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Cited by 23Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

The Candida auris Hog1 MAP kinase is essential for the colonization of murine skin and intradermal persistence

Open access
Shivarathri, Raju, Chauhan, Manju, Datta, Abhishek, Das, Diprasom, Karuli, Adela, Aptekmann, Ariel, Jenull, Sabrina, Kuchler, Karl +4 more·2024·mBio
DOI 10.1128/mbio.02748-24PMC PMC11558994
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Abstract

Candida auris , a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic C. auris infections have now been reported in more than 50 countries, with mortality rates of 30%–60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that C. auris, unlike most Candida species, displays unique skin tropism and can stay on human skin for a prolonged period. However, the molecular mechanisms responsible for C. auris skin colonization, intradermal persistence, and systemic virulence are poorly understood. Here, we report that C. auris Hog1 mitogen-activated protein kinase is essential for efficient skin colonization, intradermal persistence as well as systemic virulence. RNA-seq analysis of wild-type parental and hog1 Δ mutant strains revealed marked downregulation of genes involved in processes such as cell adhesion, cell wall rearrangement, and pathogenesis in hog1 Δ mutant compared to the wild-type parent. Consistent with these data, we found a prominent role for Hog1 in maintaining cell wall architecture, as the hog1 Δ mutant demonstrated a significant increase in cell-surface β-glucan exposure and a concomitant reduction in chitin content. Additionally, we observed that Hog1 was required for biofilm formation in vitro and fungal survival when challenged with primary murine macrophages and neutrophils ex vivo . Collectively, these findings have important implications for understanding the C. auris skin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections. IMPORTANCE: Candida auris is a World Health Organization fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention. C. auris has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. These attributes facilitate the inter- and intrahospital clonal transmission of C. auris . Therefore, understanding C. auris skin colonization mechanisms is critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis of C. auris skin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator of C. auris skin colonization. These findings lay the foundation for further characterization of unique mechanisms that promote fungal persistence on human skin.

AI snapshot

Written from the paper’s full text.

TL;DR

The *Candida auris* Hog1 MAP kinase is required for efficient murine skin colonization, intradermal persistence, biofilm formation, and systemic virulence. Loss of Hog1 alters cell wall architecture, increases phagocyte killing, and reduces fungal burden in skin, kidney, and brain.

Key findings

  • RNA-seq of hog1Δ versus wild-type parent 1184/P/15 identified 2,060 differentially expressed genes (966 upregulated, 1,094 downregulated; ≥1.5-fold, Padj ≤ 0.05), with enrichment of cell wall organization, adhesion, signal transduction, and pathogenesis categories; no detectable reads were observed for HOG1.
  • hog1Δ showed increased cell-surface β-glucan exposure and reduced chitin content, with no change in mannan content, and formed weak, dispersed biofilms compared with robust wild-type and complemented-strain biofilms.
  • hog1Δ was more sensitive to killing by murine bone marrow-derived macrophages and neutrophils at MOI 5 after 2.5 h, and neutrophil challenge with hog1Δ increased reactive oxygen species production.
  • In immunocompetent C57BL/6 mice at 72 h post-infection, hog1Δ had significantly lower fungal burdens after epicutaneous (5 × 10^7 CFUs) and intradermal (1 × 10^7 CFUs) skin infection, and after systemic infection (5 × 10^7 blastospores) had reduced kidney and brain burdens, while splenic and hepatic burdens were similar to wild type; phagocyte accumulation in skin or kidneys did not differ substantially.

Methods

  • Used *C. auris* clinical isolate 1184/P/15, a hog1Δ mutant, and a complemented strain; RNA-seq was performed on log-phase cultures in YPD at 30°C with three biological replicates per strain, followed by DESeq2/DEBrowser differential expression and GO analysis.
  • Phenotypic assays included biofilm formation on FBS-pretreated borosilicate cover glass, flow cytometry and confocal microscopy for cell wall β-glucan/chitin/mannan in synthetic sweat medium, and ex vivo killing assays with murine BMDMs and neutrophils plus Amplex Red H2O2 measurement.
  • In vivo work used 8- to 12-week-old female C57BL/6 mice for epicutaneous, intradermal, and systemic infection models; fungal burdens were quantified by CFU plating at 72 h, with histopathology and flow cytometry for immune cell profiling.

Limitations

  • The paper states that further experiments are required to identify additional factors functioning with Hog1 in skin colonization, intradermal persistence, and systemic virulence, and that future studies should examine possible Hog1–PKA genetic interactions and additional Hog1-regulated biofilm molecules.
  • Evident from the text: RNA-seq was performed only in log-phase YPD at 30°C, not under skin-like, synthetic sweat, or infection conditions, so the transcriptional program may not reflect host-relevant states.
  • Evident from the text: most mechanistic work uses one *C. auris* clinical isolate and murine cells/models; human skin colonization, immunocompromised hosts, and direct Hog1 inhibitor effects are not tested.

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

Integrity signals

Registry

Crossref · 10.1128/mbio.02748-24

Cites

68 of 68 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

20 of 26 cited sources checked · 10 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Both SCF1 and IFF4109 are functionally redundant for biofilm formation.

    “Both SCF1 and IFF4109 are functionally redundant for biofilm formation (22)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Santana DJ, Anku JAE, Zhao G, Zarnowski R, Johnson CJ, Hautau H, Visser ND, Ibrahim AS, Andes D, Nett JE, Singh S, O’Meara TR. 2023. A Candida auris-specific adhesin, Scf1, governs surface association, colonization, and virulence. Science 381: 1461– 1467. doi: 10.1126/science.adf8972 37769084 PMC11235122 source
  • Premisecitation

    Increased β-glucan in cell wall mannosylation mutant strains is associated with enhanced fungal killing by neutrophils and macrophages.

    “was associated with enhanced fungal killing by neutrophils and macrophages (62, 63).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [62] Wang Y, Zou Y, Chen X, Li H, Yin Z, Zhang B, Xu Y, Zhang Y, Zhang R, Huang X, et al.. 2022. Innate immune responses against the fungal pathogen Candida auris. Nat Commun 13: 3553. doi: 10.1038/s41467-022-31201-x 35729111 PMC9213489 source
    • cites [63] Horton MV, Johnson CJ, Zarnowski R, Andes BD, Schoen TJ, Kernien JF, Lowman D, Kruppa MD, Ma Z, Williams DL, Huttenlocher A, Nett JE. 2021. Candida auris cell wall mannosylation contributes to neutrophil evasion through pathways divergent from Candida albicans and Candida glabrata. mSphere 6: e0040621. doi: 10.1128/mSphere.00406-21 34160238 PMC8265655 source

      The Results sections on phagocytosis and cell-surface pathogen-associated molecular patterns report that C. auris mannosylation mutants expose more β-glucan and are more susceptible to killing by neutrophils. The zebrafish Results section reports similar macrophage recruitment to wild-type and mutant strains, but does not report enhanced killing by macrophages. The macrophage-killing part of the claim is therefore unsupported by this paper. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation

    Increased β-glucan in cell wall mannosylation mutant strains enhances neutrophil recruitment in a zebrafish infection model.

    “The increased β-glucan in the cell wall mannosylation mutant strains has been shown to enhance neutrophil recruitment in a zebrafish infection model (63)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [63] Horton MV, Johnson CJ, Zarnowski R, Andes BD, Schoen TJ, Kernien JF, Lowman D, Kruppa MD, Ma Z, Williams DL, Huttenlocher A, Nett JE. 2021. Candida auris cell wall mannosylation contributes to neutrophil evasion through pathways divergent from Candida albicans and Candida glabrata. mSphere 6: e0040621. doi: 10.1128/mSphere.00406-21 34160238 PMC8265655 source

      The Results sections on cell-surface PAMPs and zebrafish recruitment report that C. auris pmr1Δ and van1Δ mutants expose more β-glucan and recruit more neutrophils to the larval zebrafish hindbrain than wild type. The paper also reports increased chitin exposure and does not show that β-glucan specifically caused the increased recruitment. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingown data

    There was a significant difference in fungal burdens 72 hours post-infection from mice infected with wild-type parental and hog1Δ strains via the epicutaneous route.

    “there was a significant difference in fungal burdens 72 hours post-infection from mice infected with wild-type parental and hog1Δ strains via the epicutaneous or intradermal route (Fig. 5A and B).”
    Quote in the paperSubstantial claim
  • Findingown data

    Splenic and hepatic burdens were similar between hog1Δ and wild-type strains.

    “mice infected with the hog1Δ showed significantly reduced fungal burden in the kidneys and brain, while splenic and hepatic burdens were similar to the wild-type strain”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 22
  • May combine two claims. 12

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

    Premisecitation

    Only 3 ALS genes have been identified in C. auris, unlike C. albicans which contains at least 11 Als adhesins.

    “unlike C. albicans, which contains at least 11 Als adhesins, thus far only 3 ALS genes have been identified in C. auris (20, 22).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [20] Muñoz JF, Welsh RM, Shea T, Batra D, Gade L, Howard D, Rowe LA, Meis JF, Litvintseva AP, Cuomo CA. 2021. Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris. Genetics 218: iyab029. doi: 10.1093/genetics/iyab029 33769478 PMC8128392 source

      The Discussion (page unavailable) names three distinct C. auris ALS-related genes: an ALS4 homolog, a potential ALS adhesin, and ALS3. It does not say that only three ALS genes have been identified in C. auris, or that C. albicans has at least 11 Als adhesins. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [22] Santana DJ, Anku JAE, Zhao G, Zarnowski R, Johnson CJ, Hautau H, Visser ND, Ibrahim AS, Andes D, Nett JE, Singh S, O’Meara TR. 2023. A Candida auris-specific adhesin, Scf1, governs surface association, colonization, and virulence. Science 381: 1461– 1467. doi: 10.1126/science.adf8972 37769084 PMC11235122 source

      In “Polymer surface attachment by the adhesin SCF1” (page unavailable), the paper describes C. albicans as having ALS1 and seven other ALS genes—eight, rather than the claimed at least eleven. It does not give a count of three ALS genes for C. auris; its count of twelve combines homologs of the ALS and IFF/HYR families. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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

    Premisecitation

    C. auris Hog1 is required for antifungal drug resistance.

    “Previously, we showed that C. auris Hog1 is required for antifungal drug resistance (40).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Shivarathri R, Jenull S, Stoiber A, Chauhan M, Mazumdar R, Singh A, Nogueira F, Kuchler K, Chowdhary A, Chauhan N. 2020. The two-component response regulator Ssk1 and the mitogen-activated protein kinase Hog1 control antifungal drug resistance and cell wall architecture of Candida auris. mSphere 5: e00973-20. doi: 10.1128/mSphere.00973-20 33055262 PMC7565899 source

  • May combine two claims.

    Premisecitation

    C. auris displays unique skin tropism and can persist on human skin for a long time.

    “Unlike most Candida species, C. auris displays unique skin tropism and can persist on the human skin for a long time.”
    • Also stated in: § Abstract · plain
      “C. auris, unlike most Candida species, displays unique skin tropism and can stay on human skin for a prolonged period.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Alanio A, Snell HM, Cordier C, Desnos-Olivier M, Delliere S, Aissaoui N, Sturny-Leclere A, Silva E, Eble C, Rouveau M, Thegat M, Zebiche W, Lafaurie M, Denis B, Touratier S, Benyamina M, Dudoignon E, Hamane S, Cuomo CA, Depret F. 2022. First patient-to-patient intrahospital transmission of clade I Candida auris in France revealed after a two-month incubation period. Microbiol Spectr 10: e0183322. doi: 10.1128/spectrum.01833-22 36094221 PMC9604096 source

      The Results (Investigation of contact patients; page unavailable) report C. auris-positive skin samples in P1, supporting human skin colonization. The Discussion reports detection more than 41 days after possible exposure, but does not establish that C. auris persisted on the skin throughout that period. Our copy also does not establish that its skin tropism is unique compared with most Candida species. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Scf1 and IFF4109 were recently identified for their roles in surface colonization, adhesion, and virulence.

    “a C. auris-specific adhesin, Scf1, and the Iff family member, B9J08_004109 (IFF4109), were recently identified for their roles in surface colonization, adhesion, and virulence (22).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Santana DJ, Anku JAE, Zhao G, Zarnowski R, Johnson CJ, Hautau H, Visser ND, Ibrahim AS, Andes D, Nett JE, Singh S, O’Meara TR. 2023. A Candida auris-specific adhesin, Scf1, governs surface association, colonization, and virulence. Science 381: 1461– 1467. doi: 10.1126/science.adf8972 37769084 PMC11235122 source

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

    Premisecitation

    The C. auris cAMP/PKA signaling pathway is important for biofilm formation.

    “The C. auris cAMP/PKA signaling pathway has been shown to be important for biofilm formation (59, 60).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [59] Kim JS, Lee KT, Lee MH, Cheong E, Bahn YS. 2021. Adenylyl cyclase and protein kinase A play redundant and distinct roles in growth, differentiation, antifungal drug resistance, and pathogenicity of Candida auris. MBio 12: e0272921. doi: 10.1128/mBio.02729-21 34663094 PMC8524339 source
    • cites [60] Kim JS, Lee KT, Bahn YS. 2023. Deciphering the regulatory mechanisms of the cAMP/protein kinase A pathway and their roles in the pathogenicity of Candida auris Microbiol Spectr 11: e0215223. doi: 10.1128/spectrum.02152-23 37671881 PMC10581177 source

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

    Premisecitation

    The Candida auris strains 1184/P/15 and hog1Δ used in this study were described previously.

    “The Candida auris strains 1184/P/15 and hog1Δ used in this study were described previously (40).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Shivarathri R, Jenull S, Stoiber A, Chauhan M, Mazumdar R, Singh A, Nogueira F, Kuchler K, Chowdhary A, Chauhan N. 2020. The two-component response regulator Ssk1 and the mitogen-activated protein kinase Hog1 control antifungal drug resistance and cell wall architecture of Candida auris. mSphere 5: e00973-20. doi: 10.1128/mSphere.00973-20 33055262 PMC7565899 source

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

    Premisecitation

    The genome of C. auris contains adhesins belonging to the ALS and IFF/HYR families.

    “The genome of C. auris is reported to contain adhesins belonging to ALS and the IFF/HYR family (20, 22).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [20] Muñoz JF, Welsh RM, Shea T, Batra D, Gade L, Howard D, Rowe LA, Meis JF, Litvintseva AP, Cuomo CA. 2021. Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris. Genetics 218: iyab029. doi: 10.1093/genetics/iyab029 33769478 PMC8128392 source
    • cites [22] Santana DJ, Anku JAE, Zhao G, Zarnowski R, Johnson CJ, Hautau H, Visser ND, Ibrahim AS, Andes D, Nett JE, Singh S, O’Meara TR. 2023. A Candida auris-specific adhesin, Scf1, governs surface association, colonization, and virulence. Science 381: 1461– 1467. doi: 10.1126/science.adf8972 37769084 PMC11235122 source

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

    Premisecitation

    The C. auris genome codes for several species-specific cell surface glycoproteins that may facilitate C. auris adhesion to different substrates.

    “the C. auris genome codes for several species-specific cell surface glycoproteins that may facilitate C. auris adhesion to different substrates (20, 22).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [20] Muñoz JF, Welsh RM, Shea T, Batra D, Gade L, Howard D, Rowe LA, Meis JF, Litvintseva AP, Cuomo CA. 2021. Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris. Genetics 218: iyab029. doi: 10.1093/genetics/iyab029 33769478 PMC8128392 source

      The Results section (page unavailable) identifies several predicted GPI-anchored cell-wall proteins as candidate adhesins, supporting a possible role in adhesion. It does not establish adhesion to different substrates, and the relevant proteins are not strictly species-specific: the paper also finds them in closely related species. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [22] Santana DJ, Anku JAE, Zhao G, Zarnowski R, Johnson CJ, Hautau H, Visser ND, Ibrahim AS, Andes D, Nett JE, Singh S, O’Meara TR. 2023. A Candida auris-specific adhesin, Scf1, governs surface association, colonization, and virulence. Science 381: 1461– 1467. doi: 10.1126/science.adf8972 37769084 PMC11235122 source

      The 'Polymer surface attachment by the adhesin SCF1' section reports multiple adhesin genes, and the Discussion links SCF1 and IFF4109 to association with biological and abiotic surfaces. But the paper identifies SCF1 as the distinctive adhesin and describes IFF4109 as conserved; it does not establish that several of the implicated cell-surface proteins are species-specific glycoproteins. Page numbers are unavailable in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    C. auris skin tropism and persistence are thought to be important factors for C. auris outbreaks in healthcare settings.

    “This attribute is thought to be an important factor for C. auris outbreaks in healthcare settings (16)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Alanio A, Snell HM, Cordier C, Desnos-Olivier M, Delliere S, Aissaoui N, Sturny-Leclere A, Silva E, Eble C, Rouveau M, Thegat M, Zebiche W, Lafaurie M, Denis B, Touratier S, Benyamina M, Dudoignon E, Hamane S, Cuomo CA, Depret F. 2022. First patient-to-patient intrahospital transmission of clade I Candida auris in France revealed after a two-month incubation period. Microbiol Spectr 10: e0183322. doi: 10.1128/spectrum.01833-22 36094221 PMC9604096 source

      The Results (Investigation of contact patients; page unavailable) report C. auris on the transmitted case’s skin, and the Discussion describes delayed detection after patient-to-patient transmission. However, the paper does not identify skin tropism and persistence as important drivers of healthcare outbreaks; it considers persistent environmental contamination in this case less likely. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    C. auris Hog1 has previously been reported to be important for antifungal drug resistance, stress response, and virulence in a Caenorhabditis elegans model of infection.

    “The C. auris Hog1 has previously been reported to be important for antifungal drug resistance, stress response, and was also shown to be important for virulence in a Caenorhabditis elegans model of infection (39, 40).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [39] Day AM, McNiff MM, da Silva Dantas A, Gow NAR, Quinn J. 2018. Hog1 regulates stress tolerance and virulence in the emerging fungal pathogen Candida auris. mSphere 3: e00506-18. doi: 10.1128/mSphere.00506-18 30355673 PMC6200985 source

      The Results sections on stress resistance and virulence report that Hog1 protects C. auris against several stresses and that deleting it attenuates virulence in a C. elegans infection model. The antifungal-drug claim needs qualification: the functional-characterization Results report greater caspofungin resistance in cells lacking Hog1, while the stress-resistance Results find Hog1 dispensable for fluconazole resistance. The paper does not establish that Hog1 promotes antifungal drug resistance generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [40] Shivarathri R, Jenull S, Stoiber A, Chauhan M, Mazumdar R, Singh A, Nogueira F, Kuchler K, Chowdhary A, Chauhan N. 2020. The two-component response regulator Ssk1 and the mitogen-activated protein kinase Hog1 control antifungal drug resistance and cell wall architecture of Candida auris. mSphere 5: e00973-20. doi: 10.1128/mSphere.00973-20 33055262 PMC7565899 source

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

    Premisecitation

    There are clade-specific differences in adhesin expression between C. auris isolates.

    “there are clade-specific differences in adhesin expression between the C. auris isolates (20).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [20] Muñoz JF, Welsh RM, Shea T, Batra D, Gade L, Howard D, Rowe LA, Meis JF, Litvintseva AP, Cuomo CA. 2021. Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris. Genetics 218: iyab029. doi: 10.1093/genetics/iyab029 33769478 PMC8128392 source

      The Results section reports that Clade II lacks fourteen candidate adhesin genes present in other C. auris clades. It does not establish clade-specific differences in adhesin expression between isolates; the expression findings it cites concern biofilm growth or other conditions, not comparisons between clades. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Findingown data

    Among the DEGs, 966 were upregulated and 1,094 were downregulated.

    “Among the DEGs, 966 were upregulated, and 1,094 were downregulated”
    Quote in the paperNot a substantial claim

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

    Findingown data

    ALS4 and ALS3 expression was not affected in hog1Δ.

    “the expression of B9J08_002582 (ALS4) and B9J08_004498 (similar to C. albicans ALS3) was not affected”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The hog1Δ formed weak biofilms with dispersed multicellular cell clusters and a discontinuous growth pattern, while the wild type and complemented strain formed robust biofilms.

    “The hog1Δ formed weak biofilms, with multicellular cell clusters appearing dispersed, and a discontinuous growth pattern was visible across the cover glass surface (Fig. 2A). Conversely, the wild type and the complemented strain formed robust biofilms evident from the thick uniform growth on the cover glass”
    Quote in the paperSubstantial claim

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

    Findingown data

    SCF1 transcript was not significantly changed in the hog1Δ mutant strain.

    “there was no significant change in the transcript of SCF1 (B9J08_001458) in the hog1Δ mutant strain”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    IFF4109 transcript levels were significantly decreased in hog1Δ, while SCF1 transcripts were not affected.

    “We observed transcript levels for IFF4109 to be significantly decreased in hog1Δ, while the SCF1 transcripts were not affected in the hog1Δ compared to the wild-type parental strain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Loss of HOG1 resulted in increased β-glucan without impacting total mannan levels.

    “the loss of HOG1 resulted in the increased β-glucan without impacting the total mannan levels”
    Quote in the paperSubstantial claim

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

    Findingown data

    In hog1Δ, there is a modest increase in the transcript of TPK1.

    “in the hog1Δ, we observe a modest increase in the transcript of B9J08_004030 (TPK1) (Table S1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Hog1 promotes adherence and β-glucan masking, which have critical functions in promoting fungal persistence and intracellular survival within phagocytes.

    “In contrast, Hog1 promoted adherence and β-glucan masking, which appeared to have critical functions in promoting fungal persistence and intracellular survival within the phagocytes.”
    • Also stated in: § DISCUSSION · boosted
      “Overall, our findings confirmed the essential immunostimulatory role that the cell surface β-glucan plays while interacting with the host and uncovered a function for Hog1 in its masking for promoting the fungal survival.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Loss of Hog1 promoted enhanced ROS production and concomitantly reduced fungal viability inside macrophages and neutrophils.

    “Thus, the loss of Hog1 promoted enhanced ROS production and concomitantly reduced fungal viability inside macrophages and neutrophils.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In C. albicans, Hog1 MAPK is a major regulator of fungal stress response, morphogenesis, and virulence.

    “In C. albicans, Hog1 MAPK is a major regulator of fungal stress response, morphogenesis, and virulence (32–34, 36, 61).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [32] Alonso-Monge R, Navarro-García F, Román E, Negredo AI, Eisman B, Nombela C, Pla J. 2003. The Hog1 mitogen-activated protein kinase is essential in the oxidative stress response and chlamydospore formation in Candida albicans. Eukaryot Cell 2: 351– 361. doi: 10.1128/EC.2.2.351-361.2003 12684384 PMC154845 source
    • cites [33] Smith DA, Nicholls S, Morgan BA, Brown AJP, Quinn J. 2004. A conserved stress-activated protein kinase regulates a core stress response in the human pathogen Candida albicans. Mol Biol Cell 15: 4179– 4190. doi: 10.1091/mbc.e04-03-0181 15229284 PMC515350 source
    • cites [34] Enjalbert B, Smith DA, Cornell MJ, Alam I, Nicholls S, Brown AJP, Quinn J. 2006. Role of the Hog1 stress-activated protein kinase in the global transcriptional response to stress in the fungal pathogen Candida albicans. Mol Biol Cell 17: 1018– 1032. doi: 10.1091/mbc.e05-06-0501 16339080 PMC1356608 source
    • cites [36] Alonso-Monge R, Navarro-García F, Molero G, Diez-Orejas R, Gustin M, Pla J, Sánchez M, Nombela C. 1999. Role of the mitogen-activated protein kinase Hog1p in morphogenesis and virulence of Candida albicans. J Bacteriol 181: 3058– 3068. doi: 10.1128/JB.181.10.3058-3068.1999 10322006 PMC93760 source
    • cites [61] Alonso-Monge R, Carvaihlo S, Nombela C, Rial E, Pla J. 2009. The Hog1 MAP kinase controls respiratory metabolism in the fungal pathogen Candida albicans. Microbiology 155: 413– 423. doi: 10.1099/mic.0.023309-0 19202089 source

  • May combine two claims.

    Interpretationreasoning

    Enhanced β-glucan exposure in the hog1Δ mutant promoted the effector functions of neutrophils and macrophages and led to enhanced fungal killing by both phagocyte subsets.

    “the enhanced β-glucan exposure in the hog1Δ mutant promoted the effector functions of neutrophils and macrophages and led to an enhanced fungal killing by both the phagocyte subsets.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    Quality control of raw-sequencing reads was done using FastQC v0.11.8.

    “Quality control of raw-sequencing reads was done using FastQC v0.11.8 (65).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Andrews S. 2010. FastQC: a quality control tool for high throughput sequence data. Babraham Bioinformatics.

      Not checked in the free run.

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

    Study design and conductnone given

    Quality of RNA was assessed on a Bioanalyzer using the RNA6000 Nanochip.

    “Quality of RNA was assessed on a Bioanalyzer using the RNA6000 Nanochip (Agilent)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Hog1 is an important regulator of C. auris skin colonization, biofilm formation, and systemic infection.

    “thus elucidating the role of Hog1 as an important regulator of C. auris skin colonization, biofilm formation, and systemic infection.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The C. auris clinical isolate 1184/P/15 is representative of the C. auris species for the role of Hog1 in skin colonization, intradermal persistence, and systemic virulence.

  • May combine two claims.

    Interpretationown data

    Hog1-dependent fungal responses are necessary for countering phagocytes' effector functions but do not induce tissue recruitment.

    “Hence, our data suggest that the Hog1-dependent fungal responses are necessary for countering the phagocytes’ effector functions but do not induce tissue recruitment.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Three biological replicates for each strain were sequenced for transcriptional profiling.

    “Three biological replicates for each strain were sequenced.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Correct integration of the HOG1 open reading frame into the complemented strains was confirmed by PCR.

    “The correct integration of HOG1 ORF into the complemented strains was confirmed by PCR.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The data were expressed as the mean fluorescence intensity from three independent experiments.

    “the data were expressed as the mean fluorescence intensity (MFI) from three independent experiments.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Unstained and single-stained samples served as controls for flow cytometry.

    “Unstained and single-stained samples served as controls”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    A minimum of 10,000 events were recorded for each sample.

    “A minimum of 10,000 events were recorded for each sample”
    Quote in the paperNot a substantial claim
31 of 31

  • The paper relies on this without support.

    The molecular mechanisms responsible for C. auris skin colonization, intradermal persistence, and systemic virulence are poorly understood.

    “However, the molecular mechanisms responsible for C. auris skin colonization, intradermal persistence, and systemic virulence are poorly understood.”
    “our understanding of molecular mechanisms of C. auris skin colonization, systemic virulence, and its impacts on the interactions with the host immune system remains poorly understood.”

  • The paper relies on this without support.

    The C. auris clinical isolate 1184/P/15 is representative of the C. auris species for the role of Hog1 in skin colonization, intradermal persistence, and systemic virulence.

    “we performed RNA-seq analysis of logarithmically growing hog1Δ and wild-type parent (1184/P/15)”
    “we infected immunocompetent C57BL/6 mice with hog1Δ and wild-type parental strains using the epicutaneous, intradermal, and systemic infection models”
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?

  • Hog1 confers resistance to osmotic, cationic, acid, and reactive oxygen species-induced stress.

    “Specifically, Hog1 confers resistance to osmotic, cationic, acid, and reactive oxygen species-induced stress [75,76].”

    From Host–Candida auris interactions in the skin (2026) · cites this paper as [76]

    The Introduction says Hog1 regulates adaptation to high osmolarity and oxidative stress in C. albicans and describes its broader role in fungal stress tolerance. The Results also link C. auris Hog1 to survival during ROS-associated phagocytic killing. Our copy does not establish resistance to cationic or acid stress, so it supports only part of the attributed list. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • A HOG1-deficient mutant strain exhibited reduced epidermal colonization, intradermal persistence, and dissemination to distant organs following epicutaneous and intradermal infections in mice.

    “A HOG1-deficient mutant strain exhibited reduced epidermal colonization, intradermal persistence, and dissemination to distant organs following epicutaneous and intradermal infections in mice [76].”

    From Host–Candida auris interactions in the skin (2026) · cites this paper as [76]

    The Results section reports reduced skin fungal burden after epicutaneous and intradermal infection with the hog1Δ mutant, supporting reduced epidermal colonization and intradermal persistence. It also reports reduced kidney and brain burdens, but Fig. 5E specifies that these were measured after a separate systemic infection, not as dissemination following the skin infections. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • The Hog1 MAP kinase is essential for skin colonization in a murine model.

    “The Hog1 MAP kinase is essential for skin colonization in a murine model36.”

    From Adhesin Als4112 promotes Candida auris skin colonization through interactions with keratinocytes and extracellular matrix proteins (2025) · cites this paper as [36]

  • The protein kinase Hog1 governs C. auris adaptation to host-imposed stress conditions.

    “The protein kinase Hog1 governs C. auris adaptation to host-imposed stress conditions [75,76].”

    From Host–Candida auris interactions in the skin (2026) · cites this paper as [76]

  • During systemic murine infection, fungal proliferation in the kidney and brain was significantly decreased in the Δhog1 mutant strain.

    “Similarly, during systemic murine infection, fungal proliferation in the kidney and brain was significantly decreased in the Δhog1 mutant strain [76].”

    From Host–Candida auris interactions in the skin (2026) · cites this paper as [76]

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.

  • Cell-wall assay incubation temperatures differ

    Minor

    The Fig. 3 caption says the cells used for cell-wall quantification were grown at 30°C, while the cell-wall quantification methods specify 37°C.

  • Fungal survival is described as both CFU enumeration and an absorbance assay

    Minor

    The results state that surviving fungal cells were quantified by enumerating CFUs. The corresponding methods instead describe adding assay reagents to lysates and measuring absorbance, without a CFU-enumeration step.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. WHO. 2022. WHO fungal priority pathogens list to guide research, development and public health action. World Health Organization, Geneva.
  2. World Health Organization. 2019. Global Antimicrobial Resistance Surveillance system (GLASS) early implemenation protocol for inclusion of Candida spp.. World Health Organization, Geneva.
  3. 10.1128/spectrum.02215-23:e0221523 · DOI

Cited by

Sorted by citations

Related

Authors
Shivarathri, R., Chauhan, M., Datta, A., Das, D., Karuli, A., Aptekmann, A., Jenull, S., Kuchler, K., Thangamani, S., Chowdhary, A., Desai, J. V., & Chauhan, N.
Affiliations
  • Hackensack Meridian Health (US)
  • Purdue University West Lafayette (US)
  • Max Perutz Labs (AT)
  • University of Delhi (IN)
ORCID
Venue
mBio
Publisher
American Society for Microbiology
Published
2024-11-13
Volume
15
Issue
11
Pages
e0274824-e0274824
ISSN
2150-7511 (ISSN-L)
DOI
10.1128/mbio.02748-24
PMC
PMC11558994
OpenAlex
W4403544013
Cited by
22
References
68
Citations by year
2026: 12 · 2025: 10
FWCI
6.93
Type
journal article
Language
en
Open access
Licence
Locations
  • mBio (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • HHS | National Institutes of Health (R21AI174118, R00AI141622, R01AI177604)
  • New Jersey Health Foundation (PC 186-24)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
Candida auris, Hog1 MAP kinase, skin colonization, cell wall integrity, β-glucan, chitin, biofilm formation, macrophage survival, neutrophil survival, nosocomial transmission, multidrug resistance

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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