Immunity against fungi

Pathogenic fungi cause a wide range of syndromes in immune-competent and immune-compromised individuals, with life-threatening disease primarily seen in humans with HIV/AIDS and in patients receiving immunosuppressive therapies for cancer, autoimmunity, and end-organ failure. The discovery that specific primary immune deficiencies manifest with fungal infections and the development of animal models of mucosal and invasive mycoses have facilitated insight into fungus-specific recognition, signaling, effector pathways, and adaptive immune responses. Progress in deciphering the molecular and cellular basis of immunity against fungi is guiding preclinical studies into vaccine and immune reconstitution strategies for vulnerable patient groups. Furthermore, recent work has begun to address the role of endogenous fungal communities in human health and disease. In this review, we summarize a contemporary understanding of protective immunity against fungi.

This section focuses on antifungal immunity to different yeasts, molds, and dimorphic fungi. Contemporary animal models of fungal infection are reviewed elsewhere (8).

Fungal recognition and immune activation. The fungal cell wall contains polysaccharide and lipid moieties that activate immune responses (9) (Table 2). The cell wall is exterior to the plasma membrane and arranged in layers: the innermost layer typically consists of chitin, an N-acetylglucosamine polymer; the adjacent external layer is formed by immunoreactive β-(1,3) and β-(1,6) glucans, which are concealed by many fungi. H. capsulatum employs an α-glucan layer and the action of a glucanase (9–11). A. fumigatus resting conidia utilize a proteinaceous hydrophobin layer (12), while the hyphal cell wall layer contains galactomannan and galactosaminogalactan, the latter of which conceals inflammatory β-glucan (13, 14). The C. albicans outer cell wall consists of glycoproteins that incorporate N- and O-linked mannans and induces inflammatory responses via the mannose receptor and TLR-4 (15). C. albicans mannans conceal β-glucans as well; the latter are exposed on bud and birth scars during yeast cell division (9). The C. neoformans capsule covers the chitinous and β-glucan–rich cell wall layers and largely consists of glucuronoxylomannan and galactoxylomannan (16). Previously published reviews provide in-depth discussion of fungal cell wall architecture (9, 16–18).

Table 2

Mammalian signaling receptors and cognate fungal ligands and species

At portals of entry fungal cells encounter and bind to antibodies, complement, and soluble pattern recognition receptors. Collectively, these interactions facilitate signaling responses by membrane-bound receptors and the induction of antifungal effector mechanisms (5, 9). In the lung, the collectin pentraxin-3 (PTX3) binds to A. fumigatus conidial galactomannan (19) and facilitates complement deposition and CD32-dependent conidial uptake by neutrophils (20). Ptx3^–/– mice are susceptible to respiratory A. fumigatus challenge (19), and a PTX3 polymorphism enhances the vulnerability of hematopoietic cell transplant recipients to invasive aspergillosis (21).

The C-type lectin receptor (CLR) dectin-1 (encoded by Clec7a) binds β-glucans from a variety of fungi, including those on C. albicans bud scars and germinating A. fumigatus conidia, and activates signaling responses to Pneumocystis jiroveci, H. capsulatum, Coccidioides posadasii, and Paracoccidioides brasiliensis (5, 9, 22–24) (Figure 2). β-Glucan binding displaces regulatory phosphatases CD45 and CD148 (25), induces SRC-dependent phosphorylation of the intracellular ITAM-like motif, and recruits the SHP-2 phosphatase (26). SYK docks to this scaffold and transduces signals via PKC-δ (27) and the VAV family of GEFs (28) to CARD9, which complexes with BCL10 and MALT1 (29) to activate the canonical NF-κB subunits p65 and c-REL (30). Dectin-1 signaling also modulates the noncanonical NF-κB subunit RELB through RAF-1–dependent phosphorylation and deacetylation (31). In macrophages and dendritic cells (DCs), the CARD9/BCL10/MALT1 complex directs Il1b transcription and caspase-1– and caspase-8–dependent IL-1β release (32, 33), in part via the activity of NRLP3- and AIM2-containing inflammasomes (34). Rubicon can disrupt signal transduction and NF-κB activation via the CARD9/BCL10/MALT1 complex (35). Dectin-1/SYK/CARD9–dependent cytokines, such as TNF, CXCL2, IL-6, IL-23, and IL-1β, promote innate immune activation and Th17 differentiation (36). In addition, dectin-1/SYK signaling in DCs induces IFN-β production via IRF5 (37). The role of type I IFN signaling in defense against candidiasis remains controversial, with both protective (37) and detrimental (38) phenotypes reported.

Figure 2

Model of fungus-induced CLR signaling in antifungal defense. At the site of inoculation, particulate fungal polysaccharides bind C-type lectin receptors (CLRs) and Fc receptors (FcRs), resulting in SYK activation via ITAM signaling in the receptor tail, the FcRγ signaling adaptor, or integrin receptor activation. The ensuing PKCδ and CARD9 activation is critical for caspase-1 and caspase-8 activity, MAP kinase signaling (not shown), NF-κB activation, and cytokine production. SYK-dependent PLCγ2 activation is linked to NADPH oxidase assembly and calcineurin-dependent NFAT activation. Dectin/SYK signaling controls IRF5-dependent IFN-γ production. VAV1 and BTK can interact with dectin-1 to mediate phagocytosis of Candida albicans in macrophages. BTK may also promote calcineurin activation and the production of NFAT-regulated cytokines. The model depicts fungal killing in the phagosome. Myeloid cell–derived cytokines promote the differentiation of both Th1 cells and Th17 cells. Th17 and innately derived IL-17 activate epithelial responses that coordinate clearance of fungal cells at mucosal surfaces. The asterisks indicate genetic or humoral defects that predispose humans to a spectrum of fungal disease. Myeloid and epithelial cells collaborate to regulate CXCR2-dependent neutrophil recruitment to portals of infection. Illustrated by Mao Miyamoto.

Dectin-1 signaling regulates ERK (also known as MAP kinase) activity via H-RAS and RAS guanine nucleotide–releasing factor 1 (RASGRF1) (39). This pathway regulates macrophage IL-6, IL-1β, and TNF, but not IL-12 responses, and is protective during systemic candidiasis (39). c-JUN kinase isoform 1–deficient (JNK1-deficient) mice are resistant to systemic candidiasis (40). Dectin-1–induced JNK1 signaling negatively regulates CD23 (encoded by Fcer2) expression via nuclear factor of activated T cells (NFAT) activation. CD23 binds α-mannans and β-glucans and induces the antifungal effector NOS2. Consistent with this model, Cd23^–/– mice are susceptible to systemic candidiasis (40).

In otherwise nonphagocytic cells, dectin-1 expression promotes phagocytosis of nonopsonized β-glucan particles (5, 9). Bruton’s tyrosine kinase (BTK) and VAV-1 interact with dectin-1 in macrophages during C. albicans phagocytosis, a process impaired by genetic loss of either protein (41). Dectin-1/SYK/CARD9 signaling in NADPH oxidase activity is controversial, as dectin-1–dependent (24) and –independent (42) control of β2 integrin (CD18) activation and the respiratory burst have been reported in vitro. Murine Clec7a ^–/– and Card9^–/– neutrophils display no cell-intrinsic defect in killing A. fumigatus conidia, unlike p47phox^–/– neutrophils (43). These data can be reconciled if the major role of dectin-1/CARD9 is to modulate NADPH oxidase and fungal killing via soluble mediators, rather than by cell-intrinsic activation. β2 integrins and TLR signaling can collaborate with dectin-1 to mount macrophage inflammatory responses to H. capsulatum and other fungi (44, 45).

Dectin-2 (encoded by Clec4n) forms a complex with dectin-3 (encoded by Clec4d) to bind Candida α-mannans (46, 47) or with mincle (encoded by Clec4e) to bind Malassezia glycolipids (48). Blastomyces dermatiditis, H. capsulatum, C. posadasii, and A. fumigatus induce dectin-2 signaling (43, 49). As these CLRs lack a signaling domain, heterodimeric complexes signal via the ITAM-coupled adaptor FcRγ (9).

Following fungal recognition, the E3 ubiquitin ligase CBLB ubiquitinates dectin-1, dectin-2, and SYK, targeting them for degradation (50–52). In systemic candidiasis, Cblb^–/– mice exhibit reduced renal fungal burden and improved survival due to decreased inflammation-driven tissue damage (50–52). In contrast, TRIM62-mediated CARD9 ubiquitination is essential for BCL10 interactions, NF-κB activation, and defense against candidiasis (53).

Mincle/SYK/CARD9 signaling mediates responses to Fonsecaea pedrosii, an agent of chromoblastomycosis (54). Mincle-induced cytokines are insufficient to clear this soft tissue infection, and application of TLR-7 agonist imiquinod to fungal lesions can restore sterilizing immunity (55). In DCs, mincle signaling activates the E3 ubiquitin ligase MDM2, in turn suppressing dectin-1– and IRF1-dependent Il12a transcription (56). This MDM2-dependent pathway impairs Th1 responses and may contribute to the chronicity of chromoblastomycosis. During murine pneumocystosis and candidiasis, mincle signaling enhances fungal clearance but is dispensable for survival (57, 58).

Loss of individual CLRs results in variable susceptibility to C. albicans (22, 23) and A. fumigatus (24, 43), in part due to strain-specific differences in CLR activation, as shown for C. albicans (59). Consistent with SYK/CARD9 being central for CLR signal integration, mice with hematopoietic or DC-specific Syk deletion or with global CARD9 deficiency are highly susceptible to C. albicans (29, 60) and A. fumigatus (43) challenge. CARD9/SYK–dependent susceptibility maps to defective cytokine responses that control neutrophil, NK, and T cell trafficking or activation. During systemic candidiasis, DCs secrete IL-23 in a SYK-dependent manner, prompting IL-17A–dependent (hereafter referred to as IL-17) NK cell release of GM-CSF, thereby activating candidacidal neutrophils at infection sites (60, 61).

CLR-independent pathways also mediate fungus-induced inflammation. Fungal ligands activate TLR1–4, TLR-6, TLR-9, and NOD2 signaling in a variety of cell types (5, 9). For example, PTX3-opsonized A. fumigatus conidia activate TLR-4/MD-2/TRIF–dependent signaling that mediates IL-10 production (62). Following internalization, A. fumigatus conidia trigger macrophage TLR-9–, calcineurin-, and BTK-dependent TNF release (63); however, humans with NLR or TLR/MyD88 signaling defects do not manifest with fungal infections (64, 65). A detailed discussion of Mendelian defects that do manifest with fungal infections follows later in this review.

Fungal killing. Neutrophils rapidly internalize conidia and/or yeast cells and direct the production of ROS to the fungal phagosome (66). In macrophages, NADPH oxidase–dependent LC3-associated phagocytosis represents a potential clearance mechanism for A. fumigatus conidia (67, 68). Nutritional immunity, exemplified by zinc and iron sequestration, is critical for macrophage defense against intracellular H. capsulatum yeast cells (69), against fungal keratitis (70), and in chronic granulomatous disease (CGD) patients with defects in NADPH oxidase (71–73).

Fungal hyphae (A. fumigatus) and pseudohyphae (C. albicans) induce NADPH oxidase–dependent neutrophil extracellular trap (NET) formation (74), a form of neutrophil programmed cell death termed NETosis. NETs contain extracellular nucleic acids, histones, and granular proteins, including calprotectin and PTX3 (75, 76), and ensnare fungal organisms that are too large for phagolysosomal killing (74). Neutrophil calprotectin, a major NET component, is important for antihyphal host defense during murine A. fumigatus keratitis yet dispensable for anticonidial defense following respiratory A. fumigatus challenge (77), illustrating a fungal morphotype-specific role in host defense. A. fumigatus hydrophobins and galactosaminogalactan enhance fungal resistance to NETs (78, 79). The contribution of NETs to fungal clearance in vivo remains difficult to quantify, because researchers lack experimental tools that specifically disrupt NETosis in murine models.

Mucosal defense and fungal tissue invasion. At mucosal surfaces, IL-17 is critical for antifungal immunity. Innate lymphoid, Th17, and γδ T cells produce IL-17 following C. albicans challenge in the oropharynx or skin (80, 81). Skin sensory neurons participate in C. albicans detection and activate dermal DCs via the neuropeptide calcitonin-related gene product to direct IL-23–dependent γδ T cell IL-17 release (82). Oral epithelial cells represent an important IL-17 signaling target, as mice lacking IL-17–sensing capacity in these cells display a phenotype similar to that of Il17ra^–/– mice (83). The IL-17–dependent transcriptional response of oral epithelial cells includes antimicrobial peptides, including β-defensin 3 (DEFB3). Accordingly, Defb3^–/– mice are susceptible to oropharyngeal candidiasis (83). In C. albicans–infected kidneys, IL-17–dependent responses include activation of the kallikrein/kinin system, which prevents apoptosis of tubular cells (84). Neutrophil recruitment to infected oral tissues is complex, with reports of IL-17–dependent and –independent trafficking pathways (85, 86). One IL-17–independent mechanism involves IL-1α/β–sensing oral keratinocytes that regulate neutrophil influx via CXC-chemokine release and indirect control over G-CSF–dependent granulopoiesis (87). Thus, mucosal infections induce crosstalk between epithelial and hematopoietic cells to regulate innate activation and fungal clearance.

Fungal invasion of epithelial and endothelial cells contributes to tissue damage and disease dissemination. During mucormycosis, the endothelial receptor glucose-regulated protein 78 (GRP78) enables Rhizopus oryzae hyphae binding to endothelial cells (88) via spore coat protein surface proteins (CotH), primarily CotH3. Metabolic changes associated with hyperglycemia and diabetic ketoacidosis (DKA) enhance endothelial GRP78 expression, resulting in GRP78-dependent fungal tissue invasion (89). The widespread expression of CotH family members among Mucorales and absence from other fungal pathogens may explain the unique susceptibility of patients with DKA to mucormycosis. Consistent with this model, antibodies directed against GRP78 or CotH3 protect mice from mucormycosis (90).

The C. albicans adhesin Als3 mediates binding to biotic and abiotic surfaces, including epithelial and endothelial cells, and triggers internalization via E- and N-cadherin (91). The adhesin Hwp1 and the heat-shock protein Ssa1 also contribute to this process (92). An Als3p-based vaccine has emerged as a promising candidate to prevent mucosal and systemic disease (93) (NIH ClinicalTrials.gov identifiers: NCT01926028, NCT02996448). Following epithelial attachment, C. albicans pseudohyphae secrete the pore-forming, cytolytic peptide toxin candidalysin that is essential for virulence (94). At the onset of epithelial invasion, candidalysin activates MAPK signaling and c-FOS activation at sublytic concentrations (94). Epithelial activation leads to IL-1α, IL-6, G-CSF, and GM-CSF release, alerting host cells to the presence of invasive pseudohyphae.

A. fumigatus conidia express the lung mucin–binding lectin FleA that promotes lung macrophages to internalize conidia (95). Mice challenged with ΔfleA conidia have more severe pneumonia than animals challenged with WT conidia. Thus, FleA represents an essential target of the immune system to clear inhaled conidia. A. fumigatus hyphae also invade epithelial and endothelial cells, a property mediated in part by the CalA protein (96) and by galactosaminogalactan (14). Although CalA is dispensable for host cell adherence, CalA stimulates integrin α5β1–dependent hyphal endocytosis and is required for virulence in immunosuppressed mice (96).

Trained immunity and fungal infections. Humans maintain sterilizing antifungal immunity in the lung despite daily inhalation of thousands of fungal cells; therefore, single-inoculum animal models are limited in revealing immunologic responses that arise in response to multiple challenges. Repeated exposure to A. fumigatus antigens gives rise to RORγt⁺IL-17⁺ neutrophils in response to IL-6 and IL-23 production (97). IL-17⁺ neutrophils express IL-17RC and signal in a paracrine manner to boost fungicidal activity following secondary challenge in the eye and lung (97, 98).

Murine Ly6C^hi monocytes represent effector cells against C. albicans (99), A. fumigatus (100), and B. dermatiditis (101). During repetitive challenges with β-glucans, murine Ly6C^hi monocytes and human CD14⁺ monocytes exhibit attributes reminiscent of immunologic memory, including enhanced responsiveness, based on cytokine responses (102). β-Glucan priming induces epigenetic and metabolic changes in monocytes, the latter of which associates with a shift from oxidative phosphorylation to glycolysis via a dectin-1/AKT/mTOR/HIF-1α signaling pathway (103) and increased glutaminolysis (104). In macrophages, β-glucan priming partially reverses LPS exposure–associated chromatin modifications, specifically the silencing of proinflammatory genes (105). In humans, a recent study proposes a role for STAT1 signaling in eliciting trained immunity, and by extension, in protection against chronic mucocutaneous candidiasis (CMC) (106).

Adaptive antifungal immunity. Antibody-mediated immunity to fungal pathogens has been extensively reported in the literature (107). For example, natural fungal polysaccharide–targeting IgM antibodies enhance DC-mediated recognition of fungal antigen, the development of Th2 and Th17 responses, and B cell isotype class-switch recombination during murine pneumocystosis (108). In a model of X-linked agammaglobulinemia, pulmonary and CNS cryptococcal disease progressed rapidly, in part due to IgM-dependent defects in macrophage phagocytosis (109). Although there is significant support for the concept that antibody-dependent opsonization and complement activation enhance fungal clearance in animal models (107), loss of antibody-mediated immunity is generally compensated by alternate effector systems, such as myeloid and CD4⁺ T cell–mediated immunity. Additionally, humans with humoral immune defects are generally not susceptible to fungal disease; however, protective fungus-specific antibodies are being researched as an adjunctive therapy in preclinical models (107). Several groups have generated protective antibodies that form the basis for vaccine strategies in murine models of fungal disease and in a phase I trial for recurrent vulvovaginal candidiasis (110–113) (NIH ClinicalTrials.gov identifier: NCT01067131).

In the 1980s and 1990s, the dominant CD4⁺ T cell–dependent protection model involved the dichotomous differentiation of CD4⁺ T cells into Th1 and Th2 subsets. More recent studies have shown that antibody- or cytokine-mediated disruption of Th1 immunity or Th2-favoring interventions correlate with adverse outcomes in murine fungal infection models (5, 9). The discovery of Th17 and regulatory T cells (Tregs), the development of CD4⁺ T cell receptor–transgenic mice (114–116), the identification of fungal epitopes that elicit antigen-specific responses (117–119), and the precise phenotyping of PIDD patients with mycoses have advanced insight into CD4⁺ T cell–driven antifungal immunity (120).

At the site of infection, fungal cells and antigens are internalized by tissue-resident DC subsets and monocyte-derived cells (Mo-DCs). In the lung, Ly6C^hi monocytes and derivative Mo-DCs transport A. fumigatus conidia and B. dermatiditis yeast cells to lung-draining lymph nodes (121, 122). In a B. dermatiditis vaccine model, fungal protease–dependent cleavage of CCR2 ligands impedes lung Ly6C^hi monocyte trafficking and the development of vaccine protection (123). However, Mo-DCs are not required for direct CD4⁺ T cell priming due to antigen transfer to lymph node–resident DCs (122). Mo-DCs, as well as IRF4-dependent CD11b⁺ DCs, instruct fungal antigen–specific Th17 responses following A. fumigatus conidial challenge (124, 125). In the oral mucosa, CCR7-dependent transport of candidal antigens to draining lymph nodes results in antigen presentation by FLT3L-dependent migratory DCs and by Mo-DCs, both of which have the capacity to prime antigen-specific CD4⁺ T cells (116).

In the skin, epidermal Langerhans cells recognize C. albicans yeast cell β-glucan via dectin-1, release IL-6, and instruct Th17 cell differentiation. These Th17 cells protect against secondary skin infection, but not against secondary systemic challenge (126). When C. albicans pseudophyphae penetrate the epidermis, dermal CD11b^–CD103⁺ DCs drive differentiation of Th1 cells (126), which protect against secondary systemic challenge, but not secondary skin challenge (126). Thus, the cellular requirements for CD4⁺ T cell priming and differentiation vary by anatomic site and fungal morphology, and, in most cases, involve antigen transfer from migratory DCs and Mo-DCs to lymph node–resident DCs.

During pulmonary A. fumigatus challenge, T helper cell differentiation occurs incrementally. Expression of the transcription factor T-bet, which controls Th1 differentiation, is detectable in antigen-specific CD4⁺ T cells in lung-draining lymph nodes and is enhanced by MyD88-dependent signals. In infected airways, MyD88-independent signals promote further Th1 differentiation and IFN-γ production (114). In this model, dectin-1 signaling counters Th1 differentiation by limiting innate IL-12p35 and IFN-γ production (124). Vaccine immunity to dimorphic fungi relies primarily on pulmonary Th17 cells that likely facilitate mononuclear phagocyte– and neutrophil-dependent killing of these pathogens (127, 128). Recently, researchers identified a fungal calnexin epitope that is widely conserved among ascomycetes (118). Vaccine delivery of fungal calnexin elicited calnexin-specific CD4⁺ T cells that conferred protection against the three North American dimorphic fungal pathogens (118). Calnexin represents the most promising candidate for vaccine design against these mycoses.

Protective Th17 responses at mucosal surfaces can be enhanced by Treg-mediated IL-2 consumption, which enhances IL-17 and IL-22 release by responding Th17 cells and increases resistance to mucosal fungal infection (129). Despite the obligate requirement for IL-17 signaling during systemic candidiasis (61), FOXP3⁺ Treg–mediated potentiation of Th17 responses appears detrimental (130), consistent with the notion that high IL-17 levels lead to immunopathology, as described for type I IFN (38) and CCR1 signaling (131).

During pulmonary cryptococcosis, mammalian chitotriosidase digests fungal chitin, thereby stimulating lung-resident CD11b⁺IRF4⁺ DCs, which in turn promote a Th2-dominant response to virulent serotype A strains (119). Compared with WT mice, C. neoformans challenge in chitotriosidase-deficient animals elicited dramatically lower antigen-specific Th2 cell numbers and extended murine survival, despite similar lung fungal burden (119). These data support a model in which antigen-specific Th2 cells exacerbate cryptococcosis by augmenting tissue damage without effecting fungal growth. Consistent with these findings, chitosan-deficient (i.e., deacetylated chitin) cryptococcal strains elicit cytokine mediators that promote a Th1-biased response (132). Similarly, the chitin content of individual A. fumigatus strains correlates with the magnitude of Th2 responses and lung eosinophil recruitment (133). The role of eosinophils in fungal clearance remains poorly understood, with several recent reports suggesting these cells help mediate fungal clearance (134–136).

In the 1970s–1980s, characterization of two prototypic PIDDs that result from phagocyte oxidative machinery defects — CGD, caused by mutations in NADPH oxidase subunits and myeloperoxidase (MPO) deficiency (137, 138) — catalyzed our recognition that phagocyte oxidative cytotoxicity is critical for protection against invasive fungal disease in humans. The spectrum of clinical phenotypes of these disorders highlights the fungus-specific dependence on oxidative versus nonoxidative cytotoxic mechanisms for defense. For example, pulmonary aspergillosis is the signature fungal infection in CGD (137). Yet, only ~40% of CGD patients develop aspergillosis during their lifetime, despite daily inhalation of ubiquitous conidia. This observation indicates that nonoxidative mechanisms compensate in the remainder of the Aspergillus-exposed patients; better understanding of these mechanisms is an important future research direction (9, 69, 71, 77, 139). Invasive infections by other molds, such as Mucorales and Fusarium, or by commensal Candida yeasts are very uncommon (<5%), whereas invasive infections by endemic dimorphic fungi and Cryptococcus, or CMC do not develop in CGD (137, 140). In contrast, MPO deficiency is not permissive to infections by inhaled molds, and only a minority (<5%) of MPO-deficient patients develops invasive candidiasis. These clinical observations show that human phagocytes differentially depend on their oxidative capacity to effectively control different fungal pathogens. Importantly, while both CGD and MPO-deficient patients manifest defective hypochlorous acid production within phagocytes (137, 138), they exhibit distinct features in the phenotypic expression of fungal disease. The discrepancy in susceptibility to mold infection in these patients may reflect, at least in part, a potentially significant contribution of superoxide anion–dependent K⁺ influx in activating phagolysosomal granule proteases (141), which is defective with NAPDH oxidase, but not MPO, deficiency.

In the 1990s–2000s, the discovery of PIDDs resulting from alterations of IL-12/IFN-γ signaling uncovered the critical role of IL-12/IFN-γ–dependent lymphocyte/macrophage crosstalk in control of intracellular pathogens, including endemic dimorphic fungi, Cryptococcus, mycobacteria, and Salmonella (65). This pathway is dispensable for control of inhaled molds and mucosal fungal infection in humans. Some of these disorders respond clinically to mechanism-based immunotherapy with IFN-γ or IFN-α (142). Similarly, neutralizing IFN-γ and GM-CSF autoantibodies can underlie adult-onset acquired immunodeficiency characterized by endemic dimorphic fungal (143) and CNS cryptococcal disease (144). Patients with alveolar proteinosis due to impaired GM-CSF signaling develop aspergillosis (145), consistent with murine studies (146).

During the last decade, careful clinical phenotyping combined with next-generation sequencing technologies revealed the critical balance of JAK/STAT signaling in human antifungal immunity (147). Patients with STAT1 gain-of-function (GOF) mutations and those with hyper-IgE syndrome (Job’s syndrome) due to STAT3 loss-of-function (LOF) mutations develop fungal disease with overlapping and distinct features. STAT1 GOF mutations lead to disseminated infections by intracellular dimorphic fungi, CMC, and/or infections by inhaled molds in the absence of structural lung disease (65, 148). STAT3 LOF mutations also result in CMC, but pulmonary infections by inhaled molds occur as a consequence of structural lung disease caused by prior bacterial lung infections. In this cohort, infections by intracellular dimorphic fungi occur very rarely and, when they do, tend to involve the gastrointestinal tract (149). In contrast, LOF STAT1 mutations or GOF STAT3 mutations do not cause fungal disease (65).

Mutations in the transcription factor GATA2 result in a protean PIDD (65, 150) that brings together (a) susceptibility to bacterial, fungal and viral disease, (b) malignancy, and (c) vascular abnormalities. From a fungal disease standpoint, GATA2 haploinsufficiency leads to infections by endemic dimorphic fungi, Cryptococcus, and Aspergillus, but not Candida. GATA2-deficient patients exhibit monocytopenia that, consistent with recent murine models, likely contributes to fungal susceptibility (100, 150).

The discovery of kindreds with CMC that carry mutations in IL17F, IL17RA, IL17RC, and NF-κB activator 1 (ACT1), and complementary studies in IL-17–mutant mice discussed above indicate that IL-17 signaling is indispensable for mucosal, but not systemic, antifungal immunity (64, 65). Patients with IL17F or IL17RC mutations only develop CMC, whereas those with IL17RA or ACT1 mutations also manifest cutaneous staphylococcal and/or pulmonary bacterial infections, indicating that IL-17E/IL-25 signaling may specifically map to bacterial defense at mucosal surfaces (151, 152). CMC susceptibility has also been linked to mutations in other genes (64, 65), most of which either directly or indirectly interfere with Th17 development and/or responses (Figure 2). These include AIRE deficiency in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (153), Job’s syndrome in which STAT3 regulates RORγt-dependent Th17 development, the various genetic forms of severe combined immunodeficiency disorder (154), and mutations in STAT1, RORC, STK4, IRF8, DOCK8, IKBA, CLEC7A, and CARD9 (64, 65, 155). A CLEC7A polymorphism is also associated with susceptibility to invasive aspergillosis in hematopoietic cell transplant recipients (156).

CARD9 deficiency exhibits three distinctive features among Mendelian disorders of antifungal immunity (157). First, a substantial proportion of CARD9-deficient patients exhibit adult-onset fungal disease, in contrast to early childhood onset typical of other PIDDs. It is unclear whether a different threshold of fungal exposure and/or additional genetic, environmental, or other factors accounts for this observation. Second, CARD9 deficiency is the only PIDD in which both mucosal and systemic fungal disease develop, and susceptibility is restricted to fungi without concurrent bacterial or viral infections. Invasive candidiasis, CMC, invasive phaeohyphomycosis, and superficial and deep-seated dermatophytosis have also been reported (157). In contrast to CARD9, MALT1 or BCL-10 deficiency results in a narrower spectrum of fungal susceptibility, with only mucosal infections reported to date (157). Third, CARD9 deficiency strikingly results in infections at anatomical sites that are not typically associated with the specific pathogens. For example, CARD9-deficient patients exhibit a predilection for Candida meningoencephalitis, without disease in kidney, liver, or spleen, all of which are commonly affected in CARD9-sufficient patients (157, 158). CARD9 is critical for neutrophil recruitment to the Candida-infected CNS but not for neutrophil recruitment to the Candida-infected kidney or Staphylococcus-infected CNS (159). This tropism is mediated by CARD9-dependent production of CXC chemokines by resident glial cells and neutrophils in the Candida-infected CNS, while neutrophil-intrinsic chemotaxis and effector functions are largely intact in CARD9-deficient humans and mice (159–161). Development of CNS and intra-abdominal aspergillosis is another example of altered tissue tropism in CARD9-deficient patients (162) and results from defective CARD9-dependent neutrophil chemoattractant production in and neutrophil mobilization to extrapulmonary infection sites. The absence of pulmonary Aspergillus involvement in CARD9 deficiency may be explained by compensatory IL-1R/MyD88–dependent neutrophil lung recruitment (161, 163). Collectively, these human observations have led to our appreciation that CARD9 appears to mediate fungus-, cell type–, and organ-specific neutrophil recruitment during invasive fungal infection.

GM-CSF and G-CSF were reported to improve the outcome of a small number of CARD9-hypomorphic patients with CNS candidiasis (164). In this cohort, mutant CARD9 was impaired in its ability to complex with RASGRF1, but not with BCL10 and MALT1 (165). The mechanism by which these cytokines bypass the CARD9-dependent immune defect in this cohort and the generalizability of this protection in other CARD9-deficient patients remain to be elucidated.

While commensal fungi have been noted in humans and mice for over five decades, lack of culture-independent methods, delay in developing high-throughput rDNA sequencing methods, and paucity of annotated reference databases to classify fungal rDNA amplicons delayed characterization of endogenous fungal communities, termed the mycobiota (166, 167). Although fungi comprise less than 1% of total microbial rDNA sequences at different anatomic sites, the size of fungal cells (~3–10 μm diameter for most yeast cells, 2–5 μm diameter for typical mold conidia, and 10 to hundreds μm length for hyphae, compared with < 1 μm diameter for bacterial cells) suggests that fungal rDNA quantification underestimates fungal biomass in the microbiota. In the past five years, researchers have analyzed endogenous fungal communities in the oral cavity, gastrointestinal tract, skin, and mucosal sites in healthy and diseased individuals (168–172). In most studies, between 15 and 70 fungal genera have been identified, with Malassezia spp. predominant in the skin and Candida spp. predominant in the intestine. Recent work has defined mechanisms of Candida colonization resistance by intestinal anaerobic bacteria (173).

Our understanding of the reciprocal interplay between endogenous fungal communities and antifungal immunity remains limited. Despite high-quality studies that point to a central role for IL-17 in mucosal antifungal immunity, it remains unclear whether IL-17 controls the composition or diversity of commensal fungi. Administration of secukinumab, an IL-17–neutralizing Ab, in patients with Crohn’s disease increased the rate of fungal infections, consistent with IL-17 directing mucosal antifungal immunity (174).

Recent work has examined dectin-1 in shaping endogenous fungal communities and mycobiota-triggered immune responses in the gut. Clec7a^–/– mice developed intestinal inflammation and Candida and Trichosporon spp. overgrowth in the gut (168). In turn, Clec7a^–/– mice were unable to control Candida during dextran sulfate sodium–induced colitis and benefited from fluconazole therapy. In the absence of commensal Candida, Clec7a^–/– mice were more resistant to colitis and exhibited a reduction in colonic antimicrobial peptides that target Gram-positive bacteria, leading to an increase in commensal Lactobacillus murinus bacteria, Treg expansion, and resistance to colitis (175). Colonization of Clec7a^–/– mice with C. tropicalis reversed these effects and promoted intestinal inflammation. These findings suggest that dectin-1 signaling indirectly influences the intestinal bacterial microbiota. In humans, a two-marker CLEC7A haplotype is associated with treatment-refractory ulcerative colitis (168). Another study identified a negative correlation between a CLEC7A single nucleotide polymorphism (SNP) and Malassezia sympodialis abundance in the gut of inflammatory bowel disease (IBD) patients, though no additional (positive or negative) correlations with other fungi were reported, likely due to the small cohort size (176). These studies highlight a protective role for dectin-1 in intestinal mycobiota control and antifungal immunity.

Dectin-3 was recently reported to contribute to control of intestinal Candida and colitis. Intestinal C. tropicalis overgrowth in Clec4d^–/– mice was accompanied by a decrease in Th17 cells, impaired macrophage fungal phagocytosis, and defective intestinal epithelial cell barrier function (177). Consistent with these findings, antifungal treatment of Clec4d^–/– mice reduced C. tropicalis burden and ameliorated colitis.

CARD9 has also been implicated in IBD pathogenesis, as a nonsynonymous SNP in the CARD9-coding region strongly associates with IBD risk (178). In experimental colitis models, CARD9 signaling can be protective against fungi that contact the intestinal mucosa during colitis. Furthermore, antifungal drugs partially ameliorate intestinal inflammation in this context (179). Analysis of the intestinal microbiota of Card9^–/– mice revealed alteration in fungal and bacterial communities compared with WT animals. The intestinal microbiota in Card9^–/– mice lacked tryptophan-metabolizing bacteria and did not produce aryl hydrocarbon receptor ligands (180). As a result, Card9^–/– mice showed defective expression of Il22 and antimicrobial peptide–encoding genes Reg3g and Reg3b. Altogether, these findings suggest CARD9 may dually control fungal and bacterial populations in the gut.

Immunologic effects of intestinal fungi extend beyond the gut. In a house dust mite–induced airway allergy model, disruption of the gut fungal community with antifungal drugs increased disease severity (181). Aspergillus amstelodami, Epicoccum nigrum, and Wallemia sebi increased in abundance during antifungal drug–induced fungal dysbiosis, and intestinal supplementation with these strains replicated the detrimental effects of antifungal drugs on lung allergy (181). Similarly, antibiotic-induced fungal overgrowth exacerbated papain-induced lung allergy by promoting intestinal Candida overgrowth (182). This phenomenon, first demonstrated with C. albicans (183), is recapitulated by multiple Candida species and is mediated in part by eicosanoids (182). Thus, there is a complex interplay between endogenous fungal communities and innate immune tone and responses, both at local and distant sites.

The field of antifungal immunity has rapidly advanced in the past decade, a period marked by the dissection of fungus-specific innate and adaptive immune responses and convergence of human clinical and animal model data. The advances during this era are exemplified by insights into the pivotal role of dectin-1/CARD9 and IL-17 pathways in antifungal immunity. The discovery of β-glucan–induced trained immunity and conserved sterilizing immunity-mediating epitopes lays the foundation for clinical trials to test vaccine protection against multiple fungal genera and species. Important areas of future research include elucidation of the role of epithelial surfaces in fungal virulence and antifungal defense and the intercellular crosstalk underlying innate and adaptive antifungal immunity. It is likely that additional fungal recognition receptors and response pathways remain to be discovered, both in animal models and in human genetic studies. How the composition, diversity, and metabolism of endogenous fungal communities contribute to immune homeostasis and to inflammatory disorders remains largely unexplored, yet are central for deciphering the contribution of fungi to diverse states of human health and disease.

The authors receive support from the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (MSL), NIH grants AI093808 (TMH), DK098310 (IDI), AI123819 (IDI), a Kenneth Rainin Foundation Award (IDI), a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases Award (TMH), and a Geoffrey Beene Foundation Award (TMH). NIH Core Grant P30 CA008748 to MSKCC provided support for this manuscript. The authors apologize to many contributors in the field whose work could not be cited due to space limitations.

Address correspondence to: Michail S. Lionakis, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 11C102, Bethesda, Maryland, 20892, USA. Phone: 301.443.5089; E-mail: lionakism@niaid.nih.gov. Or to: Iliyan D. Iliev, Weill Cornell Medicine, Belfer Research Building, Room BB 718, 413 East 69th Street, New York, New York 10021, USA. Phone: 646.962.7236; E-mail: iliev@med.cornell.edu. Or to: Tobias M. Hohl, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 9, New York, New York, 10065, USA. Phone: 646.888.3596; E-mail: hohlt@mskcc.org.

Conflict of interest: The authors have declared that no conflict of interest exists.

Published: June 2, 2017

Reference information: JCI Insight. 2017;2(11):e93156. https://doi.org/10.1172/jci.insight.93156.

1. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med. 2012;4(165):165rv13.
   View this article via: PubMed Google Scholar
2. Saville SP, Lazzell AL, Monteagudo C, Lopez-Ribot JL. Engineered control of cell morphology in vivo reveals distinct roles for yeast and filamentous forms of Candida albicans during infection. Eukaryotic Cell. 2003;2(5):1053–1060.
   View this article via: PubMed CrossRef Google Scholar
3. Grzybowski A, Pietrzak K. Robert Remak (1815-1865): discoverer of the fungal character of dermatophytoses. Clin Dermatol. 2013;31(6):802–805.
   View this article via: PubMed CrossRef Google Scholar
4. Fisher MC, et al. Emerging fungal threats to animal, plant and ecosystem health. Nature. 2012;484(7393):186–194.
   View this article via: PubMed CrossRef Google Scholar
5. Underhill DM, Pearlman E. Immune interactions with pathogenic and commensal fungi: a two-way street. Immunity. 2015;43(5):845–858.
   View this article via: PubMed CrossRef Google Scholar
6. Rick EM, Woolnough K, Pashley CH, Wardlaw AJ. Allergic fungal airway disease. J Investig Allergol Clin Immunol. 2016;26(6):344–354.
   View this article via: PubMed CrossRef Google Scholar
7. Wu F, Groopman JD, Pestka JJ. Public health impacts of foodborne mycotoxins. Annu Rev Food Sci Technol. 2014;5:351–372.
   View this article via: PubMed CrossRef Google Scholar
8. Hohl TM. Overview of vertebrate animal models of fungal infection. J Immunol Methods. 2014;410:100–112.
   View this article via: PubMed CrossRef Google Scholar
9. Erwig LP, Gow NA. Interactions of fungal pathogens with phagocytes. Nat Rev Microbiol. 2016;14(3):163–176.
   View this article via: PubMed CrossRef Google Scholar
10. Rappleye CA, Eissenberg LG, Goldman WE. Histoplasma capsulatum alpha-(1,3)-glucan blocks innate immune recognition by the beta-glucan receptor. Proc Natl Acad Sci USA. 2007;104(4):1366–1370.
    View this article via: PubMed CrossRef Google Scholar
11. Garfoot AL, Shen Q, Wüthrich M, Klein BS, Rappleye CA. The Eng1 β-glucanase enhances histoplasma virulence by reducing β-glucan exposure. MBio. 2016;7(2):e01388–e01315.
    View this article via: PubMed Google Scholar
12. Aimanianda V, et al. Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature. 2009;460(7259):1117–1121.
    View this article via: PubMed CrossRef Google Scholar
13. Fontaine T, et al. Galactosaminogalactan, a new immunosuppressive polysaccharide of Aspergillus fumigatus. PLoS Pathog. 2011;7(11):e1002372.
    View this article via: PubMed CrossRef Google Scholar
14. Gravelat FN, et al. Aspergillus galactosaminogalactan mediates adherence to host constituents and conceals hyphal β-glucan from the immune system. PLoS Pathog. 2013;9(8):e1003575.
    View this article via: PubMed CrossRef Google Scholar
15. Netea MG, et al. Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J Clin Invest. 2006;116(6):1642–1650.
    View this article via: JCI PubMed CrossRef Google Scholar
16. Doering TL. How sweet it is! Cell wall biogenesis and polysaccharide capsule formation in Cryptococcus neoformans. Annu Rev Microbiol. 2009;63:223–247.
    View this article via: PubMed CrossRef Google Scholar
17. Lee MJ, Sheppard DC. Recent advances in the understanding of the Aspergillus fumigatus cell wall. J Microbiol. 2016;54(3):232–242.
    View this article via: PubMed CrossRef Google Scholar
18. Netea MG, Brown GD, Kullberg BJ, Gow NA. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol. 2008;6(1):67–78.
    View this article via: PubMed CrossRef Google Scholar
19. Garlanda C, et al. Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature. 2002;420(6912):182–186.
    View this article via: PubMed CrossRef Google Scholar
20. Moalli F, et al. Role of complement and Fc{gamma} receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus. Blood. 2010;116(24):5170–5180.
    View this article via: PubMed CrossRef Google Scholar
21. Cunha C, et al. Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med. 2014;370(5):421–432.
    View this article via: PubMed CrossRef Google Scholar
22. Taylor PR, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol. 2007;8(1):31–38.
    View this article via: PubMed CrossRef Google Scholar
23. Saijo S, et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nat Immunol. 2007;8(1):39–46.
    View this article via: PubMed CrossRef Google Scholar
24. Werner JL, et al. Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus. J Immunol. 2009;182(8):4938–4946.
    View this article via: PubMed CrossRef Google Scholar
25. Goodridge HS, et al. Activation of the innate immune receptor Dectin-1 upon formation of a ‘phagocytic synapse’. Nature. 2011;472(7344):471–475.
    View this article via: PubMed CrossRef Google Scholar
26. Deng Z, et al. Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal TH17 responses. Nat Immunol. 2015;16(6):642–652.
    View this article via: PubMed CrossRef Google Scholar
27. Strasser D, et al. Syk kinase-coupled C-type lectin receptors engage protein kinase C-σ to elicit Card9 adaptor-mediated innate immunity. Immunity. 2012;36(1):32–42.
    View this article via: PubMed CrossRef Google Scholar
28. Roth S, et al. Vav proteins are key regulators of Card9 signaling for innate antifungal immunity. Cell Rep. 2016;17(10):2572–2583.
    View this article via: PubMed CrossRef Google Scholar
29. Gross O, et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature. 2006;442(7103):651–656.
    View this article via: PubMed CrossRef Google Scholar
30. Rogers NC, et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005;22(4):507–517.
    View this article via: PubMed CrossRef Google Scholar
31. Gringhuis SI, et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk. Nat Immunol. 2009;10(2):203–213.
    View this article via: PubMed CrossRef Google Scholar
32. Gross O, et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 2009;459(7245):433–436.
    View this article via: PubMed CrossRef Google Scholar
33. Gringhuis SI, et al. Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome. Nat Immunol. 2012;13(3):246–254.
    View this article via: PubMed CrossRef Google Scholar
34. Karki R, et al. Concerted activation of the AIM2 and NLRP3 inflammasomes orchestrates host protection against Aspergillus infection. Cell Host Microbe. 2015;17(3):357–368.
    View this article via: PubMed CrossRef Google Scholar
35. Yang CS, et al. The autophagy regulator Rubicon is a feedback inhibitor of CARD9-mediated host innate immunity. Cell Host Microbe. 2012;11(3):277–289.
    View this article via: PubMed CrossRef Google Scholar
36. LeibundGut-Landmann S, et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007;8(6):630–638.
    View this article via: PubMed CrossRef Google Scholar
37. del Fresno C, et al. Interferon-β production via Dectin-1-Syk-IRF5 signaling in dendritic cells is crucial for immunity to C. albicans. Immunity. 2013;38(6):1176–1186.
    View this article via: PubMed CrossRef Google Scholar
38. Majer O, et al. Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections. PLoS Pathog. 2012;8(7):e1002811.
    View this article via: PubMed CrossRef Google Scholar
39. Jia XM, et al. CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity. J Exp Med. 2014;211(11):2307–2321.
    View this article via: PubMed CrossRef Google Scholar
40. Zhao X, et al. JNK1 negatively controls antifungal innate immunity by suppressing CD23 expression. Nat Med. 2017;23(3):337–346.
    View this article via: PubMed CrossRef Google Scholar
41. Strijbis K, et al. Bruton’s tyrosine kinase (BTK) and Vav1 contribute to Dectin1-dependent phagocytosis of Candida albicans in macrophages. PLoS Pathog. 2013;9(6):e1003446.
    View this article via: PubMed CrossRef Google Scholar
42. Boyle KB, et al. Class IA phosphoinositide 3-kinase β and δ regulate neutrophil oxidase activation in response to Aspergillus fumigatus hyphae. J Immunol. 2011;186(5):2978–2989.
    View this article via: PubMed CrossRef Google Scholar
43. Jhingran A, et al. Tracing conidial fate and measuring host cell antifungal activity using a reporter of microbial viability in the lung. Cell Rep. 2012;2(6):1762–1773.
    View this article via: PubMed CrossRef Google Scholar
44. Huang JH, et al. CR3 and Dectin-1 collaborate in macrophage cytokine response through association on lipid rafts and activation of Syk-JNK-AP-1 pathway. PLoS Pathog. 2015;11(7):e1004985.
    View this article via: PubMed CrossRef Google Scholar
45. Li X, et al. The β-glucan receptor Dectin-1 activates the integrin Mac-1 in neutrophils via Vav protein signaling to promote Candida albicans clearance. Cell Host Microbe. 2011;10(6):603–615.
    View this article via: PubMed CrossRef Google Scholar
46. Saijo S, et al. Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity. 2010;32(5):681–691.
    View this article via: PubMed CrossRef Google Scholar
47. Zhu LL, et al. C-type lectin receptors Dectin-3 and Dectin-2 form a heterodimeric pattern-recognition receptor for host defense against fungal infection. Immunity. 2013;39(2):324–334.
    View this article via: PubMed CrossRef Google Scholar
48. Ishikawa T, et al. Identification of distinct ligands for the C-type lectin receptors Mincle and Dectin-2 in the pathogenic fungus Malassezia. Cell Host Microbe. 2013;13(4):477–488.
    View this article via: PubMed CrossRef Google Scholar
49. Wang H, et al. C-type lectin receptors differentially induce Th17 cells and vaccine immunity to the endemic mycosis of North America. J Immunol. 2014;192(3):1107–1119.
    View this article via: PubMed CrossRef Google Scholar
50. Wirnsberger G, et al. Inhibition of CBLB protects from lethal Candida albicans sepsis. Nat Med. 2016;22(8):915–923.
    View this article via: PubMed CrossRef Google Scholar
51. Xiao Y, et al. Targeting CBLB as a potential therapeutic approach for disseminated candidiasis. Nat Med. 2016;22(8):906–914.
    View this article via: PubMed CrossRef Google Scholar
52. Zhu LL, et al. E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity. J Exp Med. 2016;213(8):1555–1570.
    View this article via: PubMed CrossRef Google Scholar
53. Cao Z, et al. Ubiquitin ligase TRIM62 regulates CARD9-mediated anti-fungal immunity and intestinal inflammation. Immunity. 2015;43(4):715–726.
    View this article via: PubMed CrossRef Google Scholar
54. Sousa Mda G, et al. Restoration of pattern recognition receptor costimulation to treat chromoblastomycosis, a chronic fungal infection of the skin. Cell Host Microbe. 2011;9(5):436–443.
    View this article via: PubMed CrossRef Google Scholar
55. de Sousa Mda G, et al. Topical application of imiquimod as a treatment for chromoblastomycosis. Clin Infect Dis. 2014;58(12):1734–1737.
    View this article via: PubMed CrossRef Google Scholar
56. Wevers BA, et al. Fungal engagement of the C-type lectin mincle suppresses dectin-1-induced antifungal immunity. Cell Host Microbe. 2014;15(4):494–505.
    View this article via: PubMed CrossRef Google Scholar
57. Kottom TJ, et al. The interaction of pneumocystis with the C-type lectin receptor mincle exerts a significant role in host defense against infection. J Immunol. 2017;198(9):3515–3525.
    View this article via: PubMed Google Scholar
58. Wells CA, et al. The macrophage-inducible C-type lectin, mincle, is an essential component of the innate immune response to Candida albicans. J Immunol. 2008;180(11):7404–7413.
    View this article via: PubMed CrossRef Google Scholar
59. Marakalala MJ, et al. Differential adaptation of Candida albicans in vivo modulates immune recognition by dectin-1. PLoS Pathog. 2013;9(4):e1003315.
    View this article via: PubMed CrossRef Google Scholar
60. Whitney PG, et al. Syk signaling in dendritic cells orchestrates innate resistance to systemic fungal infection. PLoS Pathog. 2014;10(7):e1004276.
    View this article via: PubMed CrossRef Google Scholar
61. Bär E, Whitney PG, Moor K, Reis e Sousa C, LeibundGut-Landmann S. IL-17 regulates systemic fungal immunity by controlling the functional competence of NK cells. Immunity. 2014;40(1):117–127.
    View this article via: PubMed CrossRef Google Scholar
62. Bozza S, et al. PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis. J Immunol. 2014;193(5):2340–2348.
    View this article via: PubMed CrossRef Google Scholar
63. Herbst S, et al. Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus. EMBO Mol Med. 2015;7(3):240–258.
    View this article via: PubMed CrossRef Google Scholar
64. Lanternier F, et al. Primary immunodeficiencies underlying fungal infections. Curr Opin Pediatr. 2013;25(6):736–747.
    View this article via: PubMed Google Scholar
65. Lionakis MS, Netea MG, Holland SM. Mendelian genetics of human susceptibility to fungal infection. Cold Spring Harb Perspect Med. 2014;4(6):a019638.
66. Warnatsch A, et al. Reactive oxygen species localization programs inflammation to clear microbes of different size. Immunity. 2017;46(3):421–432.
    View this article via: PubMed CrossRef Google Scholar
67. Akoumianaki T, et al. Aspergillus cell wall melanin blocks LC3-associated phagocytosis to promote pathogenicity. Cell Host Microbe. 2016;19(1):79–90.
    View this article via: PubMed CrossRef Google Scholar
68. Oikonomou V, et al. Noncanonical fungal autophagy inhibits inflammation in response to IFN-γ via DAPK1. Cell Host Microbe. 2016;20(6):744–757.
    View this article via: PubMed CrossRef Google Scholar
69. Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS. Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival. Immunity. 2013;39(4):697–710.
    View this article via: PubMed CrossRef Google Scholar
70. Leal SM, et al. Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum. PLoS Pathog. 2013;9(7):e1003436.
    View this article via: PubMed CrossRef Google Scholar
71. Zarember KA, Sugui JA, Chang YC, Kwon-Chung KJ, Gallin JI. Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion. J Immunol. 2007;178(10):6367–6373.
    View this article via: PubMed CrossRef Google Scholar
72. Gazendam RP, et al. Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects. Blood. 2014;124(4):590–597.
    View this article via: PubMed CrossRef Google Scholar
73. Gazendam RP, et al. Human neutrophils use different mechanisms to kill Aspergillus fumigatus conidia and hyphae: evidence from phagocyte defects. J Immunol. 2016;196(3):1272–1283.
    View this article via: PubMed CrossRef Google Scholar
74. Branzk N, et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol. 2014;15(11):1017–1025.
    View this article via: PubMed CrossRef Google Scholar
75. Jaillon S, et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med. 2007;204(4):793–804.
    View this article via: PubMed CrossRef Google Scholar
76. Urban CF, et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009;5(10):e1000639.
    View this article via: PubMed CrossRef Google Scholar
77. Clark HL, et al. Zinc and manganese chelation by neutrophil S100A8/A9 (calprotectin) limits extracellular Aspergillus fumigatus hyphal growth and corneal infection. J Immunol. 2016;196(1):336–344.
    View this article via: PubMed CrossRef Google Scholar
78. Bruns S, et al. Production of extracellular traps against Aspergillus fumigatus in vitro and in infected lung tissue is dependent on invading neutrophils and influenced by hydrophobin RodA. PLoS Pathog. 2010;6(4):e1000873.
    View this article via: PubMed CrossRef Google Scholar
79. Lee MJ, et al. The fungal exopolysaccharide galactosaminogalactan mediates virulence by enhancing resistance to neutrophil extracellular traps. PLoS Pathog. 2015;11(10):e1005187.
    View this article via: PubMed CrossRef Google Scholar
80. Gladiator A, Wangler N, Trautwein-Weidner K, LeibundGut-Landmann S. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J Immunol. 2013;190(2):521–525.
    View this article via: PubMed CrossRef Google Scholar
81. Conti HR, et al. Oral-resident natural Th17 cells and γδ T cells control opportunistic Candida albicans infections. J Exp Med. 2014;211(10):2075–2084.
    View this article via: PubMed CrossRef Google Scholar
82. Kashem SW, Riedl MS, Yao C, Honda CN, Vulchanova L, Kaplan DH. Nociceptive sensory fibers drive interleukin-23 production from CD301b⁺ dermal dendritic cells and drive protective cutaneous immunity. Immunity. 2015;43(3):515–526.
    View this article via: PubMed CrossRef Google Scholar
83. Conti HR, et al. IL-17 receptor signaling in oral epithelial cells is critical for protection against oropharyngeal candidiasis. Cell Host Microbe. 2016;20(5):606–617.
    View this article via: PubMed CrossRef Google Scholar
84. Ramani K, et al. The kallikrein-kinin system: a novel mediator of IL-17-driven anti-Candida immunity in the kidney. PLoS Pathog. 2016;12(11):e1005952.
    View this article via: PubMed CrossRef Google Scholar
85. Huppler AR, Conti HR, Hernández-Santos N, Darville T, Biswas PS, Gaffen SL. Role of neutrophils in IL-17-dependent immunity to mucosal candidiasis. J Immunol. 2014;192(4):1745–1752.
    View this article via: PubMed CrossRef Google Scholar
86. Trautwein-Weidner K, Gladiator A, Nur S, Diethelm P, LeibundGut-Landmann S. IL-17-mediated antifungal defense in the oral mucosa is independent of neutrophils. Mucosal Immunol. 2015;8(2):221–231.
    View this article via: PubMed CrossRef Google Scholar
87. Altmeier S, Toska A, Sparber F, Teijeira A, Halin C, LeibundGut-Landmann S. IL-1 coordinates the neutrophil response to C. albicans in the oral mucosa. PLoS Pathog. 2016;12(9):e1005882.
    View this article via: PubMed CrossRef Google Scholar
88. Liu M, et al. The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice. J Clin Invest. 2010;120(6):1914–1924.
    View this article via: JCI PubMed CrossRef Google Scholar
89. Gebremariam T, et al. Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis. J Clin Invest. 2016;126(6):2280–2294.
    View this article via: JCI PubMed CrossRef Google Scholar
90. Gebremariam T, et al. CotH3 mediates fungal invasion of host cells during mucormycosis. J Clin Invest. 2014;124(1):237–250.
    View this article via: JCI PubMed CrossRef Google Scholar
91. Phan QT, et al. Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells. PLoS Biol. 2007;5(3):e64.
    View this article via: PubMed CrossRef Google Scholar
92. Modrzewska B, Kurnatowski P. Adherence of Candida sp. to host tissues and cells as one of its pathogenicity features. Ann Parasitol. 2015;61(1):3–9.
    View this article via: PubMed Google Scholar
93. Schmidt CS, et al. NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults. Vaccine. 2012;30(52):7594–7600.
    View this article via: PubMed CrossRef Google Scholar
94. Moyes DL, et al. Candidalysin is a fungal peptide toxin critical for mucosal infection. Nature. 2016;532(7597):64–68.
    View this article via: PubMed CrossRef Google Scholar
95. Kerr SC, et al. FleA expression in Aspergillus fumigatus is recognized by fucosylated structures on mucins and macrophages to prevent lung infection. PLoS Pathog. 2016;12(4):e1005555.
    View this article via: PubMed CrossRef Google Scholar
96. Liu H, et al. Aspergillus fumigatus CalA binds to integrin α5β1 and mediates host cell invasion. Nat Microbiol. 2016;2:16211.
    View this article via: PubMed Google Scholar
97. Taylor PR, et al. Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORγt and dectin-2. Nat Immunol. 2014;15(2):143–151.
    View this article via: PubMed Google Scholar
98. Savers A, et al. Infection-mediated priming of phagocytes protects against lethal secondary Aspergillus fumigatus challenge. PLoS One. 2016;11(4):e0153829.
    View this article via: PubMed CrossRef Google Scholar
99. Ngo LY, Kasahara S, Kumasaka DK, Knoblaugh SE, Jhingran A, Hohl TM. Inflammatory monocytes mediate early and organ-specific innate defense during systemic candidiasis. J Infect Dis. 2014;209(1):109–119.
    View this article via: PubMed CrossRef Google Scholar
100. Espinosa V, et al. Inflammatory monocytes orchestrate innate antifungal immunity in the lung. PLoS Pathog. 2014;10(2):e1003940.
     View this article via: PubMed CrossRef Google Scholar
101. Sterkel AK, et al. Fungal mimicry of a mammalian aminopeptidase disables innate immunity and promotes pathogenicity. Cell Host Microbe. 2016;19(3):361–374.
     View this article via: PubMed CrossRef Google Scholar
102. Quintin J, et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe. 2012;12(2):223–232.
     View this article via: PubMed CrossRef Google Scholar
103. Cheng SC, et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345(6204):1250684.
     View this article via: PubMed CrossRef Google Scholar
104. Arts RJ, et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 2016;17(10):2562–2571.
     View this article via: PubMed CrossRef Google Scholar
105. Novakovic B, et al. β-Glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell. 2016;167(5):1354–1368.e14.
     View this article via: PubMed CrossRef Google Scholar
106. Ifrim DC, et al. Defective trained immunity in patients with STAT-1-dependent chronic mucocutaneaous candidiasis. Clin Exp Immunol. 2015;181(3):434–440.
     View this article via: PubMed CrossRef Google Scholar
107. Casadevall A, Pirofski LA. Immunoglobulins in defense, pathogenesis, and therapy of fungal diseases. Cell Host Microbe. 2012;11(5):447–456.
     View this article via: PubMed CrossRef Google Scholar
108. Rapaka RR, et al. Conserved natural IgM antibodies mediate innate and adaptive immunity against the opportunistic fungus Pneumocystis murina. J Exp Med. 2010;207(13):2907–2919.
     View this article via: PubMed CrossRef Google Scholar
109. Szymczak WA, Davis MJ, Lundy SK, Dufaud C, Olszewski M, Pirofski LA. X-linked immunodeficient mice exhibit enhanced susceptibility to Cryptococcus neoformans Infection. MBio. 2013;4(4):e00265.
     View this article via: PubMed Google Scholar
110. Torosantucci A, et al. A novel glyco-conjugate vaccine against fungal pathogens. J Exp Med. 2005;202(5):597–606.
     View this article via: PubMed CrossRef Google Scholar
111. Torosantucci A, et al. Protection by anti-beta-glucan antibodies is associated with restricted beta-1,3 glucan binding specificity and inhibition of fungal growth and adherence. PLoS One. 2009;4(4):e5392.
     View this article via: PubMed CrossRef Google Scholar
112. Wharton RE, Stefanov EK, King RG, Kearney JF. Antibodies generated against Streptococci protect in a mouse model of disseminated aspergillosis. J Immunol. 2015;194(9):4387–4396.
     View this article via: PubMed CrossRef Google Scholar
113. Sandini S, La Valle R, Deaglio S, Malavasi F, Cassone A, De Bernardis F. A highly immunogenic recombinant and truncated protein of the secreted aspartic proteases family (rSap2t) of Candida albicans as a mucosal anticandidal vaccine. FEMS Immunol Med Microbiol. 2011;62(2):215–224.
     View this article via: PubMed CrossRef Google Scholar
114. Rivera A, et al. Innate immune activation and CD4⁺ T cell priming during respiratory fungal infection. Immunity. 2006;25(4):665–675.
     View this article via: PubMed CrossRef Google Scholar
115. Wüthrich M, et al. A TCR transgenic mouse reactive with multiple systemic dimorphic fungi. J Immunol. 2011;187(3):1421–1431.
     View this article via: PubMed CrossRef Google Scholar
116. Trautwein-Weidner K, et al. Antigen-specific Th17 cells are primed by distinct and complementary dendritic cell subsets in oropharyngeal candidiasis. PLoS Pathog. 2015;11(10):e1005164.
     View this article via: PubMed CrossRef Google Scholar
117. Bär E, et al. A novel Th cell epitope of Candida albicans mediates protection from fungal infection. J Immunol. 2012;188(11):5636–5643.
     View this article via: PubMed CrossRef Google Scholar
118. Wüthrich M, et al. Calnexin induces expansion of antigen-specific CD4(+) T cells that confer immunity to fungal ascomycetes via conserved epitopes. Cell Host Microbe. 2015;17(4):452–465.
     View this article via: PubMed CrossRef Google Scholar
119. Wiesner DL, et al. Chitin recognition via chitotriosidase promotes pathologic type-2 helper T cell responses to cryptococcal infection. PLoS Pathog. 2015;11(3):e1004701.
     View this article via: PubMed CrossRef Google Scholar
120. Verma A, Wüthrich M, Deepe G, Klein B. Adaptive immunity to fungi. Cold Spring Harb Perspect Med. 2014;5(3):a019612.
     View this article via: PubMed Google Scholar
121. Hohl TM, et al. Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection. Cell Host Microbe. 2009;6(5):470–481.
     View this article via: PubMed CrossRef Google Scholar
122. Ersland K, Wüthrich M, Klein BS. Dynamic interplay among monocyte-derived, dermal, and resident lymph node dendritic cells during the generation of vaccine immunity to fungi. Cell Host Microbe. 2010;7(6):474–487.
     View this article via: PubMed CrossRef Google Scholar
123. Wüthrich M, Ersland K, Sullivan T, Galles K, Klein BS. Fungi subvert vaccine T cell priming at the respiratory mucosa by preventing chemokine-induced influx of inflammatory monocytes. Immunity. 2012;36(4):680–692.
     View this article via: PubMed CrossRef Google Scholar
124. Rivera A, et al. Dectin-1 diversifies Aspergillus fumigatus-specific T cell responses by inhibiting T helper type 1 CD4 T cell differentiation. J Exp Med. 2011;208(2):369–381.
     View this article via: PubMed CrossRef Google Scholar
125. Schlitzer A, et al. IRF4 transcription factor-dependent CD11b⁺ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity. 2013;38(5):970–983.
     View this article via: PubMed CrossRef Google Scholar
126. Kashem SW, et al. Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation. Immunity. 2015;42(2):356–366.
     View this article via: PubMed CrossRef Google Scholar
127. Wüthrich M, et al. Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice. J Clin Invest. 2011;121(2):554–568.
     View this article via: JCI PubMed CrossRef Google Scholar
128. Hung CY, Gonzalez A, Wüthrich M, Klein BS, Cole GT. Vaccine immunity to coccidioidomycosis occurs by early activation of three signal pathways of T helper cell response (Th1, Th2, and Th17). Infect Immun. 2011;79(11):4511–4522.
     View this article via: PubMed CrossRef Google Scholar
129. Pandiyan P, et al. CD4(+)CD25(+)Foxp3(+) regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model. Immunity. 2011;34(3):422–434.
     View this article via: PubMed CrossRef Google Scholar
130. Whibley N, et al. Expansion of Foxp3(+) T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge. Eur J Immunol. 2014;44(4):1069–1083.
     View this article via: PubMed CrossRef Google Scholar
131. Lionakis MS, et al. Chemokine receptor Ccr1 drives neutrophil-mediated kidney immunopathology and mortality in invasive candidiasis. PLoS Pathog. 2012;8(8):e1002865.
     View this article via: PubMed CrossRef Google Scholar
132. Upadhya R, Lam WC, Maybruck B, Specht CA, Levitz SM, Lodge JK. Induction of protective immunity to cryptococcal infection in mice by a heat-killed, chitosan-deficient strain of Cryptococcus neoformans. MBio. 2016;7(3):e00547.
     View this article via: PubMed Google Scholar
133. O’Dea EM, et al. Eosinophils are recruited in response to chitin exposure and enhance Th2-mediated immune pathology in Aspergillus fumigatus infection. Infect Immun. 2014;82(8):3199–3205.
     View this article via: PubMed CrossRef Google Scholar
134. Lilly LM, Scopel M, Nelson MP, Burg AR, Dunaway CW, Steele C. Eosinophil deficiency compromises lung defense against Aspergillus fumigatus. Infect Immun. 2014;82(3):1315–1325.
     View this article via: PubMed CrossRef Google Scholar
135. Guerra ES, et al. Central role of IL-23 and IL-17 producing eosinophils as immunomodulatory effector cells in acute pulmonary aspergillosis and allergic asthma. PLoS Pathog. 2017;13(1):e1006175.
     View this article via: PubMed CrossRef Google Scholar
136. Eddens T, et al. Eosinophils contribute to early clearance of Pneumocystis murina infection. J Immunol. 2015;195(1):185–193.
     View this article via: PubMed CrossRef Google Scholar
137. Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore). 2000;79(3):170–200.
     View this article via: PubMed CrossRef Google Scholar
138. Nauseef WM, Root RK, Malech HL. Biochemical and immunologic analysis of hereditary myeloperoxidase deficiency. J Clin Invest. 1983;71(5):1297–1307.
     View this article via: JCI PubMed CrossRef Google Scholar
139. Greenblatt MB, Aliprantis A, Hu B, Glimcher LH. Calcineurin regulates innate antifungal immunity in neutrophils. J Exp Med. 2010;207(5):923–931.
     View this article via: PubMed CrossRef Google Scholar
140. Henriet S, Verweij PE, Holland SM, Warris A. Invasive fungal infections in patients with chronic granulomatous disease. Adv Exp Med Biol. 2013;764:27–55.
     View this article via: PubMed Google Scholar
141. Reeves EP, et al. Killing activity of neutrophils is mediated through activation of proteases by K⁺ flux. Nature. 2002;416(6878):291–297.
     View this article via: PubMed CrossRef Google Scholar
142. Bax HI, et al. Interferon alpha treatment of patients with impaired interferon gamma signaling. J Clin Immunol. 2013;33(5):991–1001.
     View this article via: PubMed CrossRef Google Scholar
143. Browne SK, et al. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med. 2012;367(8):725–734.
     View this article via: PubMed CrossRef Google Scholar
144. Rosen LB, et al. Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis. J Immunol. 2013;190(8):3959–3966.
     View this article via: PubMed CrossRef Google Scholar
145. Punatar AD, Kusne S, Blair JE, Seville MT, Vikram HR. Opportunistic infections in patients with pulmonary alveolar proteinosis. J Infect. 2012;65(2):173–179.
     View this article via: PubMed CrossRef Google Scholar
146. Kasahara S, Jhingran A, Dhingra S, Salem A, Cramer RA, Hohl TM. Role of granulocyte-macrophage colony-stimulating factor signaling in regulating neutrophil antifungal activity and the oxidative burst during respiratory fungal challenge. J Infect Dis. 2016;213(8):1289–1298.
     View this article via: PubMed CrossRef Google Scholar
147. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161–170.
     View this article via: PubMed CrossRef Google Scholar
148. Toubiana J, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016;127(25):3154–3164.
     View this article via: PubMed CrossRef Google Scholar
149. Odio CD, et al. Endemic mycoses in patients with STAT3-mutated hyper-IgE (Job) syndrome. J Allergy Clin Immunol. 2015;136(5):1411–3.e1.
     View this article via: PubMed CrossRef Google Scholar
150. Spinner MA, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–821.
     View this article via: PubMed CrossRef Google Scholar
151. Ling Y, et al. Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. J Exp Med. 2015;212(5):619–631.
     View this article via: PubMed CrossRef Google Scholar
152. Puel A, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011;332(6025):65–68.
     View this article via: PubMed CrossRef Google Scholar
153. Ferre EM, et al. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. JCI Insight. 2016;1(13):e88782.
     View this article via: JCI Insight PubMed Google Scholar
154. Shearer WT, et al. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol. 2014;133(4):1092–1098.
     View this article via: PubMed CrossRef Google Scholar
155. Okada S, et al. IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science. 2015;349(6248):606–613.
     View this article via: PubMed CrossRef Google Scholar
156. Cunha C, et al. Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood. 2010;116(24):5394–5402.
     View this article via: PubMed CrossRef Google Scholar
157. Drummond RA, Lionakis MS. Mechanistic insights into the role of C-type lectin receptor/CARD9 signaling in human antifungal immunity. Front Cell Infect Microbiol. 2016;6:39.
     View this article via: PubMed Google Scholar
158. Lanternier F, et al. Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both. J Allergy Clin Immunol. 2015;135(6):1558–68.e2.
     View this article via: PubMed CrossRef Google Scholar
159. Drummond RA, et al. CARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system. PLoS Pathog. 2015;11(12):e1005293.
     View this article via: PubMed CrossRef Google Scholar
160. Drewniak A, et al. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood. 2013;121(13):2385–2392.
     View this article via: PubMed CrossRef Google Scholar
161. Jhingran A, et al. Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection. PLoS Pathog. 2015;11(1):e1004589.
     View this article via: PubMed CrossRef Google Scholar
162. Rieber N, et al. Extrapulmonary Aspergillus infection in patients with CARD9 deficiency. JCI Insight. 2016;1(17):e89890.
     View this article via: JCI Insight PubMed Google Scholar
163. Caffrey AK, et al. IL-1α signaling is critical for leukocyte recruitment after pulmonary Aspergillus fumigatus challenge. PLoS Pathog. 2015;11(1):e1004625.
     View this article via: PubMed CrossRef Google Scholar
164. Gavino C, et al. CARD9 deficiency and spontaneous central nervous system candidiasis: complete clinical remission with GM-CSF therapy. Clin Infect Dis. 2014;59(1):81–84.
     View this article via: PubMed CrossRef Google Scholar
165. Gavino C, et al. Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians. J Allergy Clin Immunol. 2016;137(4):1178–1188.e1.
     View this article via: PubMed CrossRef Google Scholar
166. Tang J, Iliev ID, Brown J, Underhill DM, Funari VA. Mycobiome: approaches to analysis of intestinal fungi. J Immunol Methods. 2015;421:112–121.
     View this article via: PubMed CrossRef Google Scholar
167. Underhill DM, Iliev ID. The mycobiota: interactions between commensal fungi and the host immune system. Nat Rev Immunol. 2014;14(6):405–416.
     View this article via: PubMed CrossRef Google Scholar
168. Iliev ID, et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science. 2012;336(6086):1314–1317.
     View this article via: PubMed CrossRef Google Scholar
169. Findley K, et al. Topographic diversity of fungal and bacterial communities in human skin. Nature. 2013;498(7454):367–370.
     View this article via: PubMed CrossRef Google Scholar
170. Dupuy AK, et al. Redefining the human oral mycobiome with improved practices in amplicon-based taxonomy: discovery of Malassezia as a prominent commensal. PLoS ONE. 2014;9(3):e90899.
     View this article via: PubMed CrossRef Google Scholar
171. Frykman PK, et al. Characterization of bacterial and fungal microbiome in children with Hirschsprung disease with and without a history of enterocolitis: a multicenter study. PLoS ONE. 2015;10(4):e0124172.
     View this article via: PubMed CrossRef Google Scholar
172. Nguyen LD, Viscogliosi E, Delhaes L. The lung mycobiome: an emerging field of the human respiratory microbiome. Front Microbiol. 2015;6:89.
     View this article via: PubMed Google Scholar
173. Fan D, et al. Activation of HIF-1α and LL-37 by commensal bacteria inhibits Candida albicans colonization. Nat Med. 2015;21(7):808–814.
     View this article via: PubMed CrossRef Google Scholar
174. Hueber W, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61(12):1693–1700.
     View this article via: PubMed CrossRef Google Scholar
175. Tang C, et al. Inhibition of Dectin-1 signaling ameliorates colitis by inducing Lactobacillus-mediated regulatory T cell expansion in the intestine. Cell Host Microbe. 2015;18(2):183–197.
     View this article via: PubMed CrossRef Google Scholar
176. Sokol H, et al. Fungal microbiota dysbiosis in IBD [published online ahead of print February 3, 2016]. Gut. https://doi.org/ 10.1136/gutjnl-2015-310746.
177. Wang T, et al. Dectin-3 deficiency promotes colitis development due to impaired antifungal innate immune responses in the gut. PLoS Pathog. 2016;12(6):e1005662.
     View this article via: PubMed CrossRef Google Scholar
178. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474(7351):307–317.
     View this article via: PubMed CrossRef Google Scholar
179. Sokol H, et al. Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology. 2013;145(3):591–601.e3.
     View this article via: PubMed CrossRef Google Scholar
180. Lamas B, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016;22(6):598–605.
     View this article via: PubMed CrossRef Google Scholar
181. Wheeler ML, et al. Immunological consequences of intestinal fungal dysbiosis. Cell Host Microbe. 2016;19(6):865–873.
     View this article via: PubMed CrossRef Google Scholar
182. Kim YG, Udayanga KG, Totsuka N, Weinberg JB, Núñez G, Shibuya A. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE₂. Cell Host Microbe. 2014;15(1):95–102.
     View this article via: PubMed CrossRef Google Scholar
183. Noverr MC, Noggle RM, Toews GB, Huffnagle GB. Role of antibiotics and fungal microbiota in driving pulmonary allergic responses. Infect Immun. 2004;72(9):4996–5003.
     View this article via: PubMed CrossRef Google Scholar
184. Loures FV, et al. Dectin-1 induces M1 macrophages and prominent expansion of CD8⁺IL-17⁺ cells in pulmonary Paracoccidioidomycosis. J Infect Dis. 2014;210(5):762–773.
     View this article via: PubMed CrossRef Google Scholar
185. Ifrim DC, et al. Role of Dectin-2 for host defense against systemic infection with Candida glabrata. Infect Immun. 2014;82(3):1064–1073.
     View this article via: PubMed CrossRef Google Scholar
186. Wang H, Li M, Lerksuthirat T, Klein B, Wüthrich M. The C-type lectin receptor mcl mediates vaccine-induced immunity against infection with Blastomyces dermatitidis. Infect Immun. 2015;84(3):635–642.
     View this article via: PubMed Google Scholar
187. Serrano-Gómez D, Domínguez-Soto A, Ancochea J, Jimenez-Heffernan JA, Leal JA, Corbí AL. Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin mediates binding and internalization of Aspergillus fumigatus conidia by dendritic cells and macrophages. J Immunol. 2004;173(9):5635–5643.
     View this article via: PubMed CrossRef Google Scholar
188. Lee SJ, Zheng NY, Clavijo M, Nussenzweig MC. Normal host defense during systemic candidiasis in mannose receptor-deficient mice. Infect Immun. 2003;71(1):437–445.
     View this article via: PubMed CrossRef Google Scholar
189. Netea MG, Van Der Graaf CA, Vonk AG, Verschueren I, Van Der Meer JW, Kullberg BJ. The role of Toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J Infect Dis. 2002;185(10):1483–1489.
     View this article via: PubMed CrossRef Google Scholar
190. Yauch LE, Mansour MK, Shoham S, Rottman JB, Levitz SM. Involvement of CD14, Toll-like receptors 2 and 4, and MyD88 in the host response to the fungal pathogen Cryptococcus neoformans in vivo. Infect Immun. 2004;72(9):5373–5382.
     View this article via: PubMed CrossRef Google Scholar
191. Jouault T, et al. Candida albicans phospholipomannan is sensed through Toll-like receptors. J Infect Dis. 2003;188(1):165–172.
     View this article via: PubMed CrossRef Google Scholar
192. Figueiredo RT, et al. TLR4 recognizes Pseudallescheria boydii conidia and purified rhamnomannans. J Biol Chem. 2010;285(52):40714–40723.
     View this article via: PubMed CrossRef Google Scholar
193. Zhang Y, Wu J, Xin Z, Wu X. Aspergillus fumigatus triggers innate immune response via NOD1 signaling in human corneal epithelial cells. Exp Eye Res. 2014;127:170–178.
     View this article via: PubMed CrossRef Google Scholar
194. Wagener J, et al. Fungal chitin dampens inflammation through IL-10 induction mediated by NOD2 and TLR9 activation. PLoS Pathog. 2014;10(4):e1004050.
     View this article via: PubMed CrossRef Google Scholar
195. Tomalka J, et al. A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans. PLoS Pathog. 2011;7(12):e1002379.
     View this article via: PubMed CrossRef Google Scholar
196. Hise AG, et al. An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell Host Microbe. 2009;5(5):487–497.
     View this article via: PubMed CrossRef Google Scholar
197. Tada H, et al. Saccharomyces cerevisiae- and Candida albicans-derived mannan induced production of tumor necrosis factor alpha by human monocytes in a CD14- and Toll-like receptor 4-dependent manner. Microbiol Immunol. 2002;46(7):503–512.
     View this article via: PubMed CrossRef Google Scholar
198. Means TK, et al. Evolutionarily conserved recognition and innate immunity to fungal pathogens by the scavenger receptors SCARF1 and CD36. J Exp Med. 2009;206(3):637–653.
     View this article via: PubMed CrossRef Google Scholar
199. Linden JR, De Paepe ME, Laforce-Nesbitt SS, Bliss JM. Galectin-3 plays an important role in protection against disseminated candidiasis. Med Mycol. 2013;51(6):641–651.
     View this article via: PubMed CrossRef Google Scholar
200. Hahn PY, Evans SE, Kottom TJ, Standing JE, Pagano RE, Limper AH. Pneumocystis carinii cell wall beta-glucan induces release of macrophage inflammatory protein-2 from alveolar epithelial cells via a lactosylceramide-mediated mechanism. J Biol Chem. 2003;278(3):2043–2050.
     View this article via: PubMed CrossRef Google Scholar