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Cited by 18Antifungal resistance and susceptibilityFungal Infections and StudiesNail Diseases and Treatments

The Emerging Fungal Pathogen Candida auris Induces IFNγ to Colonize the Skin

Open access
Das, Diprasom, Ganesh, Shrihari M., Mishra, Abtar, Netea, Mihai G., Thangamani, Shankar·2025·PLOS Pathogens
DOI 10.1371/journal.ppat.1013114PMC PMC12121905
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Abstract

Candida auris is an emerging multidrug-resistant skin-tropic fungal pathogen that causes serious human infections. However, the factors that regulate C. auris skin infection in vivo are still unclear. In this study, we identified that, unlike Candida albicans, which induces IL-17-secreting protective effector Th17 cells, C. auris predominately induces IFNγ-secreting pathogenic Th1 cells during reinfection. Surprisingly, we found that IFNγ enhances skin infection of C. auris but not C. albicans. Mechanistically, IFNγ enhances skin infection of C. auris by dampening the protective IL-17 responses and increasing dermal damage. Furthermore, we identified that the development of Th1 cells occurs through IL-12, produced by C. auris-induced inflammatory macrophages and monocyte-derived dendritic cells. In addition, our findings reveal that C. auris unique cell wall outer mannan layer regulates the development of Th1 and Th17 cells. Collectively, our findings, for the first time, identified that C. auris induces IFNγ to persist in the skin. These findings help explain why C. auris but not C. albicans preferentially persist in the skin long-term, with the potential to identify novel therapeutic approaches to prevent and treat this emerging fungal pathogen in humans.

AI snapshot

Written from the paper’s full text.

TL;DR

In a murine skin reinfection model, *Candida auris* predominantly induces IFNγ-secreting Th1 cells, unlike *C. albicans*, which induces protective Th17 cells. IFNγ worsens *C. auris* skin infection by suppressing IL-17 responses and increasing dermal damage, while *C. auris* outer mannan and IL-12 from inflammatory macrophages/moDCs promote this Th1 bias.

Key findings

  • *C. auris* reinfection produced higher skin fungal burden than *C. albicans*; from day 1 to day 5 post-secondary infection, *C. albicans* burden decreased by 1.48 ± 0.13 log, whereas *C. auris* decreased only 0.92 ± 0.13 log.
  • *C. auris* increased CD4+ IFNγ+ and activated CD4+CD69+IFNγ+ T cells and decreased CD4+IL-17A+ and CD4+CD69+IL-17A+ T cells compared with *C. albicans*; γδ T-cell IL-17A/IFNγ did not differ significantly.
  • In *Ifng−/−* mice, *C. auris* skin fungal load was significantly decreased, while *C. albicans* load was increased; *Ifng−/−* mice also had increased CD4+IL-17A+ cells and IL-17-signature transcripts (*Il6*, *Il1b*, *Cxcl1*, *S100a8*).
  • Macrophage depletion with clodronate or *Ccr2−/−* mice reduced IL-12p70 and fungal burden and shifted responses toward Th17; a *C. auris pmr1Δ* mutant lacking the outer mannan layer had reduced fungal load and increased Th17/decreased Th1 responses.

Methods

  • C57BL/6J wild-type, *Ifng−/−*, and *Ccr2−/−* mice were intradermally infected with *C. auris* AR0387 or *C. albicans* SC5314, rested 3 weeks, then reinfected; fungal burden and immune cells were analyzed mainly 5 days post-secondary infection.
  • Immune profiling used flow cytometry, ELISA for IL-12p70, qRT-PCR for IL-17-signature genes, scRNA-seq of skin cells, macrophage depletion with clodrosome, anti-IL-17A or anti-CD8 antibody treatment, and LDH release assays in primary keratinocytes/fibroblasts and cell lines.
  • Mouse studies used Mann-Whitney U tests; ex vivo LDH assays used paired t-tests, with significance at *p* ≤ 0.05.

Limitations

  • The paper states future studies are needed to distinguish tissue-resident memory versus recruited effector T cells, to dissect which inflammatory macrophages and/or dendritic cell types are critical for Th1 development, and to define roles of non-immune cells and NK cells.
  • The paper used one *C. auris* clade (South Asian CA 0387/B8441) and predicts, based on prior work, that CD4+ T-cell responses may not differ among clades, but this was not directly tested here.
  • Evident from the text: findings rely on a mouse intradermal reinfection model and ex vivo/cell-line assays, with no direct human skin or clinical validation reported.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1371/journal.ppat.1013114

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

60 of 76 cited sources checked · 33 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    C. auris decreases phagocytosis by neutrophils compared to C. albicans.

    “C. auris differentially stimulates cytokine production in peripheral blood mononuclear cells, decreases phagocytosis by neutrophils, and has a more potent binding to IgG than C. albicans [13–15].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [13] Y Wang, 2022, Innate immune responses against the fungal pathogen Candida auris, Nat Commun source
    • cites [14] L Yan, 2020, Unique cell surface mannan of yeast pathogen candida auris with selective binding to IgG, ACS Infect Dis source
    • cites [15] MV Horton, 2021, Candida auris cell wall mannosylation contributes to neutrophil evasion through pathways divergent from candida albicans and candida glabrata, mSphere source
  • Premisecitation

    The cell wall of C. auris is structurally and biologically unique compared to other Candida species, including C. albicans.

    “Recent evidence indicates that the cell wall of C. auris is structurally and biologically unique compared to other Candida species, including C. albicans [12].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] M Bruno, 2020, Transcriptional and functional insights into the host immune response against the emerging fungal pathogen Candida auris, Nat Microbiol source

      The Results (‘Unique structure of C. auris mannans’; page unavailable) identify a distinctive mannan structure and reduced receptor binding compared with C. albicans, supporting structural and biological differences. But the comparison is with C. albicans, not other Candida species generally, and the same section says C. auris β-glucans had no structurally unique features. The claim therefore overgeneralizes the finding to the cell wall as a whole and to other species. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    C. auris differentially stimulates cytokine production in peripheral blood mononuclear cells compared to C. albicans.

    “C. auris differentially stimulates cytokine production in peripheral blood mononuclear cells, decreases phagocytosis by neutrophils, and has a more potent binding to IgG than C. albicans [13–15].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [13] Y Wang, 2022, Innate immune responses against the fungal pathogen Candida auris, Nat Commun source

      The Results section reports that some C. auris strains elicited more cytokine production from human PBMCs than C. albicans, with higher TNF-α for all tested C. auris strains only at high MOI. It also says that most comparisons showed the same pattern of increased responsiveness to either species, so the unqualified claim overstates how consistently their effects differed. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [14] L Yan, 2020, Unique cell surface mannan of yeast pathogen candida auris with selective binding to IgG, ACS Infect Dis source
    • cites [15] MV Horton, 2021, Candida auris cell wall mannosylation contributes to neutrophil evasion through pathways divergent from candida albicans and candida glabrata, mSphere source

      The Results section compares C. auris and C. albicans in neutrophil phagocytosis assays, not cytokine production in peripheral blood mononuclear cells. Searches for PBMCs and cytokine production found no passage in our copy addressing that comparison; the cited paper therefore does not verify the specific claim. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
  • Premisecitation

    Ccr2-/- mice are defective in recruiting inflammatory macrophages and moDCs to the site of infection.

    “we utilized Ccr2-/- mice that are defective in recruiting inflammatory macrophages and moDCs to the site of infection [28].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [28] R Feuerstein, 2020, Resident macrophages acquire innate immune memory in staphylococcal skin infection, Elife source

      The Results section on infection-induced resistance reports that the infection-associated rise in Ly6Chi dermal macrophages was absent in Ccr2-/- mice, supporting defective recruitment of inflammatory macrophages. The cited paper does not establish the claimed defect in recruiting monocyte-derived dendritic cells (moDCs). No page numbers are provided in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    C. auris possesses a unique outer mannan layer compared to C. albicans.

    “Since fungal PAMPs modulate the host immune response [11], and C. auris possesses a unique outer mannan layer compared to C. albicans [12], we hypothesized that the C. auris outer cell wall mannan layer regulates the development of Th1 cells during C. auris reinfection.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] M Bruno, 2020, Transcriptional and functional insights into the host immune response against the emerging fungal pathogen Candida auris, Nat Microbiol source
  • Classified as probably not a substantial claim. 29
  • May combine two claims. 26

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Effector T cells play a critical role in the host's defense during reinfection with C. albicans, Staphylococcus aureus, Leishmania major, and HSV.

    “Effector T cells play a critical role in the host’s defense during reinfection with C. albicans, Staphylococcus aureus, Leishmania major, and HSV [28,30–35].”
    Quote in the paperNot a substantial claim7 of 7 sources checked
    • cites [28] R Feuerstein, 2020, Resident macrophages acquire innate immune memory in staphylococcal skin infection, Elife source

      In Results (‘Infection-induced resistance against S. aureus does not depend on bone marrow-derived monocytes and on mature T, B, and NK cells’; page unavailable), the paper reports enhanced protection on re-exposure in mice lacking mature T cells. It concludes that this protection does not depend on the adaptive immune system, contrary to the claim that effector T cells are critical for defense against S. aureus reinfection. The paper does not test T-cell protection against the other named pathogens. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [30] S LeibundGut-Landmann, 2021, Tissue-resident memory T cells in antifungal immunity., Front Immunol source

      In “What Are the Functional Attributes of TRMs” (page unavailable), the review says tissue-resident memory T cells rapidly control infection after re-exposure and describes protective C. albicans-responsive cells. It also discusses antiviral activity against HSV-1 reactivation, but does not establish the full claim about defense during reinfection with all four named pathogens. Its mention of S. aureus concerns atopic dermatitis, not protective reinfection immunity. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [31] SK Whitley, 2022, Local IL-23 is required for proliferation and retention of skin-resident memory TH17 cells, Sci Immunol source

      The Introduction (page not provided) describes skin-resident memory T cells protecting against secondary HSV infection and reinfection with Leishmania major. The Results section on IL-23 blockade (page not provided) demonstrates protection against subsequent C. albicans infection. Our copy does not support the Staphylococcus aureus part of the claim (searched: “Staphylococcus aureus”). (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [32] FR Kirchner, 2021, Tissue-resident memory Th17 cells maintain stable fungal commensalism in the oral mucosa, Mucosal Immunol source
    • cites [33] CO Park, 2018, Staged development of long-lived T-cell receptor αβ TH17 resident memory T-cell population to Candida albicans after skin infection, J Allergy Clin Immunol source

      The Results section (‘Skin CD4 T cells present after cutaneous C. albicans infection are pathogen-specific’; page unavailable) shows that skin-resident memory T cells protected mice against C. albicans reinfection. The Discussion also mentions protective T-cell immunity after skin viral infection, but the paper does not establish the claimed reinfection defense against Staphylococcus aureus or Leishmania major; it lists a Leishmania study only in its references. The demonstrated protective cells are resident memory T cells, rather than effector T cells at reinfection. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [34] N Iijima, 2014, T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells, Science source

      The paper’s main text (page not provided) reports that local memory CD4 T cells protect mice against secondary genital HSV-2 challenge. It does not address reinfection with C. albicans, Staphylococcus aureus, or Leishmania major, so it supports only the HSV portion of the cited sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [35] ND Glennie, 2015, Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection, J Exp Med source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    C. auris has more potent binding to IgG than C. albicans.

    “C. auris differentially stimulates cytokine production in peripheral blood mononuclear cells, decreases phagocytosis by neutrophils, and has a more potent binding to IgG than C. albicans [13–15].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [13] Y Wang, 2022, Innate immune responses against the fungal pathogen Candida auris, Nat Commun source

      The Discussion describes differences in innate immune recognition, and the Results compare cell-wall structure, but neither reports that C. auris binds IgG more strongly than C. albicans. A paper about selective IgG binding appears in the References (ref. 57); its title alone does not establish the comparative claim in this source. Searches for “IgG” and comparative IgG binding found no supporting passage. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [14] L Yan, 2020, Unique cell surface mannan of yeast pathogen candida auris with selective binding to IgG, ACS Infect Dis source
    • cites [15] MV Horton, 2021, Candida auris cell wall mannosylation contributes to neutrophil evasion through pathways divergent from candida albicans and candida glabrata, mSphere source

      The Results section reports reduced neutrophil phagocytosis of C. auris relative to C. albicans, but does not compare their binding to IgG. The IgG mentioned in the Results and fluorescent-labeling Methods is an anti-human IgG Fc antibody used to detect a dectin-1 reagent, not a measurement of Candida–IgG binding (page unavailable). Searches for IgG binding, immunoglobulin, and opsonization found no passage addressing the claimed comparison. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Fungal cell wall components represent the predominant pathogen-associated molecular patterns directly interacting with the host to orchestrate the antifungal immune response.

    “The fungal cell wall components represent the predominant pathogen-associated molecular patterns (PAMPs) directly interacting with the host to orchestrate the antifungal immune response [11].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] B Briard, 2021, Fungal cell wall components modulate our immune system, Cell Surf source

  • Classified as probably not a substantial claim.

    Premisecitation

    IFNγ and IL-17 can cross-regulate each other.

    “Since IFNγ and IL-17 can cross-regulate each other [20] and IL-17 is critical for host defense against C. auris [6], we hypothesized if increased IFNγ diminishes protective IL-17 response and increases fungal burden during C. auris-infection.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] X Hu, 2009, Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases, Immunity source

      In “Regulation of adaptive immunity: Th and Treg differentiation” (page unavailable), the review says IFN-γ suppresses Th17 differentiation and inhibits Th17-cell effector functions. It does not establish the reverse—that IL-17 regulates IFN-γ—so the claim’s reciprocal wording is not fully supported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Candida auris is an emerging multidrug-resistant skin-tropic fungal pathogen that causes serious human infections.

    “Candida auris is an emerging multidrug-resistant skin-tropic fungal pathogen that causes serious human infections.”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [1] S Ahmad, 2021, Candida auris: epidemiology, diagnosis, pathogenesis, antifungal susceptibility, and infection control measures to combat the spread of infections in healthcare facilities, Microorganisms source
    • cites [2] WHO, 2022

      Not checked in the free run.

    • cites [3] SS Kadri, 2020, Key takeaways from the U.S. CDC’s 2019 antibiotic resistance threats report for frontline providers, Crit Care Med source
    • cites [4] MS Lionakis, 2024, Candida auris infections, N Engl J Med source
    • cites [5] DJ Santana, 2023, A Candida auris-specific adhesin, Scf1, governs surface association, colonization, and virulence, Science source

  • May combine two claims.

    Premisecitation

    C. auris preferentially colonizes the human skin, leading to nosocomial transmission and outbreaks of systemic fungal infections.

    “Unlike other Candida species, such as Candida albicans that colonizes the intestinal tract, C. auris preferentially colonizes the human skin, leading to nosocomial transmission and outbreaks of systemic fungal infections [6–8].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [6] X Huang, 2021, Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies, Cell Host Microbe source
    • cites [7] PS Shastri, 2020, Candida auris candidaemia in an intensive care unit - Prospective observational study to evaluate epidemiology, risk factors, and outcome, J Crit Care source
    • cites [8] DM Proctor, 2023, One population, multiple lifestyles: Commensalism and pathogenesis in the human mycobiome, Cell Host Microbe source

  • May combine two claims.

    Premisecitation

    C. auris not only colonizes the epidermis of the skin but also enters the deeper dermis.

    “C. auris not only colonizes the epidermis of the skin but also enters the deeper dermis, a phenomenon that was not observed previously [6].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] X Huang, 2021, Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies, Cell Host Microbe source

      The Results section, “Candida auris Persistently Colonizes Skin” (page unavailable), reports C. auris on the skin surface and deeper within mouse skin tissue, including hair follicles. It does not specifically identify the deeper site as the dermis, and says deeper-tissue colonization has not been examined in human patients. The claim therefore extends the murine finding beyond what the paper establishes. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    IL-17 is critical for host defense against C. auris.

    “Since IFNγ and IL-17 can cross-regulate each other [20] and IL-17 is critical for host defense against C. auris [6], we hypothesized if increased IFNγ diminishes protective IL-17 response and increases fungal burden during C. auris-infection.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] X Huang, 2021, Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies, Cell Host Microbe source

      The Results section reports that mice lacking IL-17R-dependent responses had significantly higher C. auris burdens and concludes that the IL-17A/IL-17F–IL-17R response helps control skin colonization. That supports a protective role, but the study establishes it in a murine skin-colonization model, not for C. auris infection or host defense generally. Page numbers were not supplied. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The outer cell wall mannan layer in C. auris is highly enriched in β-1,2-linkages and contains two unique Mα1-phosphate side chains not found in other Candida species.

    “The outer cell wall mannan layer in C. auris is highly enriched in β-1,2-linkages and contains two unique Mα1-phosphate side chains not found in other Candida species [12].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] M Bruno, 2020, Transcriptional and functional insights into the host immune response against the emerging fungal pathogen Candida auris, Nat Microbiol source

      The Results section, “Unique structure of C. auris mannans” (page unavailable), reports β-1,2-mannose among the linkages in C. auris mannan side chains and identifies two distinct M-α-1-phosphate side chains as a unique structural feature. It does not say the β-1,2 linkages are highly enriched, and its structural comparison is with C. albicans, not all other Candida species. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    C. auris can persist in skin tissues for several months and evade routine clinical surveillance.

    “C. auris can persist in skin tissues for several months and evade routine clinical surveillance [6,10].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [6] X Huang, 2021, Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies, Cell Host Microbe source

      In Results, “Candida auris Persistently Colonizes Skin,” live C. auris was recovered from deeper mouse skin tissue for up to four months, after surface swabs had become negative. The study used those swabs to model clinical surveillance, but the Discussion says deep-tissue persistence in humans remains a possibility, not a demonstrated cause of missed clinical detection. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [10] DM Proctor, 2021, Integrated genomic, epidemiologic investigation of Candida auris skin colonization in a skilled nursing facility, Nat Med source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Th1 cells protect the host against reinfection from HSV and L. major.

    “Th17 cells play a critical role in host defense against C. albicans [30–33,36], whereas Th1 cells protect the host against reinfection from HSV and L. major [34,35].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [34] N Iijima, 2014, T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells, Science source

      In the main text (page not specified), the paper reports that IFN-γ–secreting CD4 tissue-resident memory cells protect mice against secondary genital HSV-2 challenge. It does not address reinfection with L. major, and it describes the protective cells as CD4 memory cells rather than explicitly identifying them as Th1 cells. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [35] ND Glennie, 2015, Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection, J Exp Med source

  • Classified as probably not a substantial claim.

    Premisecitation

    Fungal PAMPs modulate the host immune response.

    “Since fungal PAMPs modulate the host immune response [11], and C. auris possesses a unique outer mannan layer compared to C. albicans [12], we hypothesized that the C. auris outer cell wall mannan layer regulates the development of Th1 cells during C. auris reinfection.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] B Briard, 2021, Fungal cell wall components modulate our immune system, Cell Surf source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-17-producing TRM cells play a critical role in host defense against C. albicans during reinfection.

    “Previous findings suggest that IL-17-producing TRM cells play a critical role in host defense against C. albicans during reinfection [30–33,36].”
    Quote in the paperNot a substantial claim5 of 5 sources checked
    • cites [30] S LeibundGut-Landmann, 2021, Tissue-resident memory T cells in antifungal immunity., Front Immunol source

      The ‘What Are the Functional Attributes of TRMs?’ section (page unavailable) reports that C. albicans-responsive TRM cells produce IL-17 and links them to host protection in barrier tissues. It discusses these cells in persistent colonization and immunosurveillance, however, rather than establishing a critical role against C. albicans during reinfection. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [31] SK Whitley, 2022, Local IL-23 is required for proliferation and retention of skin-resident memory TH17 cells, Sci Immunol source
    • cites [32] FR Kirchner, 2021, Tissue-resident memory Th17 cells maintain stable fungal commensalism in the oral mucosa, Mucosal Immunol source
    • cites [33] CO Park, 2018, Staged development of long-lived T-cell receptor αβ TH17 resident memory T-cell population to Candida albicans after skin infection, J Allergy Clin Immunol source
    • cites [36] SW Kashem, 2015, Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation, Immunity source

      The Results section, “Compartmentalization of Th cell responses” (page unavailable), reports that Th17 cells protected mice against subsequent cutaneous C. albicans challenge. The paper does not establish that those cells were tissue-resident memory (TRM) cells, and its Introduction distinguishes cutaneous protection by Th17 cells from systemic protection by Th1 cells. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CD69 is an activation marker expressed by both effector T cells and tissue-resident memory cells.

    “CD69 is an activation marker expressed by both effector T cells and tissue-resident (TRM) memory cells [37].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] D Cibrian, 2017, CD69: from activation marker to metabolic gatekeeper, Eur J Immunol source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Excess IFN-γ responses can impair the oral mucosal barrier and drive oral C. albicans infection during AIRE deficiency.

    “Previous findings from the Lionakis lab suggest that excess IFN-γ responses can impair the oral mucosal barrier and drive oral C. albicans infection during AIRE deficiency [21].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] TJ Break, 2021, Aberrant type 1 immunity drives susceptibility to mucosal fungal infections., Science source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    IFN-γ induces apoptosis in epithelial cells and fibroblasts and can enhance cell-mediated cytotoxicity.

    “Since IFN-γ induces apoptosis in epithelial cells and fibroblasts and can enhance cell-mediated cytotoxicity [21–23], we examined if the increased production of IFN-γ in C. auris-infected mice might promote increased cell death and enhance fungal burden.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [21] TJ Break, 2021, Aberrant type 1 immunity drives susceptibility to mucosal fungal infections., Science source

      The section on IFN-γ/STAT1 responses in AIRE deficiency (page not provided) reports dose-dependent death of human oral epithelial cells after prolonged IFN-γ exposure. It does not establish that the death was apoptosis, and the cited passages do not support the claims about fibroblasts or enhanced cell-mediated cytotoxicity. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [22] TP Singh, 2023, Regulatory T cells control Staphylococcus aureus and disease severity of cutaneous leishmaniasis., J Exp Med source

      The Results section (“IFN-γ mediates increased inflammation, epidermal damage, and S. aureus burden”; page unavailable) states that IFN-γ induces keratinocyte apoptosis and can enhance cell-mediated cytotoxicity. It also reports increased death of S. aureus–exposed keratinocytes treated with IFN-γ. Keratinocytes are epithelial cells, but the cited paper does not support the added claim about fibroblast apoptosis. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] W Niedelman, 2013, Cell death of gamma interferon-stimulated human fibroblasts upon Toxoplasma gondii infection induces early parasite egress and limits parasite replication, Infect Immun source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Th17 cells play a critical role in host defense against C. albicans.

    “Th17 cells play a critical role in host defense against C. albicans [30–33,36], whereas Th1 cells protect the host against reinfection from HSV and L. major [34,35].”
    Quote in the paperNot a substantial claim5 of 5 sources checked
    • cites [30] S LeibundGut-Landmann, 2021, Tissue-resident memory T cells in antifungal immunity., Front Immunol source
    • cites [31] SK Whitley, 2022, Local IL-23 is required for proliferation and retention of skin-resident memory TH17 cells, Sci Immunol source
    • cites [32] FR Kirchner, 2021, Tissue-resident memory Th17 cells maintain stable fungal commensalism in the oral mucosa, Mucosal Immunol source
    • cites [33] CO Park, 2018, Staged development of long-lived T-cell receptor αβ TH17 resident memory T-cell population to Candida albicans after skin infection, J Allergy Clin Immunol source
    • cites [36] SW Kashem, 2015, Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation, Immunity source

      The Discussion reports that Th17 cells protected against cutaneous C. albicans challenge, supporting their role in host defense. It also states that Th17 expansion did not protect against systemic challenge, so the unqualified claim is broader than this paper's finding. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    C. auris colonizes the human skin long-term, leading to nosocomial transmission and outbreaks of skin systemic infection.

    “C. auris colonizes the human skin long-term, leading to nosocomial transmission and outbreaks of skin systemic infection [6,7].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [6] X Huang, 2021, Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies, Cell Host Microbe source
    • cites [7] PS Shastri, 2020, Candida auris candidaemia in an intensive care unit - Prospective observational study to evaluate epidemiology, risk factors, and outcome, J Crit Care source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    No fungal vaccine has been approved for humans.

    “However, no fungal vaccine has been approved for humans [17,41].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [17] LVN Oliveira, 2021, Vaccines for human fungal diseases: close but still a long way to go, NPJ Vaccines source
    • cites [41] AS Ibrahim, 2005, Vaccination with recombinant N-terminal domain of Als1p improves survival during murine disseminated candidiasis by enhancing cell-mediated, not humoral, immunity, Infect Immun source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NDV-3A protects mice from disseminated C. auris infection.

    “Recent evidence suggests that NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) protects mice from disseminated C. auris infection, although its role in protecting against skin C. auris infection remains unclear [42].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] S Singh, 2019, The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection, PLoS Pathog source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Different clades of C. auris elicit different innate immune responses.

    “Previous findings suggest that different clades of C. auris elicit different innate immune responses [12].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] M Bruno, 2020, Transcriptional and functional insights into the host immune response against the emerging fungal pathogen Candida auris, Nat Microbiol source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The role of NDV-3A in protecting against skin C. auris infection remains unclear.

    “Recent evidence suggests that NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) protects mice from disseminated C. auris infection, although its role in protecting against skin C. auris infection remains unclear [42].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] S Singh, 2019, The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection, PLoS Pathog source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Other cell types, such as keratinocytes and NK cells, also express IL-17A and IFNγ, respectively.

    “Furthermore, previous findings from our laboratory [16] and others [35] suggest that other cell types, such as keratinocytes and NK cells, also express IL-17A and IFNγ, respectively.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [16] A Balakumar, 2024, Single-cell transcriptomics unveils skin cell specific antifungal immune responses and IL-1Ra- IL-1R immune evasion strategies of emerging fungal pathogen Candida auris, PLoS Pathog source
    • cites [35] ND Glennie, 2015, Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection, J Exp Med source

      The Results passage on L. major–specific CD4+ T cells reports IFN-γ production by CD4+ T cells, not NK cells. The passages on immune-skin transcription describe IFN-responsive genes but do not identify keratinocytes as IL-17A producers. Searches for NK-cell IFN-γ and keratinocyte IL-17A found no passage supporting either attribution; page numbers were not available in our copy. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    C. auris is an emerging fungal pathogen that can cause serious human infections.

    “C. auris is an emerging fungal pathogen that can cause serious human infections [1,5,38,39].”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [1] S Ahmad, 2021, Candida auris: epidemiology, diagnosis, pathogenesis, antifungal susceptibility, and infection control measures to combat the spread of infections in healthcare facilities, Microorganisms source
    • cites [5] DJ Santana, 2023, A Candida auris-specific adhesin, Scf1, governs surface association, colonization, and virulence, Science source
    • cites [38] CA Vu, 2022, Challenges and opportunities in stewardship among solid organ transplant recipients with Candida auris bloodstream infections, Transpl Infect Dis source
    • cites [39] M Ademe, 2020, Candida auris: from multidrug resistance to pan-resistant strains, Infect Drug Resist source

  • May combine two claims.

    Findingown data

    IFNγ enhances skin infection of C. auris but not C. albicans.

    “Surprisingly, we found that IFNγ enhances skin infection of C. auris but not C. albicans.”
    • Also stated in: § Discussion · plain
      “The Th1 cytokine IFNγ enhances skin infection of C. auris but not C. albicans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In C. auris-infected mice compared to C. albicans-infected mice, the percentage and absolute number of total CD4+ IL-17A+ T cells and activated CD4+ CD69+ IL-17A+ T cells were significantly decreased in the skin.

    “We identified that the percentage and absolute number of total CD4 + IL-17A + T cells and activated CD4 + CD69 + IL-17A + T cells were significantly decreased, whereas total CD4 + IFNγ+ T cells and activated CD4 + CD69 + IFNγ+ T cells were significantly increased in the skin of the C. auris-infected mice compared to the C. albicans-infected group (Figs 1C, 1D, S1A and S1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In C. auris-infected mice compared to C. albicans-infected mice, the percentage and absolute number of total CD4+ IFNγ+ T cells and activated CD4+ CD69+ IFNγ+ T cells were significantly increased in the skin.

    “We identified that the percentage and absolute number of total CD4 + IL-17A + T cells and activated CD4 + CD69 + IL-17A + T cells were significantly decreased, whereas total CD4 + IFNγ+ T cells and activated CD4 + CD69 + IFNγ+ T cells were significantly increased in the skin of the C. auris-infected mice compared to the C. albicans-infected group (Figs 1C, 1D, S1A and S1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After secondary infection, total TCRβ+ T cells and CD4+ T cells were not significantly different between C. auris and C. albicans infected groups.

    “After secondary infection, total TCRβ+ T cells and CD4 + T cells were not significantly different between C. auris and C. albicans infected groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Fungal burden from day 1 to day 5 post-infection decreased by almost 1.48 ± 0.13 log in C. albicans-infected mice and by only 0.92 ± 0.13 log in C. auris-infected mice.

    “Furthermore, fungal burden from day 1 to day 5 post-infection in C. albicans-infected mice showed almost 1.48 ± 0.13 log decrease, whereas C. auris-infected mice decreased only 0.92 ± 0.13 log.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The percentage and absolute cell numbers of total CD4+ IL17A+ cells and activated CD4+ CD69+ IL17A+ cells were significantly increased in mice infected with the pmr1Δ strain compared with mice infected with the WT strain.

    “We observed that the percentage and absolute cell numbers of total CD4 + IL17A+ cells and activated CD4 + CD69 + IL17A+ cells were significantly increased, whereas total CD4 + IFNγ+ cells and activated CD4 + CD69 + IFNγ+ cells were decreased in mice infected with (pmr1Δ) strain compared with mice infected with WT strain that has intact outer mannan layer (Fig 5C and 5D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Total CD4+ IFNγ+ cells and activated CD4+ CD69+ IFNγ+ cells were decreased in mice infected with the pmr1Δ strain compared with mice infected with the WT strain.

    “We observed that the percentage and absolute cell numbers of total CD4 + IL17A+ cells and activated CD4 + CD69 + IL17A+ cells were significantly increased, whereas total CD4 + IFNγ+ cells and activated CD4 + CD69 + IFNγ+ cells were decreased in mice infected with (pmr1Δ) strain compared with mice infected with WT strain that has intact outer mannan layer (Fig 5C and 5D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Th17 cells significantly increased, whereas Th1 cells significantly decreased in Ccr2-/- mice compared to WT mice groups.

    “We found that Th17 cells significantly increased, whereas Th1 cells significantly decreased in the Ccr2-/- mice compared to WT mice groups (Fig 3F and 3G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Th17 cells significantly increased, whereas Th1 cells significantly decreased in CL-treated mice compared to PBS-treated control groups.

    “We found that Th17 cells significantly increased, whereas Th1 cells significantly decreased in the CL-treated mice compared to PBS-treated control groups (Fig 3I and 3J).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Th1 cells protect the host against fungal pathogens, including C. albicans.

    “Th1 cells protect the host against fungal pathogens, including C. albicans [18,19].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] L Romani, 1999, Immunity to Candida albicans: Th1, Th2 cells and beyond, Curr Opin Microbiol source
    • cites [19] E Cenci, 1998, IFN-gamma is required for IL-12 responsiveness in mice with Candida albicans infection, J Immunol source

  • May combine two claims.

    Interpretationown data

    C. albicans cutaneous infection induces predominantly Th17 cells, whereas C. auris induces Th1 responses in the skin during reinfection.

    “These results suggest that C. albicans cutaneous infection induces predominantly Th17 cells, whereas C. auris induces Th1 responses in the skin during reinfection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Increased IFNγ dampens the protective IL-17 response and IL-17 is necessary to protect the host from secondary infection against C. auris.

    “These findings confirm that increased IFNγ dampens protective IL-17 response and IL-17 is necessary to protect the host from secondary infection against C. auris.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The C. auris outer cell wall mannan layer drives Th1 and Th17 responses and fibroblast cell death during C. auris reinfection.

    “These findings suggest that C. auris outer cell wall mannan layer drives Th1 and Th17 responses and fibroblast cell death during C. auris reinfection.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    IL-12 is critical for developing Th1 cells.

    “IL-12 is critical for developing Th1 cells, and IL-12 produced by macrophages can modulate the Th1 immune response during re-infection with Listeria monocytogenes [24].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] CS Hsieh, 1993, Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages, Science source

  • May combine two claims.

    Interpretationown data

    C. auris but not C. albicans induces IFN-γ responses.

    “Our findings suggest that C. auris but not C. albicans induces IFN-γ responses, leading to barrier damage and increased fungal burden during reinfection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The mechanism appears to be excess IFNγ dampening protective IL-17 responses and increasing barrier damage in the skin during reinfection.

    “The mechanism appears to be excess IFNγ dampening protective IL-17 responses and increasing barrier damage in the skin during reinfection (Fig 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    C. auris infection induces Th1 polarizing cytokines, including IL-12, in macrophages that could potentially regulate the development of Th1 cells after secondary infection.

    “These results indicate that C. auris infection induces Th1 polarizing cytokines, including IL-12, in macrophages that could potentially regulate the development of Th1 cells after secondary infection.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-12 produced by macrophages can modulate the Th1 immune response during re-infection with Listeria monocytogenes.

    “IL-12 is critical for developing Th1 cells, and IL-12 produced by macrophages can modulate the Th1 immune response during re-infection with Listeria monocytogenes [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] CS Hsieh, 1993, Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages, Science source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All animal studies were performed, and experimental protocols were approved by Purdue University IACUC.

    “All animal studies were performed, and experimental protocols were approved by the Purdue University Institutional Animal Care and Use Committee (IACUC Protocol no. 2110002211).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The observed differences in Th1 and Th17 cells during C. auris reinfection may be due to recruited effector T cells and/or TRM cells in the skin.

    “The observed differences in Th1 and Th17 cells during C. auris reinfection may be due to recruited effector T cells and (or) TRM cells in the skin.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Samples with more than 85% viability and less cell debris were used for single-cell RNA sequencing.

    “The viability of the cells was measured under a microscope, and samples with more than 85% viability and less cell debris were enumerated and sent for single-cell partition and RNA library preparation.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Macrophage depletion was confirmed by flow cytometry.

    “Depletion was confirmed by flow cytometry.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-12 produced by macrophages modulates the Th1 immune response during re-infection with L. monocytogenes.

    “Previous findings suggest that IL-12 produced by macrophages modulates the Th1 immune response during re-infection with L. monocytogenes [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] CS Hsieh, 1993, Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages, Science source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All experiments used age- and sex-matched mice between 6 and 12 weeks old.

    “All experiments used age- and sex-matched mice between 6 and 12 weeks old.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Each experiment was performed three independent times.

    “Each experiment was performed three independent times.”
    Quote in the paperNot a substantial claim
49 of 49

  • The paper relies on this without support.

    The role of T cell immune responses during secondary C. auris skin infection or reinfection is unknown.

    “However, almost nothing is known regarding the immune responses against C. auris during reinfection.”
    “The potential role of T cell responses in establishing resistance to secondary infection of C. auris in the skin remains unknown, and as a result, developing effective fungal vaccines remains an elusive goal [17].”
    “However, the role of T cell immune responses during secondary infection with C. auris, an emerging fungal pathogen that colonizes human and mouse skin long-term, is unknown.”

  • The paper relies on this without support.

    Most C. auris isolates exhibit resistance to several FDA-approved antifungal drugs.

    “Given that most C. auris isolates exhibit resistance to several FDA-approved antifungal drugs, a deeper understanding of the antifungal host defense mechanisms is critical to developing new host-directed therapeutic approaches to prevent and treat this newly emerging skin tropic fungal pathogen.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting anti-IL-17A treatment schedules

    Minor

    The Results state that anti-IL-17 antibody was administered on days −2, 0, and +2 of secondary infection, whereas the Methods specify days −1, +1, and +3.

  • Ccr2-/- T-cell results cite panels for different measurements

    Minor

    The Ccr2-/- paragraph cites Fig 3F and 3G for Th17 and Th1 cells. The Fig 3 legend assigns those panels to dendritic cells and IL-12, respectively; the Ccr2-/- T-cell measurements are labeled Fig 4F and 4G.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. WHO, 2022, WHO fungal priority pathogens list to guide research, development and public health action

Cited by

Sorted by citations

Related

Authors
Das, D., Ganesh, S. M., Mishra, A., Netea, M. G., & Thangamani, S.
Affiliations
  • Purdue University West Lafayette (US)
  • University of Bonn (DE)
Corresponding author
Thangamani, Shankar
ORCID
Venue
PLOS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2025-04-28
Volume
21
Issue
4
Pages
e1013114
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1013114
PMC
PMC12121905
OpenAlex
W4409882717
Semantic Scholar
0f8d34cbd45b7ce2670fa82ce78dae87dc39c18b
Cited by
18
References
50
Citations by year
2026: 14 · 2025: 4
FWCI
12.68
Type
journal article
Language
en
Update notices
new_version (2025-05-29)
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, cc-by-nc-sa)
  • PubMed Central (submittedVersion, public-domain)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Allergy and Infectious Diseases (1R01AI177604)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Health Sciences › Medicine › Epidemiology › Nail Diseases and Treatments
Keywords
Candida auris, interferon-gamma, Th1 cells, Th17 cells, IL-17, IL-12, skin colonization, fungal skin infection, Candida albicans, dendritic cells, macrophages, reinfection, host immune response
MeSH terms
Candida auris, Animals, Candida albicans, Candidiasis, Candidiasis, Cutaneous, Female, Humans, Interferon-gamma, Mice, Inbred C57BL, Skin, Th1 Cells, Interleukin-17, Mice, Th17 Cells

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.

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