Schäfer M, Sparwasser T, Peschel C, Förster I, Ruland J (2006) Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442: 651- 656
  • Heinsbroek SEM, Taylor PR, Martinez FO, Martinez-Pomares L, Brown GD, Gordon S (2008) Stage-specific sampling by pattern recognition receptors during Candida albicans phagocytosis. PLoS Pathog 4: e1000218
  • Hirata O, Tsumura M, Mizoguchi Y, Okada S, Minegishi S, Morio T, Kobayashi M (2012) Gain-of-function mutations of STAT1 in Japanese patients with CMCD. J Clin Immunol 32: S104- S105
  • Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, et al (2007) STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 357: 1608- 1619
  • Johnson MD, Plantinga TS, van de Vosse E, Velez Edwards DR, Smith PB, Alexander BD, Yang JC, Kremer D, Laird GM, Oosting M, et al (2012) Cytokine gene polymorphisms and the outcome of invasive candidiasis: a prospective cohort study. Clin Infect Dis 54: 502- 510
  • Jouault T, Ibata-Ombetta S, Takeuchi O, Trinel P-A, Sacchetti P, Lefebvre P, Akira S, Poulain D (2003) Candida albicans phospholipomannan is sensed through toll-like receptors. J Infect Dis 188: 165- 172
  • Jurevic RJ, Bai M, Chadwick RB, White TC, Dale BA (2003) Single-nucleotide polymorphisms (SNPs) in human beta-defensin 1: high-throughput SNP assays and association with Candida carriage in type I diabetics and nondiabetic controls. J Clin Microbiol 41: 90- 96
  • Lalor SJ, Dungan LS, Sutton CE, Basdeo SA, Fletcher JM, Mills KHG (2011) Caspase-1-processed cytokines IL-1β and IL-18 promote IL-17 production by γδ and CD4 T cells that mediate autoimmunity. J Immunol 186: 5783- 5784
  • Lanternier F, Pathan S, Vincent Q, Liu L, Cypowij S, Prando C, Migaud M, Taibi L, Ammar-Khodja A, Stambouli OB, et al (2012) Human invasive dermatophytic disease is caused by inborn errors of CARD9. J Clin Immunol 32: S94
  • Leentjens J, Kox M, Koch RM, Preijers F, Joosten LAB, van der Hoeven JG, Netea MG, Pickkers P (2012) Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med 186: 838- 845
  • Lev-Sagie A, Prus D, Linhares IM, Lavy Y, Ledger WJ, Witkin SS (2009) Polymorphism in a gene coding for the inflammasome component NALP3 and recurrent vulvovaginal candidiasis in women with vulvar vestibulitis syndrome. Am J Obstet Gynecol 200: 303.e1- 303.e6
  • Lilic D (2002) New perspectives on the immunology of chronic mucocutaneous candidiasis. Curr Opin Infect Dis 15: 143- 147
  • Liu L, Okada S, Kong X-F, Kreins AY, Cypowyj S, Abhyankar A, Toubiana J, Itan Y, Audry M, Nitschke P, et al (2011) Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 208: 1635- 1648
  • Ma CS, Chew GYJ, Simpson N, Priyadarshi A, Wong M, Grimbacher B, Fulcher DA, Tangye SG, Cook MC (2008) Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med 205: 1551- 1557
  • Martinez-Martinez L, Fuentes-Prior P, Herrera-Ramos E, Rubiales MV, Lopez-Rodriguez M, Barnadas M, Badell I, Rodriguez-Gallego C, la Calle-Martin de O (2012) A novel STAT1 muation responsible for chronic mucocutaneous candidiasis. J Clin Immunol 32: S314- S315
  • McGreal EP, Rosas M, Brown GD, Zamze S, Wong SYC, Gordon S, Martinez-Pomares L, Taylor PR (2006) The carbohydrate-recognition domain of Dectin-2 is a C-type lectin with specificity for high mannose. Glycobiology 16: 422- 430
  • Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, et al (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452: 773- 776
  • Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamura N, Ariga T, et al (2006) Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25: 745- 755
  • Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, et al (2007) Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448: 1058- 1062
  • Moreira I, Filardi L, Bravo Kleiman A, Seminario A, Ballve DD, Comas D, Gaillard MI, Gomez Raccio A, Di Giovanni D, Bezrodnik L (2012) Laboratory findings in three patients with gain-of-function mutations in STAT1. J Clin Immunol 32: S112- S113
  • Moyes DL, Runglall M, Murciano C, Shen C, Nayar D, Thavaraj S, Kohli A, Islam A, Mora-Montes H, Challacombe SJ, et al (2010) A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 8: 225- 235
  • Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, et al (1997) Positional cloning of the APECED gene. Nat Genet 17: 393- 398
  • Nahum A, Bates A, Sharfe N, Roifman CM (2008) Association of the lymphoid protein tyrosine phosphatase, R620W variant, with chronic mucocutaneous candidiasis. J Allergy Clin Immunol 122: 1220- 1222
  • Nahum A, Dadi H, Bates A, Roifman CM (2011) The L412F variant of Toll-like receptor 3 (TLR3) is associated with cutaneous candidiasis, increased susceptibility to cytomegalovirus, and autoimmunity. J Allergy Clin Immunol 127: 528- 531
  • Nahum A, Dadi H, Bates A, Roifman CM (2012) The biological significance of TLR3 variant, L412F, in conferring susceptibility to cutaneous candidiasis, CMV and autoimmunity. Autoimmun Rev 11: 341- 347
  • Netea MG, Gow NAR, Munro CA, Bates S, Collins C, Ferwerda G, Hobson RP, Bertram G, Hughes HB, Jansen T, et al (2006) Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J Clin Invest 116: 1642- 1650
  • Netea MG, Brown GD, Kullberg BJ, Gow NAR (2008) An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol 6: 67- 78
  • Odds FC (1988) Candida and Candidosis, 2nd ed. London: Bailliere Tindall
  • Okada S, Kong XF, Cypowyj S, Kreins A, Liu L, Abel L, Picard C, Boisson-Dupuis S, Puel A, Casanova JL (2012) Gain-of-function mutations in STAT1 underlie autosomal dominant chronic mucocutaneous candidiasis. J Clin Immunol 32: S92- S93
  • Ortega M, Rovira M, Almela M, Marco F, la Bellacasa de JP, Martínez JA, Carreras E, Mensa J (2005) Bacterial and fungal bloodstream isolates from 796 hematopoietic stem cell transplant recipients between 1991 and 2000. Ann Hematol 84: 40- 46
  • Pearce SH, Cheetham T, Imrie H, Vaidya B, Barnes ND, Bilous RW, Carr D, Meeran K, Shaw NJ, Smith CS, et al (1998) A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. Am J Hum Genet 63: 1675- 1684
  • Plantinga TS, van der Velden WJFM, Ferwerda B, van Spriel AB, Adema G, Feuth T, Donnelly JP, Brown GD, Kullberg BJ, Blijlevens NMA, et al (2009) Early stop polymorphism in human DECTIN-1 is associated with increased candida colonization in hematopoietic stem cell transplant recipients. Clin Infect Dis 49: 724- 732
  • Plantinga TS, Johnson MD, Scott WK, van de Vosse E, Velez Edwards DR, Smith PB, Alexander BD, Yang JC, Kremer D, Laird GM, et al (2012) Toll-like receptor 1 polymorphisms increase susceptibility to candidemia. J Infect Dis 205: 934- 943
  • Puel A, Döffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, Cobat A, Ouachée-Chardin M, Toulon A, Bustamante J, et al (2010) Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 207: 291- 297
  • Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, Migaud M, Israel L, Chrabieh M, Audry M, et al (2011) Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332: 65- 68
  • Puel A, Cypowyj S, Marodi L, Abel L, Picard C, Casanova J-L (2012) Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol 12: 616- 622
  • Robinson MJ, Osorio F, Rosas M, Freitas RP, Schweighoffer E, Groß O, Verbeek JS, Ruland J, Tybulewicz V, Brown GD, et al (2009) Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. J Exp Med 206: 2037- 2051
  • Rodríguez-Gallego JC, Ouederni M, Boisson-Dupuis S, Puel A, Picard C, Sologuren I, Bustamante J, Samarina A, Herrera-Ramos E, López-Rodríguez M et al (2012) Clincal features of candidiasis in patients with interleukin-12 receptor B1 deficiency. J Clin Immunol 32: S305
  • Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, Williams DL, Gordon S, Tybulewicz VL, Brown GD, Reis e Sousa C (2005) Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22: 507- 517
  • Rosentul DC, Plantinga TS, Oosting M, Scott WK, Velez Edwards DR, Smith PB, Alexander BD, Yang JC, Laird GM, Joosten LAB, et al (2011) Genetic variation in the dectin-1/CARD9 recognition pathway and susceptibility to candidemia. J Infect Dis 204: 1138- 1145
  • Saijo S, Ikeda S, Yamabe K, Kakuta S, Ishigame H, Akitsu A, Fujikado N, Kusaka T, Kubo S, Chung S-H, et al (2010) Dectin-2 recognition of α-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity 32: 681- 691
  • Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155: 1151- 1164
  • Sharfe N, Dadi HK, Shahar M, Roifman CM (1997) Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci USA 94: 3168- 3171
  • Shimoda K, Kato K, Aoki K, Matsuda T, Miyamoto A, Shibamori M, Yamashita M, Numata A, Takase K, Kobayashi S, et al (2000) Tyk2 plays a restricted role in IFNα signaling, although it is required for IL-12-mediated T cell function. Immunity 13: 561- 571
  • Smeekens SP, Plantinga TS, van de Veerdonk FL, Heinhuis B, Hoischen A, Joosten LAB, Arkwright PD, Gennery A, Kullberg BJ, Veltman JA, et al (2011) STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis. PLoS ONE 6: e29248
  • Smeekens SP, Ng A, Kumar V, Johnson MD, Plantinga TS, van Diemen C, Arts P, Verwiel ETP, Gresnigt MS, Fransen K, et al (2013) Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans. Nat Commun 4: 1342
  • Sobel JD (2007) Vulvovaginal candidosis. Lancet 369: 1961- 1971
  • Springer J, Chatterjee S (2012) Candida albicans prosthetic shoulder joint infection in a patient with rheumatoid arthritis on multidrug therapy. J Clin Rheumatol 18: 52- 53
  • Strasser D, Neumann K, Bergmann H, Marakalala MJ, Guler R, Rojowska A, Hopfner K-P, Brombacher F, Urlaub H, Baier G, et al (2012) Syk kinase-coupled C-type lectin receptors engage protein kinase C-δ to elicit card9 adaptor-mediated innate immunity. Immunity 36: 36- 42
  • van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LAB, Gilissen C, Arts P, Rosentul DC, Carmichael AJ, Smits-van der Graaf CAA, et al (2011) STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med 365: 54- 61
  • Van der Graaf CAA, Netea MG, Morré SA, Heijer Den M, Verweij PE, van der Meer JWM, Kullberg BJ (2006) Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw 17: 29- 34
  • Viscoli C, Girmenia C, Marinus A, Collette L, Martino P, Vandercam B, Doyen C, Lebeau B, Spence D, Krcmery V, et al (1999) Candidemia in cancer patients: a prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). Clin Infect Dis 28: 1071- 1079
  • Wells CA, Salvage-Jones JA, Li X, Hitchens K, Butcher S, Murray RZ, Beckhouse AG, Lo Y-L-S, Manzanero S, Cobbold C, et al (2008) The macrophage-inducible C-type lectin, mincle, is an essential component of the innate immune response to Candida albicans. J Immunol 180: 7404- 7413
  • Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39: 309- 317
  • Woehrle T, Du W, Goetz A, Hsu H-Y, Joos TO, Weiss M, Bauer U, Brueckner UB, Marion Schneider E (2008) Pathogen specific cytokine release reveals an effect of TLR2 Arg753Gln during Candida sepsis in humans. Cytokine 41: 322- 329
  • Yamasaki S, Ishikawa E, Sakuma M, Hara H, Ogata K, Saito T (2008) Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol 9: 1179- 1188