Cell aggregation mediated by ACE2 deletion in Candida auris modulates fungal colonization and host immune responses in the skin
Open accessAbstract
Candida auris is an emerging multi-drug-resistant fungal pathogen that colonizes the skin and causes invasive infections in hospitalized patients. Multi-cellular aggregative phenotype is widely reported in the C. auris isolates, but its role in skin colonization and host immune response is not yet known. In this study, we generated aggregative phenotype by deleting the ACE2 gene in C. auris and determined the fungal colonization and host immune response using an intradermal mouse model of C. auris skin infection. Our results indicate that mice infected with ace2 Δ strain had significantly lower fungal load after 3 and 14 days post-infections compared to the non-aggregative wild-type and the ACE2 reintegrated strain. The colonization of ace2 Δ is associated with increased recruitment of CD11b + Ly6G + neutrophils and decreased accumulation of CD11b + Ly6 C hi inflammatory monocytes and CD11b + MHCII + CD64 + macrophages. Furthermore, Th17 cells and type 3 innate lymphoid cells (ILCs) were significantly increased in the skin tissue of ace2 Δ infected mice. Our findings suggest that aggregative phenotype mediated by ACE2 deletion in C. auris induces potent neutrophil and IL-17-mediated immune response and reduces fungal colonization in the skin. IMPORTANCE: C. auris is a rapidly emerging fungal pathogen that can colonize hospitalized patients, especially in skin tissue, and cause invasive infections. C. auris isolates exhibit morphological heterogeneity, and the multicellular aggregative phenotype of C. auris is reported frequently in clinical settings. Understanding the role of fungal morphotypes in colonization, persistence, and immune response in the skin microenvironment will have potential applications in clinical diagnosis and novel preventive and therapeutic measures. Here, we utilized the murine model of intradermal infection and determined that the aggregative phenotype of C. auris as the result of ACE2 gene deletion elicits potential innate and adaptive immune responses in mice. These observations will help explain the differences in the skin colonization and immune responses of the aggregative morphotype of C. auris and open the door to developing novel antifungal therapeutics.
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Written from the paper’s full text.
TL;DR
Deleting ACE2 in C. auris AR0387 produces an aggregative phenotype that reduces skin fungal load at 3 and 14 days post-intradermal infection in mice without altering in vitro growth. This lower burden is accompanied by increased neutrophils, type 3 ILCs, and IL-17-producing CD4+ T cells and decreased inflammatory monocytes/macrophages.
Key findings
- Mice infected with ace2Δ had significantly lower fungal DNA load in skin tissue at 3 and 14 days post-infection compared with WT C. auris or ace2Δ + ACE2; reintegration of ACE2 restored fungal burden to WT-like levels, and no in vitro growth defect was observed for ace2Δ.
- At 3 days post-infection, ace2Δ-infected mice showed significantly increased percentage and absolute numbers of CD11b+ Ly6G+ neutrophils, while CD11b+ Ly6Chi inflammatory monocytes and CD11b+ MHCII+ CD64+ macrophages were significantly decreased relative to WT or ace2Δ + ACE2 groups (Fig. 2; 12 infected mice).
- At 14 days post-infection, IL-17A+, IL-17F+, and IL-22+ type 3 ILCs were significantly increased in ace2Δ-infected skin (Fig. 3; eight infected mice). CD4+ IL-17A+ and CD4+ IL-17F+ T cells were also significantly increased, total γδ+ T cell absolute numbers were significantly lower, CD8+ IFNγ+ percentage was increased, and γδ+ or CD8+ IL-17A/F populations were unchanged (Fig. 4; 8–10 infected mice).
Methods
- CRISPR-Cas9 LEUpOUT system was used to delete ACE2 (B9J08_000468) in C. auris AR0387 and to reintegrate ACE2; mutants were confirmed by PCR and Sanger sequencing.
- Intradermal murine infection used 6–8-week-old C57BL/6J mice with ~1–2 × 10^6 fungal cells per mouse; skin fungal load was measured by C. auris-specific qPCR normalized to mouse GAPDH at 3 and 14 days post-infection, and immune cells were analyzed by flow cytometry.
- In vitro growth was measured in RPMI-MOPS at 30°C by OD600 at 0, 6, 18, and 24 h; statistical comparisons used Mann-Whitney U tests in GraphPad Prism 9.4.1, with data shown as mean ± SEM.
Limitations
- Stated: the authors note that future studies are required to understand how C. auris morphology drives specific T helper responses, how different morphotypes are recognized by phagocytic cells, and which downstream fungal effector pathways control immune response and persistence; they also state that enumerating aggregative cells is inherently difficult and that CFU plating may not accurately represent fungal burden, so they used qPCR.
- Evident: experiments use a single C. auris strain/background (AR0387, South Asian clade) and an intradermal infection model, so findings may not generalize to other clades or natural skin colonization.
- Evident: no causal or neutralization experiments link the observed immune changes directly to reduced fungal burden, and qPCR measures fungal DNA rather than viable fungal cells.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
35 of 45 cited sources checked · 20 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Skin immune responses to C. auris are different from C. albicans.
“Furthermore, our recent findings suggest that skin immune responses to C. auris are different from C. albicans (5).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Datta A, Das D, Nett JE, Vyas JM, Lionakis MS, Thangamani S. 2023. Differential skin immune responses in mice intradermally infected with Candida auris and Candida albicans. Microbiol Spectr 11: e0221523. doi: 10.1128/spectrum.02215-23 37811989 PMC10848846 source
- Findingcitation
The ACE2 deletion in the C. auris AR0387 strain results in a multicellular aggregative phenotype consistent with previous findings.
“The ACE2 deletion in the C. auris AR0387 strain results in a multicellular aggregative phenotype consistent with previous findings (Fig. 1A) (9).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Santana DJ, O’Meara TR. 2021. Forward and reverse genetic dissection of morphogenesis identifies filament-competent Candida auris strains. Nat Commun 12: 7197. doi: 10.1038/s41467-021-27545-5 34893621 PMC8664941 source
The Results section, “ACE2 and TAO3 are regulators of C. auris morphogenesis” (page unavailable), reports that ACE2 deletion produced aggregating cells in strains AR0382 and AR0381. It does not report this phenotype for an ACE2 deletion in AR0387, so the strain-specific part of the claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Insertional mutation in the ACE2 gene resulted in an aggregative phenotype.
“Among them, insertional mutation in the ACE2 gene resulted in an aggregative phenotype.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Santana DJ, O’Meara TR. 2021. Forward and reverse genetic dissection of morphogenesis identifies filament-competent Candida auris strains. Nat Commun 12: 7197. doi: 10.1038/s41467-021-27545-5 34893621 PMC8664941 source
- Premisecitation
The antifungal susceptibility of clinical isolates of aggregative C. auris shows reduced susceptibility to fluconazole.
“The antifungal susceptibility of clinical isolates of aggregative C. auris shows reduced susceptibility to fluconazole (14).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] Borman AM, Szekely A, Johnson EM. 2016. Comparative pathogenicity of United Kingdom isolates of the emerging pathogen Candida auris and other key pathogenic Candida species. mSphere 1: e00189-16. doi: 10.1128/mSphere.00189-16 27547827 PMC4990711 source
- Premisecitation
A recent in vitro study on co-culturing of the aggregative phenotype of C. auris with macrophage demonstrated that the macrophage does not recognize and clear the aggregates due to the morphology.
“A recent in vitro study on co-culturing of the aggregative phenotype of C. auris with macrophage demonstrated that the macrophage does not recognize and clear the aggregates due to the morphology (18).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Pelletier C, Shaw S, Alsayegh S, Brown AJP, Lorenz A. 2024. Candida auris undergoes adhesin-dependent and -independent cellular aggregation. PLOS Pathog 20: e1012076. doi: 10.1371/journal.ppat.1012076 38466738 PMC10957086 source
The Results section (‘Aggregates are not cleared by macrophages’; page not provided) reports that macrophages struggled to engulf aggregates and that their ability to clear them was dampened. It explicitly says there was no issue sensing C. auris under aggregating conditions, so the claim that macrophages did not recognize the aggregates is not supported. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Premisecitation
IL-17-producing T cells, such as CD4+ T cells, CD8+ T cells, and γδ T cells, regulate C. auris skin colonization by promoting host defense in the skin.
“The IL-17-producing T cells, such as CD4+ T cells, CD8+ T cells, and γδ T cells, regulate C. auris skin colonization by promoting host defense in the skin (4).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [4] Huang X, Hurabielle C, Drummond RA, Bouladoux N, Desai JV, Sim CK, Belkaid Y, Lionakis MS, Segre JA. 2021. Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies. Cell Host Microbe 29: 210– 221. doi: 10.1016/j.chom.2020.12.002 33385336 PMC7878403 source
- Premisecitation
C. auris produces a significantly lower IL-17 response compared with C. albicans in the murine skin.
“Previous findings from our laboratory identified that C. auris produces a significantly lower IL-17 response compared with C. albicans in the murine skin (5).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Datta A, Das D, Nett JE, Vyas JM, Lionakis MS, Thangamani S. 2023. Differential skin immune responses in mice intradermally infected with Candida auris and Candida albicans. Microbiol Spectr 11: e0221523. doi: 10.1128/spectrum.02215-23 37811989 PMC10848846 source
- Findingown data
Mice infected with ace2Δ strain induce potent CD11b+ Ly6G+ neutrophil response compared with the WT or ace2Δ + ACE2 infected mice groups.
“Mice infected with ace2Δ strain induce potent CD11b+ Ly6G+ neutrophil response compared with the WT or ace2Δ + ACE2 infected mice groups (Fig. 2A).”
Quote in the paperSubstantial claim - Findingown data
There were no changes in the percentage and absolute number of IL17A+ and IL17F+ producing CD8+ T-cell population in ace2Δ-infected skin tissue.
“On the other hand, there were no changes in the percentage and absolute number of IL17A+ and IL17F+ producing CD8+ T-cell population in ace2Δ-infected skin tissue (Fig. 4K and L) (Fig. S3).”
Quote in the paperNot a substantial claim - Findingown data
The percentage and absolute cell number of CD11b+ Ly6 Chi inflammatory monocytes and CD11b+ MHCII+ CD64+ macrophages were significantly decreased in the skin tissue of ace2Δ infected mice compared with WT or ace2Δ + ACE2 groups.
“On the other hand, the percentage and absolute cell number of CD11b+ Ly6 Chi inflammatory monocytes and CD11b+ MHCII+ CD64+ macrophages were significantly decreased in the skin tissue of ace2Δ infected mice compared with WT or ace2Δ + ACE2 groups (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
The absolute cell number of IL17A+, IL17F+, and IL22+ ILCs were significantly increased in ace2Δ mice skin tissue.
“The absolute cell number of IL17A+, IL17F+, and IL22+ ILCs were significantly increased in ace2Δ mice skin tissue (Fig. 3A through C).”
Quote in the paperSubstantial claim - Findingown data
There was no difference in the growth curve of the ace2Δ compared with the WT C. auris or ace2Δ + ACE2 strain.
“We observed that there was no difference in the growth curve of the ace2Δ compared with the WT C. auris or ace2Δ + ACE2 strain (Fig. 1D).”
Quote in the paperSubstantial claim - Findingown data
There were no changes in the percentage and absolute number of CD4+IFNγ+ cells among the ace2Δ infected groups compared with the WT and ace2Δ + ACE2 groups.
“There were no changes in the percentage and absolute number of CD4+IFNγ+ cells among the ace2Δ infected groups compared with the WT and ace2Δ + ACE2 groups (Fig. 4F) (Fig. S2).”
Quote in the paperNot a substantial claim - Findingown data
A decrease in fungal load in the skin tissue of mice infected with ace2Δ after 14 days post-infection correlates with potent IL-17 response observed in the skin tissue of mice infected with ace2Δ relative to WT groups.
“We observed that a decrease in fungal load in the skin tissue of mice infected with ace2Δ after 14 days post-infection correlates with potent IL-17 response observed in the skin tissue of mice infected with ace2Δ relative to WT groups.”
Quote in the paperSubstantial claim- Rests on an assumption: The qPCR quantification of fungal DNA copy number accurately reflects fungal burden in skin tissue for the aggregative ace2Δ strain.
- Findingown data
The increased neutrophil response correlates with the lower fungal burden recovered from the skin tissue of the ace2Δ-infected mice.
“The increased neutrophil response also correlates with the lower fungal burden recovered from the skin tissue of the ace2Δ-infected mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The qPCR quantification of fungal DNA copy number accurately reflects fungal burden in skin tissue for the aggregative ace2Δ strain.
- Findingown data
The fungal DNA copy number of ace2Δ does not correlate with the CFU of the wild type (WT) and ace2Δ + ACE2.
“we employed quantification of the fungal DNA of C. auris using qPCR and determined that the fungal DNA copy number of ace2Δ does not correlate with the CFU of the wild type (WT) and ace2Δ + ACE2 (Fig. 1B).”
Quote in the paperSubstantial claim - Findingown data
The absolute number, but not the percentage, of total CD8+ T cells was significantly decreased in the skin tissue of mice infected with ace2Δ.
“The absolute number, but not the percentage of total CD8+ T cells, was significantly decreased in the skin tissue of mice infected with ace2Δ (Fig. 4I).”
Quote in the paperNot a substantial claim - Findingown data
The percentage of IFNγ-producing CD8+ T-cells was increased dramatically in the skin tissue of mice infected with ace2Δ compared with the WT and ace2Δ + ACE2 groups.
“Similarly, the percentage of IFNγ-producing CD8+ T-cells was increased dramatically in the skin tissue of mice infected with ace2Δ compared with the WT and ace2Δ + ACE2 groups (Fig. 4J) (Fig. S2).”
Quote in the paperNot a substantial claim - Findingown data
The absolute number of total γδ+ T cells was significantly lower in the skin tissue of ace2Δ infected mice compared with the WT and ace2Δ + ACE2 groups.
“The absolute number of total γδ+ T cells was significantly lower in the skin tissue of ace2Δ infected mice compared with the WT and ace2Δ + ACE2 groups (Fig. 4A).”
Quote in the paperNot a substantial claim - Findingown data
The percentage of IL17A+, IL17F+, and IL22+ ILCs were significantly increased in ace2Δ mice relative to WT or ace2Δ + ACE2 groups.
“The percentage of all three ILC subsets, IL17A+, IL17F+, and IL22 +ILCs, were significantly increased in ace2Δ mice relative to WT or ace2Δ + ACE2 groups (Fig. 3A through C).”
Quote in the paperSubstantial claim - Findingown data
The percentage and absolute numbers of CD4+IL17A+ and CD4+IL17F+ cells were significantly increased in the skin tissue of mice infected with ace2Δ compared with WT or ace2Δ + ACE2 infected mice.
“However, the percentage and absolute numbers of CD4+IL17A+ and CD4+IL17F+ cells were significantly increased in the skin tissue of mice infected with ace2Δ compared with WT or ace2Δ + ACE2 infected mice (Fig. 4G and H) (Fig. S3).”
- Also stated in: § Mice infected with ace2Δ strain with aggregative phenotype induce potent IL-17-producing CD4+ T helper cells · plain
“Taken together, IL-17-producing CD4+ T cells, which are important for host defense against C. auris skin infection, were significantly increased in the skin tissue of mice infected with ace2Δ relative to WT or ace2Δ + ACE2 infected groups.”
Quote in the paperSubstantial claim - Also stated in: § Mice infected with ace2Δ strain with aggregative phenotype induce potent IL-17-producing CD4+ T helper cells · plain
- Findingown data
The absolute number of total CD4+ T cells remains unchanged in ace2Δ infected mice.
“However, the absolute number of total CD4+ T cells remains unchanged (Fig. 4E).”
Quote in the paperNot a substantial claim - Findingown data
Mice infected with ace2Δ had significantly lower fungal load in the skin tissue after 3 and 14 days post-infection compared with mice infected with WT C. auris or ace2Δ + ACE2 strain.
“Our results indicate that mice infected with ace2Δ had significantly lower fungal load in the skin tissue after 3 and 14 days post-infection compared with mice infected with WT C. auris or ace2Δ + ACE2 strain (Fig. 1C).”
Quote in the paperSubstantial claim- Rests on an assumption: The qPCR quantification of fungal DNA copy number accurately reflects fungal burden in skin tissue for the aggregative ace2Δ strain.
- Findingown data
The percentage of total CD4+ T cells was significantly increased in the skin tissue of mice infected with ace2Δ compared with the WT and ace2Δ + ACE2 groups.
“The percentage of total CD4+ T cells was significantly increased in the skin tissue of mice infected with ace2Δ compared with the WT and ace2Δ + ACE2 groups.”
Quote in the paperNot a substantial claim - Interpretationown data
The aggregative phenotype of C. auris as the result of ACE2 gene deletion elicits potential innate and adaptive immune responses in mice.
“Here, we utilized the murine model of intradermal infection and determined that the aggregative phenotype of C. auris as the result of ACE2 gene deletion elicits potential innate and adaptive immune responses in mice.”
Quote in the paperSubstantial claim - Interpretationown data
Aggregative phenotype mediated by ACE2 deletion in C. auris reduces fungal colonization in the skin.
“Taken together, our findings suggest that aggregative phenotype mediated by ACE2 deletion in C. auris reduces fungal colonization in the skin.”
Quote in the paperSubstantial claim- Rests on an assumption: The qPCR quantification of fungal DNA copy number accurately reflects fungal burden in skin tissue for the aggregative ace2Δ strain.
- Rests on an assumption: ACE2 deletion affects skin colonization and immune response solely through the aggregative phenotype, not through other ACE2-dependent effects.
- Interpretationreasoning
The difference in the in vivo fungal burden of ace2Δ aggregative form in the murine skin tissue is not due to the difference in the growth physiology.
“Hence, the difference in the in vivo fungal burden of ace2Δ aggregative form in the murine skin tissue is not due to the difference in the growth physiology.”
Quote in the paperSubstantial claim- Rests on an assumption: The qPCR quantification of fungal DNA copy number accurately reflects fungal burden in skin tissue for the aggregative ace2Δ strain.
- Rests on an assumption: ACE2 deletion affects skin colonization and immune response solely through the aggregative phenotype, not through other ACE2-dependent effects.
- Classified as probably not a substantial claim. 17
- May combine two claims. 17
Classified as probably not a substantial claim.
PremisecitationClinical isolates of C. auris can exhibit different morphotypes, such as yeast, filamentous, and aggregative forms.
“Clinical isolates of C. auris can exhibit different morphotypes, such as yeast, filamentous, and aggregative forms (9–13).”
Quote in the paperSubstantial claim4 of 5 sources checked- cites [9] Santana DJ, O’Meara TR. 2021. Forward and reverse genetic dissection of morphogenesis identifies filament-competent Candida auris strains. Nat Commun 12: 7197. doi: 10.1038/s41467-021-27545-5 34893621 PMC8664941 source
The Introduction (page unavailable) describes C. auris cellular polymorphism, including filamentous strains recovered after murine infection and aggregating patient isolates. The Results section on ELM1 (page unavailable) also contrasts filament-like mutants with wild-type budding yeast. The copy supports the range of morphotypes, but does not establish that filamentous forms were observed in clinical isolates as collected from patients. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [10] Fan S, Yue H, Zheng Q, Bing J, Tian S, Chen J, Ennis CL, Nobile CJ, Huang G, Du H. 2021. Filamentous growth is a general feature of Candida auris clinical isolates. Med Mycol 59: 734– 740. doi: 10.1093/mmy/myaa116 33485272 PMC8257410 source
- cites [11] Brown JL, Delaney C, Short B, Butcher MC, McKloud E, Williams C, Kean R, Ramage G. 2020. Candida auris phenotypic heterogeneity determines pathogenicity in vitro mSphere 5: e00371-20. doi: 10.1128/mSphere.00371-20 32581078 PMC7316489 source
The Materials and Methods table and Results describe aggregative and nonaggregative clinical isolates, and the Discussion describes individual yeast cells mixed with aggregates. The paper does not establish filamentous clinical-isolate morphotypes; its Discussion instead says C. auris cannot form hyphae under normal physiological conditions. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [12] Du H, Bing J, Hu T, Ennis CL, Nobile CJ, Huang G. 2020. Candida auris: epidemiology, biology, antifungal resistance, and virulence. PLoS Pathog 16: e1008921. doi: 10.1371/journal.ppat.1008921 33091071 PMC7581363 source
- cites [13] Bryak G, Cox A, Lionakis MS, Thangamani S. 2024. Yeast and filamentous Candida auris stimulate distinct immune responses in the skin. mSphere 9: e0005524. doi: 10.1128/msphere.00055-24 38904381 PMC11288036 source
The OBSERVATION section says clinical isolates can have yeast and filamentous forms, but its list names pseudohyphal—not aggregative—forms as the third example. The searched passages provide no support for the aggregative part of the claim; page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationC. auris has a unique ability to colonize and persist in human and murine skin long term, resulting in nosocomial transmission and outbreaks of systemic infections.
“Unlike other Candida species, such as Candida albicans, that colonize the intestine, C. auris has a unique ability to colonize and persist in human and murine skin long term, resulting in nosocomial transmission and outbreaks of systemic infections (4–8).”
Quote in the paperNot a substantial claim3 of 5 sources checked- cites [4] Huang X, Hurabielle C, Drummond RA, Bouladoux N, Desai JV, Sim CK, Belkaid Y, Lionakis MS, Segre JA. 2021. Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies. Cell Host Microbe 29: 210– 221. doi: 10.1016/j.chom.2020.12.002 33385336 PMC7878403 source
The Introduction reports that C. auris persists on patients’ skin for months, unlike other Candida species, and the Results document months-long residence in murine skin tissue. The Introduction says skin and environmental persistence likely contribute to nosocomial transmission, while skin colonization is a risk factor for subsequent bloodstream infection. It does not establish that skin persistence directly results in outbreaks of systemic infections, as the claim’s wording implies. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [5] Datta A, Das D, Nett JE, Vyas JM, Lionakis MS, Thangamani S. 2023. Differential skin immune responses in mice intradermally infected with Candida auris and Candida albicans. Microbiol Spectr 11: e0221523. doi: 10.1128/spectrum.02215-23 37811989 PMC10848846 source
- cites [6] Shastri PS, Shankarnarayan SA, Oberoi J, Rudramurthy SM, Wattal C, Chakrabarti A. 2020. Candida auris candidaemia in an intensive care unit - prospective observational study to evaluate epidemiology, risk factors, and outcome. J Crit Care 57: 42– 48. doi: 10.1016/j.jcrc.2020.01.004 32062286 source
- cites [7] Proctor DM, Drummond RA, Lionakis MS, Segre JA. 2023. One population, multiple lifestyles: commensalism and pathogenesis in the human mycobiome. Cell Host Microbe 31: 539– 553. doi: 10.1016/j.chom.2023.02.010 37054674 PMC10155287 source
The Introduction’s “Persistent colonization of skin” section says C. auris can colonize people for months or up to a year, and “Clinical significance of persistent colonization” identifies skin colonization as the largest risk factor for later bloodstream infection. The Introduction also describes outbreaks in healthcare settings. Our copy does not establish long-term persistence on murine skin or an ability unique to C. auris among Candida species. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [8] Balakumar A, Bernstein D, Thangamani S. 2024. The adhesin SCF1 mediates Candida auris colonization. Trends Microbiol 32: 4– 5. doi: 10.1016/j.tim.2023.10.008 37951769 PMC10872899 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationExperimental host-driven evolution of C. auris in the murine model of systemic infection identified multicellular aggregative morphologies with point mutations at several gene loci.
“Furthermore, the experimental host-driven evolution of C. auris in the murine model of systemic infection identified multicellular aggregative morphologies with point mutations at several gene loci (20).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [20] Bing J, Guan Z, Zheng T, Ennis CL, Nobile CJ, Chen C, Chu H, Huang G. 2024. Rapid evolution of an adaptive multicellular morphology of Candida auris during systemic infection. Nat Commun 15: 2381. doi: 10.1038/s41467-024-46786-8 38493178 PMC10944540 source
May combine two claims.
PremisecitationWithout the ACE2 transcript, daughter cells fail to separate after budding; the cells remain clumps or aggregates resistant to physical stress and disruption.
“Without the ACE2 transcript, daughter cells fail to separate after budding; the cells remain clumps or aggregates resistant to physical stress and disruption (14).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [14] Borman AM, Szekely A, Johnson EM. 2016. Comparative pathogenicity of United Kingdom isolates of the emerging pathogen Candida auris and other key pathogenic Candida species. mSphere 1: e00189-16. doi: 10.1128/mSphere.00189-16 27547827 PMC4990711 source
The Results and Discussion section (page not provided) reports that some C. auris isolates form aggregates that resist vigorous vortex mixing and detergent treatment. Microscopy suggests reduced daughter-cell separation after budding, but the paper does not identify absence of an ACE2 transcript as the cause, and it presents the separation mechanism as a suggestion rather than a certainty. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationNeutrophils are crucial for fungal defense.
“Neutrophils are crucial for fungal defense (27, 28).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [27] Koh AY, Köhler JR, Coggshall KT, Van Rooijen N, Pier GB. 2008. Mucosal damage and neutropenia are required for Candida albicans dissemination. PLoS Pathog 4: e35. doi: 10.1371/journal.ppat.0040035 18282097 PMC2242836 source
- cites [28] Netea MG, Joosten LAB, van der Meer JWM, Kullberg B-J, van de Veerdonk FL. 2015. Immune defence against Candida fungal infections. Nat Rev Immunol 15: 630– 642. doi: 10.1038/nri3897 26388329 source
Classified as probably not a substantial claim.
PremisecitationSuppression of the ACE2 locus due to point mutations or loss of ORF region was reported during C. auris adaptive evolution in the host.
“Among them, suppression of the ACE2 locus due to point mutations or loss of ORF region was reported during C. auris adaptive evolution in the host.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [20] Bing J, Guan Z, Zheng T, Ennis CL, Nobile CJ, Chen C, Chu H, Huang G. 2024. Rapid evolution of an adaptive multicellular morphology of Candida auris during systemic infection. Nat Commun 15: 2381. doi: 10.1038/s41467-024-46786-8 38493178 PMC10944540 source
The Results (page not provided) report ACE2 mutations in eight host-evolved C. auris isolates and describe mutations or ORF-region losses across the evolved strains. They do not establish that the ORF losses specifically affected ACE2; the ACE2 deletion described in Methods was experimentally constructed, not observed during host evolution. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationClinical isolates of C. auris with rough morphological colonies were reported to harbor single nucleotide polymorphism (SNP) at the ACE2 locus.
“Recent evidence suggests that the clinical isolates of C. auris with rough morphological colonies were reported to harbor single nucleotide polymorphism (SNP) at the ACE2 locus (19).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [19] Tian S, Bing J, Chu Y, Li H, Wang Q, Cheng S, Chen J, Shang H. 2023. Phenotypic and genetic features of a novel clinically isolated rough morphotype Candida auris. Front Microbiol 14: 1174878. doi: 10.3389/fmicb.2023.1174878 37350781 PMC10282645 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationC. auris replicates within macrophages by bypassing the NLRP3 pathway.
“Recent evidence suggests that C. auris replicates within macrophages by bypassing the NLRP3 pathway (33, 34).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [33] Bruno M, Kersten S, Bain JM, Jaeger M, Rosati D, Kruppa MD, Lowman DW, Rice PJ, Graves B, Ma Z, Jiao YN, Chowdhary A, Renieris G, van de Veerdonk FL, Kullberg B-J, Giamarellos-Bourboulis EJ, Hoischen A, Gow NAR, Brown AJP, Meis JF, Williams DL, Netea MG. 2020. Transcriptional and functional insights into the host immune response against the emerging fungal pathogen Candida auris. Nat Microbiol 5: 1516– 1531. doi: 10.1038/s41564-020-0780-3 32839538 PMC9204844 source
The Results section on macrophage phagocytosis reports that C. auris continued to multiply within macrophage phagosomes. Our copy does not establish that it does so by bypassing the NLRP3 pathway; a search for NLRP3 found no passage supporting that mechanism. Page numbers were not available. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [34] Weerasinghe H, Simm C, Djajawi TM, Tedja I, Lo TL, Simpson DS, Shasha D, Mizrahi N, Olivier FAB, Speir M, Lawlor KE, Ben-Ami R, Traven A. 2023. Candida auris uses metabolic strategies to escape and kill macrophages while avoiding robust activation of the NLRP3 inflammasome response. Cell Rep 42: 112522. doi: 10.1016/j.celrep.2023.112522 37204928 source
May combine two claims.
PremisecitationNeutrophils are less efficient in recognizing and killing C. auris due to the presence of a dense mannan layer and recruit significantly fewer neutrophils than C. albicans in the murine infection.
“Recent evidence suggests that neutrophils are less efficient in recognizing and killing C. auris (29) due to the presence of a dense mannan layer (30) and recruit significantly fewer neutrophils than the C. albicans in the murine infection (5, 31).”
Quote in the paperNot a substantial claim4 of 4 sources checked- cites [29] Johnson CJ, Davis JM, Huttenlocher A, Kernien JF, Nett JE. 2018. Emerging fungal pathogen Candida auris evades neutrophil attack. MBio 9: e01403-18. doi: 10.1128/mBio.01403-18 30131360 PMC6106086 source
- cites [30] 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
- cites [5] Datta A, Das D, Nett JE, Vyas JM, Lionakis MS, Thangamani S. 2023. Differential skin immune responses in mice intradermally infected with Candida auris and Candida albicans. Microbiol Spectr 11: e0221523. doi: 10.1128/spectrum.02215-23 37811989 PMC10848846 source
- cites [31] 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
May combine two claims.
PremisecitationACE2 is a zinc finger transcription factor expressed during the G2 phase and controls the expression of chitinase CTS1, which is required for septal degradation and cell separation.
“ACE2 is a zinc finger transcription factor expressed during the G2 phase and controls the expression of chitinase CTS1, which is required for septal degradation and cell separation (9).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Santana DJ, O’Meara TR. 2021. Forward and reverse genetic dissection of morphogenesis identifies filament-competent Candida auris strains. Nat Commun 12: 7197. doi: 10.1038/s41467-021-27545-5 34893621 PMC8664941 source
The Results section (‘ACE2 and TAO3 are regulators of C. auris morphogenesis’; page not provided) reports that deleting ACE2 significantly reduces CTS1 expression and describes CTS1’s role in primary-septum degradation during daughter-cell separation in S. cerevisiae. The Discussion also describes CauCTS1 as a putative chitinase regulated by CauACE2. Our copy does not state that ACE2 is a zinc finger transcription factor or that it is expressed during G2. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationC. auris can undergo adhesin-dependent and -independent aggregation.
“Broadly, C. auris can undergo adhesin-dependent and -independent aggregation (18).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [18] Pelletier C, Shaw S, Alsayegh S, Brown AJP, Lorenz A. 2024. Candida auris undergoes adhesin-dependent and -independent cellular aggregation. PLOS Pathog 20: e1012076. doi: 10.1371/journal.ppat.1012076 38466738 PMC10957086 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCell aggregation in C. auris is a complex phenomenon, and more than one mechanism has been proven responsible.
“Cell aggregation in C. auris is a complex phenomenon, and more than one mechanism has been proven responsible (17).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [17] Malavia-Jones D, Farrer RA, Stappers MHT, Edmondson MB, Borman AM, Johnson EM, Lipke PN, Gow NAR. 2023. Strain and temperature dependent aggregation of Candida auris is attenuated by inhibition of surface amyloid proteins. Cell Surf 10: 100110. doi: 10.1016/j.tcsw.2023.100110 37559873 PMC10407437 source
The Discussion (page not provided) describes C. auris aggregation as a complex, polygenic property and reports evidence that surface amyloid proteins contribute. It says other factors may also contribute, but does not establish that more than one mechanism has been proven responsible; its experiments found no obvious cell-separation defect in the isolates tested. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationAggregative phenotype affects the virulence, antifungal susceptibility, and biofilm formation of C. auris.
“Emerging evidence shows that aggregative phenotype affects the virulence, antifungal susceptibility, and biofilm formation of C. auris (11, 14, 15).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [11] Brown JL, Delaney C, Short B, Butcher MC, McKloud E, Williams C, Kean R, Ramage G. 2020. Candida auris phenotypic heterogeneity determines pathogenicity in vitro mSphere 5: e00371-20. doi: 10.1128/mSphere.00371-20 32581078 PMC7316489 source
- cites [14] Borman AM, Szekely A, Johnson EM. 2016. Comparative pathogenicity of United Kingdom isolates of the emerging pathogen Candida auris and other key pathogenic Candida species. mSphere 1: e00189-16. doi: 10.1128/mSphere.00189-16 27547827 PMC4990711 source
The Results and Discussion report that aggregate-forming C. auris strains were less virulent than nonaggregating strains in G. mellonella larvae. Table 1 lists antifungal MICs alongside isolate morphology, but the paper does not establish that aggregation affects susceptibility; it calls possible protection from antifungal agents a question for further study. Our copy does not address an effect on biofilm formation. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [15] Sherry L, Ramage G, Kean R, Borman A, Johnson EM, Richardson MD, Rautemaa-Richardson R. 2017. Biofilm-forming capability of highly virulent, multidrug-resistant Candida auris. Emerg Infect Dis 23: 328– 331. doi: 10.3201/eid2302.161320 28098553 PMC5324806 source
The Study reports different biofilm biomass among aggregative and nonaggregative C. auris strains and suggests enhanced virulence for the nonaggregative phenotype in a larval model. Its antifungal testing says the strains had mostly similar sensitivity profiles, with some strain-specific exceptions; it does not establish a general effect of aggregative phenotype on antifungal susceptibility. Page numbers are unavailable in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationILCs were known to promote IL-17 response in C. auris.
“ILCs were known to promote IL-17 response in C. auris (4).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [4] Huang X, Hurabielle C, Drummond RA, Bouladoux N, Desai JV, Sim CK, Belkaid Y, Lionakis MS, Segre JA. 2021. Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies. Cell Host Microbe 29: 210– 221. doi: 10.1016/j.chom.2020.12.002 33385336 PMC7878403 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDeletion of ACE2 in Candida glabrata provoked virulence.
“but in Candida glabrata provoked virulence (38, 39)”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [38] MacCallum DM, Findon H, Kenny CC, Butler G, Haynes K, Odds FC. 2006. Different consequences of ACE2 and SWI5 gene disruptions for virulence of pathogenic and nonpathogenic yeasts. Infect Immun 74: 5244– 5248. doi: 10.1128/IAI.00817-06 16926418 PMC1594847 source
The Abstract reports that the C. glabrata ace2 null mutant was hypervirulent in temporarily neutropenic mice. The Discussion says tests in immunologically unaltered mice found no evidence of hypervirulence, so the unqualified claim omits a decisive host-condition limit. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [39] Kamran M, Calcagno A-M, Findon H, Bignell E, Jones MD, Warn P, Hopkins P, Denning DW, Butler G, Rogers T, Mühlschlegel FA, Haynes K. 2004. Inactivation of transcription factor gene ACE2 in the fungal pathogen Candida glabrata results in hypervirulence. Eukaryot Cell 3: 546– 552. doi: 10.1128/EC.3.2.546-552.2004 15075283 PMC387657 source
May combine two claims.
PremisecitationMice intravenously infected with host-evolved Candida auris with suppression of ACE2 locus did not survive after 5 days post-infection, denoting its virulence traits in C. auris.
“Interestingly, the mice intravenously infected with host-evolved C. auris with suppression of ACE2 locus did not survive after 5 days post-infection, denoting its virulence traits in C. auris (20).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [20] Bing J, Guan Z, Zheng T, Ennis CL, Nobile CJ, Chen C, Chu H, Huang G. 2024. Rapid evolution of an adaptive multicellular morphology of Candida auris during systemic infection. Nat Commun 15: 2381. doi: 10.1038/s41467-024-46786-8 38493178 PMC10944540 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDeletion of ACE2 in Candida albicans and Saccharomyces cerevisiae resulted in attenuation of virulence.
“The deletion of ACE2 in C. albicans and Saccharomyces cerevisiae resulted in the attenuation of virulence”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [38] MacCallum DM, Findon H, Kenny CC, Butler G, Haynes K, Odds FC. 2006. Different consequences of ACE2 and SWI5 gene disruptions for virulence of pathogenic and nonpathogenic yeasts. Infect Immun 74: 5244– 5248. doi: 10.1128/IAI.00817-06 16926418 PMC1594847 source
- cites [39] Kamran M, Calcagno A-M, Findon H, Bignell E, Jones MD, Warn P, Hopkins P, Denning DW, Butler G, Rogers T, Mühlschlegel FA, Haynes K. 2004. Inactivation of transcription factor gene ACE2 in the fungal pathogen Candida glabrata results in hypervirulence. Eukaryot Cell 3: 546– 552. doi: 10.1128/EC.3.2.546-552.2004 15075283 PMC387657 source
May combine two claims.
Findingown dataBoth the percentage and the absolute cell number of CD11b+ Ly6G+ neutrophil was significantly increased in the skin tissue of ace2Δ infected mice.
“Both the percentage and the absolute cell number of CD11b+ Ly6G+ neutrophil was significantly increased in the skin tissue of ace2Δ infected mice.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataReintegration of ACE2 in the ace2Δ strain restored the difference in the fungal burden in the mice; mice infected with ace2Δ + ACE2 complemented strain had increased fungal load similar to mice infected with the WT C. auris strain.
“The reintegration of ACE2 in the ace2Δ strain restored the difference in the fungal burden in the mice. Mice infected with ace2Δ + ACE2 complemented strain had increased fungal load similar to mice infected with the WT C. auris strain (Fig. 1C).”
Quote in the paperSubstantial claim- Rests on an assumption: The qPCR quantification of fungal DNA copy number accurately reflects fungal burden in skin tissue for the aggregative ace2Δ strain.
May combine two claims.
Findingown dataThe percentage and absolute number of IFNγ, IL17A, and IL17F producing γδ+ T-cell population remains unchanged in ace2Δ infected mice.
“However, the percentage and absolute number of IFNγ, IL17A, and IL17F producing γδ+ T-cell population remains unchanged in ace2Δ infected mice (Fig. 4B through D) (Fig. S2 and S3).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn ace2Δ cultures, cells clumped together as aggregates, so a single colony did not represent a single cell.
“In ace2Δ, the cells were clumped together as aggregates, and a single colony would not represent a single cell (Fig. 1B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the murine skin infection model, C. auris ace2Δ showed lower fungal burden at early and late time points, accompanied by enhanced innate and adaptive immune responses.
“In our study, the lower fungal burden during the early and late time points of the murine skin infection with C. auris ace2Δ is accompanied by an enhanced innate and adaptive immune response.”
Quote in the paperSubstantial claim- Rests on an assumption: Fungal burden in skin tissue is proportional to the weight of the tissue.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRAM pathway kinases are usually conserved between species.
“They are usually conserved between the species”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Saputo S, Chabrier-Rosello Y, Luca FC, Kumar A, Krysan DJ. 2012. The RAM network in pathogenic fungi. Eukaryot Cell 11: 708– 717. doi: 10.1128/EC.00044-12 22544903 PMC3370468 source
May combine two claims.
Interpretationown dataAggregative phenotype mediated by ACE2 deletion in C. auris induces potent neutrophil and IL-17-mediated immune response and reduces fungal colonization in the skin.
“Our findings suggest that aggregative phenotype mediated by ACE2 deletion in C. auris induces potent neutrophil and IL-17-mediated immune response and reduces fungal colonization in the skin.”
Quote in the paperSubstantial claim- Rests on an assumption: The qPCR quantification of fungal DNA copy number accurately reflects fungal burden in skin tissue for the aggregative ace2Δ strain.
- Rests on an assumption: ACE2 deletion affects skin colonization and immune response solely through the aggregative phenotype, not through other ACE2-dependent effects.
May combine two claims.
Study design and conductown dataace2Δ and ace2Δ + ACE2 were confirmed by PCR and Sanger sequencing.
“ace2Δ and ace2Δ + ACE2 were confirmed by PCR and Sanger sequencing (Table S1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationExposure to triazoles and echinocandins induced cell aggregation in C. auris clinical isolates of the South Asian clade, which are non-aggregative.
“On the other hand, the exposure to triazoles and echinocandins also induced cell aggregation in C. auris clinical isolates of the South Asian clade, which are non-aggregative (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Szekely A, Borman AM, Johnson EM. 2019. Candida auris isolates of the southern Asian and South African lineages exhibit different phenotypic and antifungal susceptibility profiles In Vitro. J Clin Microbiol 57: e02055-18. doi: 10.1128/JCM.02055-18 30867237 PMC6498034 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationType 3 ILCs are distributed on the mucosal surface of the skin and promote defense against evading skin pathogens by promoting IL-17 and IL-22 responses.
“The type 3 ILCs are distributed on the mucosal surface of the skin and promote defense against evading skin pathogens by promoting IL-17 and IL-22 responses (36).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Gladiator A, Wangler N, Trautwein-Weidner K, LeibundGut-Landmann S. 2013. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J Immunol 190: 521– 525. doi: 10.4049/jimmunol.1202924 23255360 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe RAM pathway in pathogenic fungi is the signaling network of protein kinases that regulate morphology and cellular functions.
“The RAM pathway in pathogenic fungi is the signaling network of protein kinases that regulate morphology and cellular functions.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Saputo S, Chabrier-Rosello Y, Luca FC, Kumar A, Krysan DJ. 2012. The RAM network in pathogenic fungi. Eukaryot Cell 11: 708– 717. doi: 10.1128/EC.00044-12 22544903 PMC3370468 source
May combine two claims.
Study design and conductown dataThe ACE2 deletion was verified by colony PCR and confirmed by agarose gel electrophoresis and Sanger sequencing.
“The deletion was verified using colony PCR by designing primers nesting the upstream and downstream of the ACE2 ORF. The ACE2 deletion was confirmed by agarose gel electrophoresis and Sanger sequencing (Fig. S1B) (Table S1).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataA standard curve was established for WT C. auris 0387, ace2Δ, and ace2Δ + ACE2 strains by plotting CT values of fungal DNA amplified from 10^7, 10^6, and 10^5 cells against CFU.
“The cycle threshold values of the fungal DNA amplified from 107, 106, and 105 cells were plotted against the CFU determined to establish a standard curve for WT C. auris 0387, ace2Δ, and ace2Δ + ACE2 strains.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningThe relative quantity of C. auris fungal DNA was determined by normalizing CT values of mouse GAPDH gene using the ΔCT method, because fungal burden in skin tissue is proportional to tissue weight.
“The relative quantity of fungal DNA of C. auris was determined by normalizing the threshold cycle (CT) values of mouse GAPDH gene using the ΔCT method, since the fungal burden in skin tissue is proportional to the weight of the tissue.”
Quote in the paperSubstantial claim- Rests on an assumption: Fungal burden in skin tissue is proportional to the weight of the tissue.
The paper relies on this without support.
The qPCR quantification of fungal DNA copy number accurately reflects fungal burden in skin tissue for the aggregative ace2Δ strain.
“Due to the aggregative nature of the ace2Δ, the fungal DNA was quantified from the infected mice’s skin tissues to assess the fungal load.”
“we adapted quantification of fungal DNA copy number to access the in vivo fungal load from mice skin tissues, since the traditional CFU plating may not accurately represent fungal burden.”
The paper relies on this without support.
The intradermal murine model reflects human skin colonization and immune responses to C. auris.
“Using the intradermal murine skin infection model, we examined the colonization and skin immune response of aggregative (ace2Δ) and non-aggregative (WT) forms of C. auris AR0387.”
The paper relies on this without support.
The aggregative phenotype caused by ACE2 deletion is representative of clinical aggregative C. auris isolates.
“In this study, we examined the murine skin colonization and host immune response in the aggregative phenotype of C. auris due to the loss of the ACE2 locus.”
The paper relies on this without support.
ACE2 deletion affects skin colonization and immune response solely through the aggregative phenotype, not through other ACE2-dependent effects.
“Taken together, our findings suggest that aggregative phenotype mediated by ACE2 deletion in C. auris reduces fungal colonization in the skin.”
The paper relies on this without support.
DNA copy number per fungal cell is constant across WT, ace2Δ, and ace2Δ + ACE2 strains.
“The CFU to cell number ratio was determined by qPCR amplification of fungal DNA copy number compared with WT C. auris 0387 to establish the infection dose for in vivo murine infection (Table S2).”
The paper relies on this without support.
Fungal burden in skin tissue is proportional to the weight of the tissue.
“since the fungal burden in skin tissue is proportional to the weight of the tissue.”
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?
The aggregative phenotype of C. auris is controlled at least in part by the zinc-finger transcription factor ACE2 that governs cell separation via the chitinase CST1.
“Additional studies recently examined how the aggregative phenotype of C. auris, a complex phenomenon controlled at least in part by the zinc-finger transcription factor ACE2 that governs cell separation via the chitinase CST1, regulates Th17 cell development [109,110].”
From Host–Candida auris interactions in the skin (2026) · cites this paper as [109]
The Introduction identifies ACE2 as a zinc-finger transcription factor involved in C. auris aggregation and cell separation. It names the chitinase whose expression ACE2 controls as CTS1, however, not CST1 as the claim states. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn a murine model of intradermal infection, the ace2Δ mutant strain of C. auris induces greater Th17 responses compared to wild-type or complemented strains.
“In a murine model of intradermal infection, the ace2Δ mutant strain of C. auris induced greater Th17 responses compared to wild-type or complemented strains [109].”
From Host–Candida auris interactions in the skin (2026) · cites this paper as [109]
C. auris morphogenesis is linked to adaptive immunity, suggesting that morphotype-specific cues may determine the quality and strength of protective IL-17 responses.
“These observations reveal a link between C. auris morphogenesis and adaptive immunity, suggesting that morphotype-specific cues may determine the quality and strength of protective IL-17 responses.”
From Host–Candida auris interactions in the skin (2026) · cites this paper as [109]
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.
Figure 1 reports a different tissue mass for fungal-load measurement
MinorThe Figure 1 caption says fungal DNA was quantified in 25 grams of tissue, whereas the method specifies 25 mg. These are substantially different sample masses for the reported fungal-load result.
“The bar graph represents the relative quantity of fungal DNA in murine skin tissue quantified in 25 grams of tissue weight”
“Briefly, gDNA was extracted from 25 mg of tissue from each sample using Qiagen’s DNeasy blood and tissue kit.”
Standard-curve caption and methods list different cell counts
MinorThe Figure 1 caption lists four cell counts for the qPCR standard curve, including 104, but the methods list only three counts and omit 104.
“Standard curve of the 107, 106, 105, and 104 fungal cells of WT, ace2Δ, and ace2Δ + ACE2 strains quantified using qPCR.”
“The fungal cells of WT C. auris 0387 or ace2Δ or ace2Δ + ACE2 strains were enumerated in the hemocytometer, and 107, 106, and 105 cells were taken for fungal DNA extraction”
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Candida auris undergoes adhesin-dependent and -independent cellular aggregation
Pelletier, C., Shaw, S., Alsayegh, S., Brown, A. J. P., & Lorenz, A. (2024) · PLOS Pathogens · doi:10.1371/journal.ppat.1012076 · Cited by 44 · see citing works
Innate lymphoid cells: new players in IL-17-mediated antifungal immunity
Gladiator, A., & LeibundGut-Landmann, S. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003763 · Cited by 35 · see citing works
Ambati, S., Ellis, E. C., Pham, T., Lewis, Z., Lin, X., & Meagher, R. B. (2021) · mBio · doi:10.1128/mbio.00030-21 · Cited by 32 · see citing works
Narayanan, A., Selvakumar, P., Siddharthan, R., & Sanyal, K. (2022) · Microbiology Spectrum · doi:10.1128/spectrum.00634-22 · Cited by 31 · see citing works
Datta, A., Das, D., Nett, J. E., Vyas, J. M., Lionakis, M. S., & Thangamani, S. (2023) · Microbiology Spectrum · doi:10.1128/spectrum.02215-23 · Cited by 30 · see citing works
Self-citationMalavia-Jones, D., Farrer, R. A., Stappers, M. H. T., Edmondson, M. B., Borman, A. M., Johnson, E. M., Lipke, P. N., & Gow, N. A. R. (2023) · The Cell Surface · doi:10.1016/j.tcsw.2023.100110 · Cited by 29 · see citing works
<i>Candida auris</i> —macrophage cellular interactions and transcriptional response
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Colonization and effector functions of innate lymphoid cells in mucosal tissues
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Yeast and filamentous <i>Candida auris</i> stimulate distinct immune responses in the skin
Bryak, G., Cox, A., Lionakis, M. S., & Thangamani, S. (2024) · mSphere · doi:10.1128/msphere.00055-24 · Cited by 13 · cited 1× · see citing works
“Clinical isolates of C. auris can exhibit different morphotypes, such as yeast, fila mentous, and aggregative forms (9–13).”
Self-citationThe adhesin SCF1 mediates Candida auris colonization
Balakumar, A., Bernstein, D., & Thangamani, S. (2024) · Trends in Microbiology · doi:10.1016/j.tim.2023.10.008 · Cited by 11 · see citing works
Self-citationPhenotypic and genetic features of a novel clinically isolated rough morphotype Candida auris
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Flagged first, then by citations
Research works printed but not linked: 1
- Sati H. 2022. WHO fungal priority pathogens list to guide research, development and public health action. World Health Organization: Geneva, Switzerland.
Cited by
Sorted by citations
Cha, H., Won, D., Kang, S., Kim, E.-S., Lee, K.-A., Lee, W.-J., Lee, K.-T., & Bahn, Y.-S. (2025) · PLOS Pathogens · doi:10.1371/journal.ppat.1013363 · Cited by 24 · see citing works
Host–Candida auris interactions in the skin
Thangamani, S., Balakumar, A., Datta, A., Bryak, G., & Lionakis, M. S. (2026) · PLOS Pathogens · doi:10.1371/journal.ppat.1014075 · Cited by 3 · see citing works
Self-citation
- Authors
- Balakumar, A., Cox, A., & Thangamani, S.
- Affiliations
- Purdue University West Lafayette (US)
- Venue
- mSphere
- Publisher
- American Society for Microbiology
- Published
- 2024-11-21
- Volume
- 9
- Issue
- 11
- Pages
- e0073424-e0073424
- ISSN
- 2379-5042 (ISSN-L)
- PMC
- PMC11580408
- OpenAlex
- W4403893187
- Semantic Scholar
- 93ed4880aeb23a09bda2d91765d4ee0b41039507
- Cited by
- 12
- References
- 40
- Citations by year
- 2026: 5 · 2025: 7
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mSphere (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- HHS | NIH | 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Candida auris, skin colonization, host immune response, neutrophils, inflammatory monocytes, macrophages, Th17 cells, ILC3, IL-17, intradermal infection, antifungal therapy, fungal morphotypes
- MeSH terms
- Angiotensin-Converting Enzyme 2, Candida auris, Animals, Candidiasis, Disease Models, Animal, Female, Fungal Proteins, Immunity, Innate, Macrophages, Mice, Inbred C57BL, Neutrophils, Skin, Gene Deletion, Mice, Th17 Cells
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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