Metabolic disorders and diet

Surveillance studies across diverse geographical regions have identified diabetes as an underlying condition among patients with C. auris skin colonization (52% of cases) [37–39]; diabetes has also been repeatedly associated with an increased risk of C. auris systemic infection [15,40–43]. However, a study using topical application of C. auris in diabetic db/db mice, a widely used genetic model of type 2 diabetes, did not increase skin colonization [3], and susceptibility to C. auris skin colonization in chemically induced diabetic models, such as streptozotocin-treated mice, remains unexplored. Consuming a high-fat diet has been shown to alter skin architecture and local immune responses [33], which may help explain the association between obesity and C. auris infection in certain clinical studies [44]. Yet, short-term exposure to a high-fat western diet did not increase skin colonization by C. auris in mice [3]. Thus, longer-term or combined metabolic perturbations may better model human risk. Collectively, the contribution and mechanistic underpinnings of metabolic dysregulation and C. auris colonization and infection remain incompletely defined and warrant further investigation.

Antibacterial agents

C. auris skin colonization frequently occurs in patients recently exposed to prolonged courses of broad-spectrum antibiotics, particularly carbapenems and vancomycin, with 43.3% of colonized patients treated with carbapenems, and 41.7% with vancomycin [40–43,45–47]. Antibiotics may facilitate fungal colonization by disrupting the skin microbiome and/or by dampening local host defenses. For example, vancomycin has been shown to promote C. auris growth in vitro and in a Galleria mellonella infection model [48] and to impair lymphocyte-dependent IL-17 responses at mucosal barriers [49]. Broad-spectrum antibiotic use has also been shown to alter the skin microbiome composition and to enrich for multidrug-resistant organisms such as Pseudomonas aeruginosa, Proteus mirabilis, Acinetobacter baumannii, Klebsiella pneumoniae, and Providencia stuartii, potentially creating a permissive microbial niche for C. auris [12,13]. Jo and colleagues demonstrated that systemic antibiotic administration, such as doxycycline and trimethoprim/sulfamethoxazole (TMP/SMX), can penetrate the dermis and epidermis, altering the skin bacterial microbiome and enriching antibiotic-resistant strains [50]. This alteration in the microbiome may create a permissive environment for C. auris to colonize. In mice, pre-exposure to select antibiotics alone (tetracycline, trimethoprim-sulfamethoxazole) or in combination (ampicillin, metronidazole, neomycin, vancomycin [AMNV]) did not affect C. auris skin colonization [3]. These findings underscore interspecies differences in microbiota composition. Staphylococcus species such as S. epidermidis, S. hominis, and S. capitis are specific to human skin, whereas S. saprophyticus, S. aureus, and S. lentus are predominant species in mice [51,52]. This highlights the need for additional human-based studies to delineate the mechanisms by which microbial dysbiosis may influence C. auris persistence or colonization resistance.

Antifungal agents

The use of antifungals can alter or decrease the abundance of the skin’s mycobiome. A previous study shows that the human skin mycobiome regulates C. auris colonization in the skin [12]. Prior use of antifungals such as fluconazole has been associated with an increased risk for C. auris skin colonization and infection, which represented 11.7% of the cases [45] and 65.2% of the invasive infections in humans [53]. These findings suggest that exposure to antifungals may be a possible risk factor for C. auris colonization and infection in hospitalized patients. However, the human subjects in these studies had pre-existing comorbidities and medical conditions.

Immunosuppressive drugs

Immunosuppressive medications, especially corticosteroids, have been reported to be a predisposing factor for C. auris colonization. Studies assessing potential risk factors of C. auris show that ~35% of patients who received corticosteroids were associated with C. auris colonization [42,54] It is likely that suppression of IL-17-mediated responses is critical for cutaneous antifungal defenses [3,55] and/or inhibition of other innate and adaptive antifungal immune responses [56]. Cyclophosphamide-induced neutropenia increased mortality in mouse models of systemic C. auris infection [57,58], suggesting that immunosuppression augments susceptibility to C. auris colonization and dissemination, as has also been observed with other Candida species [59].

Age

The skin barrier function weakens with age, and the microbiome composition changes significantly across age groups. Proteobacteria and Corynebacterium were reported to be the predominant phylum and genus, respectively, on the skin with aging [60,61]. The skin of older individuals also shows reduced lipid content and natural moisturizing factors, which are essential for maintaining an effective stratum corneum barrier [62,63]. The age of the individual has been reported as a predisposing factor for C. auris skin colonization in some studies, with C. auris-colonized patients aged 65–80 years at greater risk [62–64].

Prolonged hospitalization

C. auris demonstrates a remarkable ability to persist on both host skin and inanimate objects for extended periods of time, posing great challenges to eradicate from hospital settings. Notably, many hospital-grade disinfectants have limited efficacy against C. auris [12,64,65]. As a result, patients with long-term hospital stays, especially those in long-term acute care hospitals (LTACHs) [66,67], were found to be likely to have C. auris skin colonization.

Other clinical risk factors

Additional clinical conditions associated with C. auris colonization and/or systemic infection include chronic kidney disease, hemodialysis, malignancy, central venous or urinary catheterization, and total parenteral nutrition, mirroring known risk factors for infections by other Candida species [45,46,59]. How these comorbidities, individually or collectively, increase the risk of C. auris skin colonization and infection remains to be studied.

Bacterial microbiome

A point prevalence survey conducted by Proctor and colleagues in a ventilator-capable skilled nursing facility in Chicago showed that patients colonized with C. auris on their skin harbor a distinct skin bacterial microbiome compared with uncolonized individuals from the same facility [12]. Patients with C. auris skin colonization were frequently co-colonized with multidrug-resistant gram-negative bacteria, including Proteus mirabilis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Providencia stuartii, and Morganella morganii (Fig 2) [12,13]. In contrast, patients who were not colonized with C. auris harbored a distinct set of bacteria, such as Staphylococcus hominis, Staphylococcus caprae, Anaerococcus nagyae, Peptoniphilus tyrrelliae, Anaerococcus octavius, Corynebacterium tuberculostearicum, and Staphylococcus epidermidis (Fig 2) [12]. These findings suggest that C. auris colonization is associated with distinct bacterial communities, potentially reflecting either ecological compatibility or loss of colonization resistance. Whether this cohabitation is mutualistic or opportunistic remains unclear. Future studies employing animal models and longitudinal human sampling are needed to define bacterial taxa that modulate C. auris persistence and identify mechanisms of microbial interference at the skin barrier.

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Fig 2. Microbiome alterations in Candida auris-positive and negative human skin.

Shown are bacterial and fungal communities distributed on the skin during normal homeostasis and during dysbiosis, which has been associated with C. auris skin colonization. The figure was generated using licensed BioRender.

https://doi.org/10.1371/journal.ppat.1014075.g002

Fungal mycobiome

Several fungal species constitute a significant proportion of the skin microbiome, termed the mycobiome, which may potentially influence C. auris colonization [68]. Proctor and colleagues identified four distinct mycobiome clusters in patients, distinguished by the relative abundance of Malassezia and Candida species [12]. Skin samples enriched for Malassezia species, including M. globosa, M. furfur, M. restricta, and M. arunalokei, which dominate the healthy human skin mycobiome, were rarely positive for C. auris [12,69]. Conversely, C. auris abundance correlated with other Candida species such as C. tropicalis, C. parapsilosis, C. orthopsilosis, and C. metapsilosis (Fig 2) [12]. Similarly, C. auris-positive dog ears exhibited reduced abundance of Malassezia species [70]. These observations suggest that Malassezia species may confer colonization resistance, whereas coexisting Candida species may create a permissive niche for C. auris. Since skin microbial communities can restrict bacterial pathogens through metabolic competition and immune modulation [69–72], dissecting inter-fungal and bacterial-fungal interactions will be essential for a better understanding of C. auris colonization and for developing microbiome-based preventive and therapeutic strategies.

Adhesins: Scf1, Iff4109, and Als4112

By performing an elegant forward genetic screen of insertional mutants in C. auris, Santana and colleagues identified a novel adhesin, Scf1 (surface colonizing factor), which promotes fungal adhesion to inert abiotic surfaces through cation-dependent interactions and enhances biofilm formation on murine and human skin [6]. SCF1 functions redundantly with the adhesin IFF4109, a member of the IFF/HYR adhesin family, as their double deletion in the Δscf1 Δiff4109 mutant strain significantly decreased skin colonization. Notably, SCF1 expression varies between C. auris clades and within strains of the same clade and correlates with adhesive capacity; thus, SCF1 expression is low in the poorly adherent strain AR0387 and elevated in the highly adherent strain AR0382. Furthermore, overexpression of SCF1 in the poorly adherent strain AR0387 restored its adherence capacity and increased its colonization potential in murine and human skin [6].

Als4112, a member of the agglutinin-like sequence (Als) adhesin family, further enhances C. auris cell aggregation and biofilm formation [72,73]. Clinical isolates of C. auris exhibiting aggregative phenotypes often harbor amplification of the sub-telomeric ALS4112 locus, conferring robust biofilm formation and colonization on murine skin [73]. Als4112 physically interacts with Scf1 through the Flo11 and serine–threonine-rich domains, and together these adhesins mediate in cell-cell adherence, aggregation, and biofilm integrity for skin colonization [74].

C. auris colonizes both superficial and deep skin layers and can reside within hair follicles that are lined by keratinocytes [3]. A recent study performed unbiased insertional mutant screening in C. auris and confirmed that ALS4112 mediates keratinocyte adherence [11]. ALS4112 deletion abolished the adherence capacity on human keratinocytes across strains from multiple C. auris clades, while its overexpression enhanced adherence in the poorly-adherent strain AR0382 [11]. Concordantly, among C. auris clinical isolates, the magnitude of ALS4112 expression correlated with their keratinocyte adherence capacity, with Clade IV exhibiting comparatively higher adherence. Moreover, it was recently shown that C. auris binds avidly to extracellular matrix (ECM) proteins, such as tropoelastin, collagen V, and laminin, with Als4112 mediating binding to the principal ECM protein, laminin [11].

The skin colonization potential varies among the different geographically stratified clades of C. auris [3]. This shows that differential fungal factors and their gene expression across clades may contribute to variable propensities for C. auris skin colonization. Recent studies suggest that the gene expression of SCF1 and ALS4112 varies among different clades and clinical strains of C. auris, and exhibits a strong positive correlation with C. auris adherence activity [6,11]. C. auris strains belonging to clade III highly express SCF1 and ALS4112, associated with greater adherence capacity. On the other hand, clade II had low expression of SCF1 and ALS4112, and exhibited low adherence capacity. Furthermore, strains belonging to clades I and IV uncoordinatedly express SCF1 and ALS4112, with regulation independent among the individual strains. Moreover, deletion of Δscf1Δiff4109 and ΔAls4112 significantly reduced skin colonization, suggesting a vital role of these adhesins in C. auris colonization of the skin [6,11]. This suggests that the gene expression of SCF1 and ALS4112 across C. auris clades and strains may affect their skin colonization potential. Collectively, adhesins Scf1, Iff4109, and Als4112 are key effectors that enable C. auris attachment to keratinocytes and the ECM, providing a molecular basis for understanding its skin tropism and representing potential targets for antifungal drug development.

Protein kinase Hog1

The protein kinase Hog1 governs C. auris adaptation to host-imposed stress conditions [75,76]. Specifically, Hog1 confers resistance to osmotic, cationic, acid, and reactive oxygen species-induced stress [75,76]. A HOG1-deficient mutant strain exhibited reduced epidermal colonization, intradermal persistence, and dissemination to distant organs following epicutaneous and intradermal infections in mice [76]. Similarly, during systemic murine infection, fungal proliferation in the kidney and brain was significantly decreased in the Δhog1 mutant strain [76]. Thus, Hog1-dependent stress tolerance is critical for both cutaneous and systemic spread of C. auris.

Other pathways of C. auris governing stress tolerance and metabolic adaptation in the skin

C. auris can proliferate in the nutrient-poor environment of the skin, in which other pathogenic fungi fail to persist long-term. In recent years, additional pathways governing stress tolerance and C. auris metabolic adaptation in the skin have been explored to understand how C. auris remodels its metabolism and activates survival pathways distinct from those of other Candida species. Sebum and sweat, which are rich in free fatty acids and amino acids, are the major nutrients of the skin. In nutrient-poor environments lacking glucose, C. auris utilizes free fatty acids via β-oxidation, followed by the glyoxylate cycle to obtain energy from the carbon source. Recent evidence suggests that deletion of FOX2 (β-oxidation), CAT2 (fatty acid transport), and ICL1 (glyoxylate cycle) results in defective growth in sweat media [77]. This metabolic adaptation of C. auris may favor long-term persistence in the skin.

C. auris further regulates other stress resistance pathways, such as calcineurin [78] and Ras/cAMP/PKA [79] pathways for thermotolerance, morphological plasticity, and biofilm formation, which contribute to pathogenesis in C. auris. Cha and colleagues demonstrated that ablation of the calcineurin pathway by CNA1 deletion in C. auris significantly reduced abscess and fungal burden in the murine skin in a subcutaneous infection model [78]. In ex vivo murine skin, the Δcna1 strain had significantly lower adhesion to the skin shortly post-association [78]. This suggests that the CNA1 is indispensable for virulence properties needed for C. auris skin colonization and infection [78]. Furthermore, hyperactivation of the Ras/cAMP/PKA pathway by BCY1 or PDE2 deletion attenuated the virulence during murine systemic infection by reducing the ability to thrive in nutrient-deficient conditions [79,80]. However, the precise mechanisms by which these pathways contribute to C. auris persistence in the skin remain unclear and require further investigation.

Neutrophils are critical for skin immunity against C. auris

Neutrophils are critical in host defense against several fungal pathogens, yet their role in cutaneous immunity to C. auris in the skin has only recently been defined [82,83]. Unlike C. albicans, C. auris exhibits remarkable resistance to neutrophil phagocytosis and killing ex vivo, attributable to its unique cell wall composition [18,84]. Johnson and colleagues reported that primary human neutrophils show reduced phagocytosis and impaired neutrophil extracellular trap (NET) formation against C. auris ex vivo compared to C. albicans [84]. Using a zebrafish model of invasive candidiasis, reduced neutrophil recruitment in vivo was observed during C. auris compared to C. albicans infection [84]. Similarly, in an intradermal mouse model of C. auris infection, neutrophil accumulation was significantly lower in C. auris-infected compared to C. albicans-infected mice in vivo [85]. Despite the blunted neutrophil accumulation during C. auris infection, antibody-mediated neutrophil depletion in mice significantly increased fungal burden in the skin in vivo, establishing neutrophils as a contributing factor to anti-C. auris skin defense, albeit being functionally subverted during infection [86].

Recent work linked this neutrophil evasion to C. auris cell wall mannosylation [87]. CRISPR-mediated deletion of PMR1 and VAN1, genes required for N-mannan synthesis and branching, significantly reduced cell wall mannan content and reciprocally increased exposure of β-glucan and chitin [87]. These mutant strains exhibited improved recognition and killing by human neutrophils ex vivo, and their inoculation into the zebrafish model of invasive candidiasis resulted in increased neutrophil recruitment, associated with reduced fungal burden [87]. Correspondingly, wild-type C. auris resisted neutrophil killing, whereas deletion of PMR1 and VAN1 in C. albicans and C. glabrata did not alter their engagement with neutrophils, thereby highlighting a species-specific role for C. auris mannosylation in neutrophil evasion [87].

scRNA-seq of C. auris murine skin during infection identified IL1RN (encoding IL-1 receptor antagonist, IL-1Ra) as a key host factor modulating neutrophil activity during C. auris infection [86]. IL-1Ra is produced predominantly by macrophages in response to C. auris and inhibits IL-1α and IL-1β signaling by competitively binding to IL-1R [88,89]. Exogenous IL-1Ra decreased the killing capacity of neutrophils ex vivo against C. auris, while IL-1Ra neutralization in C. auris-infected mice in vivo significantly reduced cutaneous fungal burden, demonstrating that excessive IL-1Ra dampens protective neutrophil responses and favors fungal growth in the skin. Notably, ex vivo macrophages primed with wild-type C. auris, but not the pmr1Δ mutant strain lacking outer mannan, produced elevated IL-1Ra, linking the fungal mannan layer to the IL-1R pathway inhibition. In turn, IL-1R deficiency impaired neutrophil recruitment even against the pmr1Δ mutant strain, confirming the requirement of IL-1 signaling for anti-C. auris antifungal immunity in the skin.

Together, these findings uncover a two-tiered evasion strategy: C. auris masks immunogenic β-glucan through mannosylation to avoid neutrophil recognition and simultaneously induces macrophage-derived IL-1Ra to suppress IL-1R-dependent neutrophil recruitment and activation. This mannan-IL-1Ra axis represents a critical checkpoint exploited by C. auris to persist in the skin and a potential therapeutic target.

Macrophages are associated with increased skin fungal burden

Macrophages are pivotal in host defense against several fungal pathogens, yet during C. auris skin infection appears to facilitate, rather than restrict, fungal persistence [81]. Flow cytometric and scRNA-seq analyses revealed increased accumulation of macrophages at the site of C. auris skin infection in mice [86], but their functional role remained poorly defined. Recent studies showed that C. auris can replicate within macrophages, using metabolic plasticity to survive and escape the phagolysosomal environment [90,91]. The fungus induces host glucose starvation and metabolic stress, leading to macrophage death without triggering classical activation of the NLRP3 inflammasome or its effector molecules IL-1β and caspase-1, unlike C. albicans [90]. Disruption of mitochondria and iron homeostasis restricts the proliferation of C. auris within macrophages, underscoring the metabolic dependence of this phenomenon [91].

In vivo, macrophage depletion in murine C. auris skin infection markedly reduced fungal burden. This protective effect likely reflects macrophage-derived IL-1Ra and increased neutrophil antifungal activity, though direct deprivation of an intracellular replication niche may also contribute. Future studies should define how C. auris modulates macrophage metabolism and viability during skin infection, and whether its distinctive mannan layer of C. auris conceals fungal PAMPs from inflammasome detection and activation.

Essential role of ILCs against C. auris in the skin

ILCs contribute to effective host defense against mucocutaneous fungal challenge [92,93]. In an intradermal mouse model, IL-17⁺ ILCs accumulated in the skin during C. auris infection [85]. Similarly, Huang and colleagues demonstrated in an epicutaneous model that both Rag2-deficient mice, which lack T cells but retain ILC populations, as well as Rag2 Il2rg double-knockout mice, which lack ILCs in addition to all other lymphoid cells, were highly susceptible to C. auris skin colonization [3]. Susceptibility was greatest in Rag2 Il2rg double-knockout mice, confirming that IL-17A/IL-17F-producing lymphoid populations, including but not limited to ILCs, are essential for protection against C. auris skin colonization [3].

The type-17 cytokine, IL-22, although critical for protection against C. albicans oral infection, appears dispensable for immunity in the setting of skin C. auris colonization [3,94]. These findings highlight distinct cytokine requirements across mucocutaneous tissues and underscore IL-17-producing ILCs as key effectors that maintain antifungal barrier immunity in the skin.

Role of non-immune skin cells in antifungal immunity to C. auris

Non-immune skin cells contribute to barrier defense by maintaining epithelial integrity, producing AMPs, and releasing chemokines to recruit immune effector cells [95,96]. Thus, keratinocytes, fibroblasts, and endothelial cells together form a dynamic frontline against microbial invasion.

Dermal fibroblasts are central among those populations. During S. aureus subcutaneous infection in mice, dermal fibroblasts undergo reactive adipogenesis and expand as preadipocytes that secrete CAMP (Cathelicidin Antimicrobial Peptide) [97]. A similar fibroblast-to-preadipocyte transition has been observed during C. albicans intradermal infection of mice, where CAMP production by preadipocytes is regulated through the FGFR-MEK-ERK signaling pathway [98]. Utilizing an intradermal mouse model of C. auris skin infection, scRNA-seq identified a fibroblast subset expressing adipocyte lineage markers as the only proliferating non-immune cell population [83], suggesting an analogous reactive adipogenesis during cutaneous C. auris infection. Skin fibroblast subsets also expressed a broad array of cytokines, chemokines, PRRs, and AMPs in response to C. auris, including Il33, Csf1, Tgfb2, Ccl2, Ccl7, Ccl11, Cxcl1, Cxcl5, Cxcl9, Cxcl10, Cxcl12, Cxcl14, Clec3b, Clec11a, Nod1, Mrc2, Lgals1, Lgals9, Lman1, Lnc2, Adm and Ang [86]. These mediators likely coordinate neutrophil, monocyte, and macrophage recruitment and promote local antimicrobial activity during C. auris skin infection.

Endothelial cells, likewise, upregulate several neutrophil chemoattractant molecules during C. auris skin infection, likely supporting neutrophil extravasation and recruitment from the blood to the infected tissue. A broader spectrum of cutaneous stromal cells was also identified with a dynamic transcriptional program during C. auris infection (Fig 3). Together, these findings demonstrate that non-immune stromal cells mount a coordinated innate response during C. auris infection, coupling structural maintenance with immune activation. Future in vivo studies using cell-specific conditional knockout mice will be critical to define how keratinocyte-, fibroblast-, and endothelium-derived mediators influence fungal containment during C. auris infection.

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Fig 3. Non-immune cells and Candida auris skin infection.

(A) Non-immune cells accumulated during C. auris skin infection in vivo as identified by single-cell RNA sequencing data generated in [86]. (B) Potential involvement of stromal cells, such as fibroblast subsets and adipocytes, in regulating immune response during C. auris skin infection by production of AMPs and neutrophil chemoattractants. The figure was generated using licensed BioRender. Abbreviations: BEC, Blood endothelial cells; LEC, Lymphatic endothelial cells; UHFCs, Upper hair follicle cells; AMPs, Antimicrobial peptides; F1, Fibroblast 1; F2, Fibroblast 2; F3, Fibroblast 3; F4, Fibroblast 4.

https://doi.org/10.1371/journal.ppat.1014075.g003

Protective role of IL-17 in skin against C. auris

In both epicutaneous colonization and intradermal infection mouse models, C. auris induces the accumulation of CD4⁺ IL-17A⁺ and CD4⁺ IL-17F⁺ Th17 cells in the skin [3,85]. Using Act1-deficient mice lacking IL-17 receptor signaling, Huang and colleagues showed that IL-17A/IL-17F responses are critical for cutaneous protection against C. auris colonization (Fig 4) [3]. As noted above, Rag2-deficient mice display similarly increased susceptibility to C. auris skin colonization, indicating that both αβ T cells and γδ T cells are crucial for IL-17-dependent immunity in this model. Future studies using CD4-, CD8-, TCRαβ-, and TCRγδ-deficient mice will be essential to delineate the relative contributions of Th17 cells, Tc17 cells, and IL-17-producing γδ T cells to cutaneous defense against C. auris.

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Fig 4. Protective role of IL-17 and pathogenic role of IFN-γ during Candida auris skin infection.

IL-17 produced by Th17 cells, γδ T cells, or ILCs in response to C. auris in the skin plays a protective role in host defense. IL-12 induced by macrophages and dendritic cells during C. auris interaction triggers Th1 cells to produce IFN-γ, which compromises dermal integrity and induces fibroblast cell death. The yeast, filamentous, and aggregative forms of C. auris can induce differential magnitudes of Th17 responses. The figure was generated using licensed BioRender.

https://doi.org/10.1371/journal.ppat.1014075.g004

In contrast to C. albicans, a deficiency in the CLR adaptor Card9, required for the induction of Th17 cells during cutaneous Malassezia infection [10,101,102], did not affect C. auris control in the skin [3]. Moreover, whereas LCs promote the induction of Th17 cells during C. albicans skin infection [103], LC-deficient mice controlled C. auris colonization normally, collectively indicating that C. auris elicits protective IL-17 immunity through Card9- and LC-independent pathways during colonization of the skin [3]. Notably, C. auris induces a weaker Th17 cell response than C. albicans, which may contribute to its long-term persistence [85]. Defining the fungal determinants that regulate Th17 responses during the C. auris-skin interaction remains a key area for investigation.

Fungal morphology shapes Th17 immunity

Fungal morphology profoundly influences virulence and host immunity [103]. In the skin, C. albicans exists as a yeast form in the stratum corneum, whereas in the dermis and systemic organs, it predominantly exists as filamentous forms. Of note, the yeast-locked form of C. albicans induces a robust Th17 response [103]. Clinical isolates of C. auris exhibit distinct morphologies, including yeast, aggregative, and filamentous [104–108]. To investigate the skin immune response against yeast and filamentous forms of C. auris, deletion of ELM1, a negative regulator of filamentation, was employed to convert the wild-type South Asian C. auris strain AR0387 to a filamentous strain; this elicited markedly greater Th17 cell responses and reduced fungal burden in murine intradermal skin infection [104]. Correspondingly, complementation restored yeast morphology and baseline Th17 responses [104]. These findings, consistent with prior C. albicans studies [86], demonstrate that C. auris morphotypes qualitatively and quantitatively regulate IL-17 immunity and fungal burden in skin.

Additional studies recently examined how the aggregative phenotype of C. auris, a complex phenomenon controlled at least in part by the zinc-finger transcription factor ACE2 that governs cell separation via the chitinase CST1, regulates Th17 cell development [109,110]. As such, cells lacking ACE2 fail to separate following budding and remain clumped together or “aggregate”, becoming resistant to physical stress and disruption [111]. Recent reports showed that clinical isolates of C. auris that harbor ACE single-nucleotide polymorphisms form rough, adherent colonies [112]. In a murine model of intradermal infection, the ace2Δ mutant strain of C. auris induced greater Th17 responses compared to wild-type or complemented strains [109]. Collectively, yeast, filamentous, and aggregative forms of C. auris elicit distinct magnitudes of Th17 activation, likely reflecting differences in cell wall composition and surface antigen exposure (Fig 4) [87,113].

These observations reveal a link between C. auris morphogenesis and adaptive immunity, suggesting that morphotype-specific cues may determine the quality and strength of protective IL-17 responses. Elucidating how C. auris morphology shapes T helper cell polarization and effector responses will be critical for designing antifungal vaccines or immunotherapies that restore effective skin immunity.

The pathogenic role of IFN-γ during C. auris skin infection

Whereas type-17 responses are protective in cutaneous antifungal defense, the contribution of type-1 immunity remained unclear during C. auris interaction with the skin [103,114]. Recent studies have shown that C. auris infection preferentially induces IFN-γ-secreting pathogenic Th1 cells upon re-infection (Fig 4) [115,116]. IFN-γ exacerbates skin infection by C. auris but not C. albicans via two independent mechanisms [115]. First, Ifng-/- mice displayed lower fungal burden associated with increased Th17 cells and expression of IL-17 receptor-dependent genes such as Cxcl1, S100a8, Il6, and Il1b. These findings suggest that excess IFN-γ partially attenuates protective IL-17-mediated responses following secondary infection with C. auris, thereby promoting persistence. Secondly, IFN-γ drives apoptosis of epithelial cells and fibroblasts and disrupts barrier integrity [117–119]. As such, wild-type mice exhibited higher frequencies of dead EpCAM⁺ epithelial cells and PDGFRα⁺ fibroblasts than Ifng−/− mice, and IFN-γ exposure caused dose-dependent cell death in primary keratinocytes and fibroblasts in vitro, particularly following C. auris challenge [115]. Consistently, keratinocyte-specific IFNγR1 conditional knockout mice were protected from barrier damage and fungal proliferation and persistence in vivo [116]. These findings were also corroborated in the context of IL-17 deficiency, thereby uncoupling the detrimental effects of excessive IFN-γ from its indirect effects on IL-17 responses and demonstrating that IFN-γ directly injures epithelial barriers, thereby enhancing C. auris colonization [116]. These findings extend a broader paradigm [120], which was first established in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome caused by loss-of-function variants in the autoimmune regulator (AIRE) gene, in which chronic excessive IFN-γ-driven mucosal inflammation promotes chronic mucocutaneous candidiasis by disrupting the integrity of the oral epithelial barrier [117,121].

At the cellular level, IL-12-producing inflammatory macrophages and monocyte-derived dendritic cells are the key sources of IFN-γ-inducing signals during C. auris re-infection (Fig 4). Indeed, depletion of these populations with clodronate liposome or Ccr2−/− mice decreased IL-12 production and Th1 cell development in vivo [122]. Given that the host immune response is modulated by fungal PAMPs [17] and that C. auris features a structurally unique outer mannan layer [18], that study also examined whether this distinct cell wall structure modulates Th1 cell development. Infection with the C. auris mannosylation-deficient pmr1Δ mutant strain resulted in decreased Th1 and increased Th17 cells, indicating that the C. auris outer mannan layer skews adaptive immunity toward type-1 polarization to promote fungal persistence in the skin [115].

Together, these findings define excessive IFN-γ as a pathogenic amplifier that damages epithelial barriers, suppresses Th17 responses, and favors chronic C. auris infection in the skin (Fig 4) [115]. This mechanistic insight suggests that selective modulation of type-1 cytokine pathways, such as with IFN-γ or IL-12 blockade, may represent a novel therapeutic approach to restore skin immunity and prevent persistent C. auris infection in vulnerable patients.