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Cited by 47Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

Functional redundancy in Candida auris cell surface adhesins crucial for cell-cell interaction and aggregation

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Wang, Tristan W., Sofras, Dimitrios, Montelongo-Jauregui, Daniel, Paiva, Telmo O., Carolus, Hans, Dufrêne, Yves F., Alfaifi, Areej A., McCracken, Carrie +3 more·2024·Nature Communications
DOI 10.1038/s41467-024-53588-5PMC PMC11511831

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Abstract

Candida auris is an emerging nosocomial fungal pathogen associated with life-threatening invasive disease due to its persistent colonization, high level of transmissibility and multi-drug resistance. Aggregative and non-aggregative growth phenotypes for C. auris strains with different biofilm forming abilities, drug susceptibilities and virulence characteristics have been described. Using comprehensive transcriptional analysis we identified key cell surface adhesins that were highly upregulated in the aggregative phenotype during in vitro and in vivo grown biofilms using a mouse model of catheter infection. Phenotypic and functional evaluations of generated null mutants demonstrated crucial roles for the adhesins Als4112 and Scf1 in mediating cell-cell adherence, coaggregation and biofilm formation. While individual mutants were largely non-aggregative, in combination cells were able to co-adhere and aggregate, as directly demonstrated by measuring cell adhesion forces using single-cell atomic force spectroscopy. This co-adherence indicates their role as complementary adhesins, which despite their limited similarity, may function redundantly to promote cell-cell interaction and biofilm formation. Functional diversity of cell wall proteins may be a form of regulation that provides the aggregative phenotype of C. auris with flexibility and rapid adaptation to the environment, potentially impacting persistence and virulence.

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Crossref · 10.1038/s41467-024-53588-5

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  • Als4112 physically interacts with Scf1 through the Flo11 and serine-threonine-rich domains, and together these adhesins mediate cell-cell adherence, aggregation, and biofilm integrity for skin colonization.

    “Als4112 physically interacts with Scf1 through the Flo11 and serine–threonine-rich domains, and together these adhesins mediate in cell-cell adherence, aggregation, and biofilm integrity for skin colonization [74].”

    From Host–Candida auris interactions in the skin (2026) · cites this paper as [74]

    The Results (Scf1 domain organization; cell–cell adherence and aggregation; pages not provided) identify Scf1’s Flo11 domain and serine–threonine-rich region and show that the two adhesins support adherence and aggregation. The Discussion describes complementary Als4112–Scf1 binding, but does not establish that binding occurs through both named domains. The biofilm experiments concern laboratory surfaces and catheters implanted in mice, not skin colonization. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Adhesion to inert surface in UME6HA is essentially triggered by Scf1.

    “Adhesion to inert surface was essentially triggered by Scf1.”

    From Ume6-dependent pathways of morphogenesis and biofilm formation in <i>Candida auris</i> (2024) · cites this paper as [40]

    The Results section on in vitro biofilm formation reports that deleting SCF1 significantly reduced biofilm formation, while deleting ALS4112 did not; the Methods specify polystyrene plates. This supports a role for Scf1 in biofilm formation on an inert surface, but does not establish that Scf1 essentially triggers initial surface adhesion or show this in UME6HA. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Scf1 plays a crucial role in adhesion to inert surfaces.

    “These data confirm the crucial role of Scf1 in adhesion to inert surfaces as recently described (27, 40).”

    From Ume6-dependent pathways of morphogenesis and biofilm formation in <i>Candida auris</i> (2024) · cites this paper as [40]

    The Results section on in vitro biofilm formation reports that deleting SCF1 significantly reduced biofilm formation, and the Methods specify that these assays used polystyrene plates. The Discussion also reports sparse Δscf1 biofilms in catheters. These findings support a role for Scf1 in biofilms on inert surfaces, but the paper identifies its adhesion mechanism as cell–cell adherence; it does not establish that Scf1 is crucial for direct adhesion to the inert surface itself. The indexed copy provides no page numbers for these passages. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Deletion of ALS4112 in an aggregative clade I isolate results in an aggregation defect.

    “Deletion of ALS4112 in an aggregative clade I isolate resulted in aggregation defect (40).”

    From Ume6-dependent pathways of morphogenesis and biofilm formation in <i>Candida auris</i> (2024) · cites this paper as [40]

  • Scf1 plays a crucial role in adhesion and biofilm formation.

    “The crucial role of Scf1 in adhesion and biofilm formation has been recently demonstrated (27, 40).”

    From Ume6-dependent pathways of morphogenesis and biofilm formation in <i>Candida auris</i> (2024) · cites this paper as [40]

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Cites

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Research works printed but not linked: 44

  1. [1]Vila, T., Sultan, A. S., Montelongo-Jauregui, D. & Jabra-Rizk, M. A. Candida auris: a fungus with identity crisis. Pathog. Dis. 78, ftaa034 (2020). 32643757 PMC7371155 · DOI
  2. [2]Lockhart, S. R. et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin. Infect. Dis. 64, 134–140 (2017). 27988485 PMC5215215 · DOI · Paper page
  3. [3]Cortegiani, A., Misseri, G., Giarratano, A., Bassetti, M. & Eyre, D. The global challenge of Candida auris in the intensive care unit. Crit. Care Med. 23, 150 (2019). PMC6495550 31046836
  4. [5]de Jong, A. W. & Hagen, F. Attack, defend and persist: how the fungal pathogen Candida auris was able to emerge globally in healthcare environments. Mycopathologia 148, 353–365 (2019). 31209693 · DOI
  5. [6]Wickes, B. L. Analysis of a Candida auris outbreak provides new insights into an emerging pathogen. J. Clin. Microbiol. 58, e02083–19 (2020). 31996439 PMC7098746 · DOI
  6. [7]Lockhart, S. R. Candida auris and multidrug resistance: defining the new normal. Fungal Genet. Biol. 131, 103243 (2019). 31228646 PMC12012538 · DOI · Paper page
  7. [8]Chaabane, F., Graf, A., Jequier, L. & Coste, A. T. Review on antifungal resistance mechanisms in the emerging pathogen Candida auris. Front Microbiol. 10, 2788 (2019). 31849919 PMC6896226 · DOI · Paper page
  8. [11]Fisher, M. C. et al. Tackling the emerging threat of antifungal resistance to human health. Nat. Rev. Microbiol. 20, 557–571 (2022). 35352028 PMC8962932 · DOI · Paper page
  9. [12]Harris, E. Candida auris fungal infections and drug resistance on the rise. JAMA 329, 1248 (2023). 36988997
  10. [13]Fisher, M. C. & Denning, D. W. The WHO fungal priority pathogens list as a game-changer. Nat. Rev. Microbiol. 21, 211–212 (2023). 36747091 PMC9901396 · DOI · Paper page
  11. [14]Larkin, E. et al. The emerging pathogen Candida auris: Growth phenotype, virulence factors, activity of antifungals, and effect of SCY-078 on growth morphology and biofilm formation., a novel glucan synthesis inhibitor. Antimicrob. Agents Chemother. 61, e02396–02316 (2017). 28223375 PMC5404565 · DOI · Paper page
  12. [15]Sherry, L. et al. Biofilm-forming capability of highly virulent, multidrug-resistant Candida auris. Emerg. Infect. Dis. 23, 328–331 (2017). 28098553 PMC5324806 · DOI · Paper page
  13. [18]Willaert, R. G., Kayacan, Y. & Devreese, B. The Flo adhesin family. Pathogens 10, 1397 (2021). 34832553 PMC8621652 · DOI
  14. [20]Brown, J. L. et al. Candida auris phenotypic heterogeneity determines pathogenicity in vitro. mSphere5, e00371-00320 (2020). PMC7316489 32581078
  15. [21]Short, B. et al. Candida auris exhibits resilient biofilm characteristics in vitro: implications for environmental persistence. J. Hosp. Infect. 103, 92–96 (2019). 31226270 · DOI · Paper page
  16. [22]Szekely, A., Borman, A. M. & Johnsona, E. M. Candida auris isolates of the southern Asian and South African lineages exhibit different phenotypic and antifungal susceptibility profiles in vitro. J. Clin. Microbiol. 57, 1–12 (2019). PMC6498034 30867237 · DOI · Paper page
  17. [25]Dehullu, J. et al. Fluidic force microscopy demonstrates that homophilic adhesion by Candida albicans Als proteins is mediated by amyloid bonds between cells. Nano Lett. 19, 3846–3853 (2019). 31038969 PMC6638552 · DOI
  18. [26]Malavia-Jones, D. et al. Strain and temperature dependent aggregation of Candida auris is attenuated by inhibition of surface amyloid proteins. Cell Surf. 10, 100110 (2023). 37559873 PMC10407437 · DOI · Paper page
  19. [27]Bing, J. et al. Clinical isolates of Candida auris with enhanced adherence and biofilm formation due to genomic amplification of ALS4. PLoS Pathog. 19, e1011239 (2023). 36913408 PMC10035925 · DOI · Paper page
  20. [29]Nobile, C. J. et al. Complementary adhesin function in C. albicans biofilm formation. Curr. Biol. 18, 1017–1024 (2008). 18635358 PMC2504253 · DOI · Paper page
  21. [30]Soll, D. R. The role of phenotypic switching in the basic biology and pathogenesis of Candida albicans. J. Oral Microbiol.6, 22993 (2014). PMC3895265 24455104
  22. [32]Viljoen, A. et al. Force spectroscopy of single cells using atomic force microscopy. Nat. Rev. Methods Prim. 1, 64 (2021). · DOI
  23. [33]Alsteens, D., Garcia, M. C., Lipke, P. N. & Dufrêne, Y. F. Force-induced formation and propagation of adhesion nanodomains in living fungal cells. Proc. Natl. Acad. Sci. USA 107, 20744–20749 (2010). 21059927 PMC2996417 · DOI
  24. [35]Muñoz, J. F. et al. Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris. Genetics 218, iyab029 (2021). 33769478 PMC8128392 · DOI · Paper page
  25. [36]Balakumar, A., Bernstein, D. & Thangamani, S. The adhesin SCF1 mediates Candida auris colonization. Trends Microbiol. 32, 4–5 (2024). 37951769 PMC10872899 · DOI · Paper page
  26. [37]Monniot, C. et al. Rbt1 protein domains analysis in Candida albicans brings insights into hyphal surface modifications and Rbt1 potential role during adhesion and biofilm formation. PLoS ONE 8, e82395 (2013). 24349274 PMC3857780 · DOI
  27. [38]Ene, I. V. & Bennett, R. J. Hwp1 and related adhesins contribute to both mating and biofilm formation in Candida albicans. Eukaryot. Cell 8, 1909–1913 (2009). 19837954 PMC2794213 · DOI
  28. [39]Nobile, C. J., Nett, J. E., Andes, D. R. & Mitchell, A. P. Function of Candida albicans adhesin Hwp1 in biofilm formation. Eukaryot. Cell 5, 1604–1610 (2006). 17030992 PMC1595337 · DOI · Paper page
  29. [40]Rauceo, J. M. et al. Global cell surface conformational shift mediated by a Candida albicans adhesin. Infect. Immun. 72, 4948–4955 (2004). 15321986 PMC517415 · DOI
  30. [41]Hoyer, L. L., Green, C. B., Oh, S. H. & Zhao, X. Discovering the secrets of the Candida albicans agglutinin-like sequence (ALS) gene family-a sticky pursuit. Med. Mycol. 46, 1–15 (2008). 17852717 PMC2742883 · DOI · Paper page
  31. [42]Gaur, N. K., Klotz, S. A. & Henderson, R. L. Overexpression of the Candida albicans ALA1 gene in Saccharomyces cerevisiae results in aggregation following attachment of yeast cells to extracellular matrix proteins, adherence properties similar to those of Candida albicans. Infect. Immun. 67, 6040–6047 (1999). 10531265 PMC96991 · DOI
  32. [43]Gaur, N. K., Smith, R. L. & Klotz, S. A. Candida albicans and Saccharomyces cerevisiae expressing ALA1/ALS5 adhere to accessible threonine, serine, or alanine patches. Cell Commun. Adhes. 9, 45–57 (2002). 12200964 · DOI
  33. [44]Klotz, S. A. et al. Degenerate peptide recognition by Candida albicans adhesins Als5p and Als1p. Infect. Immun. 72, 2029–2034 (2004). 15039323 PMC375204 · DOI
  34. [45]Dehullu, J., Vorholt, J. A., Lipke, P. N. & Dufrêne, Y. F. Fluidic force microscopy captures amyloid bonds between microbial cells. Trends Microbiol. 27, 728–730 (2019). 31272796 · DOI
  35. [46]Lipke, P. N., Klotz, S. A., Dufrene, Y. F., Jackson, D. N. & Garcia-Sherman, M. C. Amyloid-like β-aggregates as force-sensitive switches in fungal biofilms and infections. Microbiol. Mol. Biol. Rev. 82, e00035 (2017). 29187516 PMC5813885
  36. [47]Mourer, T., El Ghalid, M., d’Enfert, C. & Bachellier-Bassi, S. Involvement of amyloid proteins in the formation of biofilms in the pathogenic yeast Candida albicans. Res. Microbiol. 172, 103813 (2021). 33515679 · DOI
  37. [48]Carolus, H. et al. Diagnostic allele-specific PCR for the identification of Candida auris clades. J. Fungi 7, 754 (2021). PMC8471779 34575792 · DOI
  38. [49]Kim, D., Paggi, J. M., Park, C., Bennett, C. & Salzberg, S. L. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat. Biotechnol. 37, 907–915 (2019). 31375807 PMC7605509 · DOI · Paper page
  39. [50]Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, 10 (2010). PMC3218662 20979621 · DOI · Paper page
  40. [51]Kucharíková, S., Tournu, H., Holtappels, M., Van Dijck, P. & Lagrou, K. In vivo efficacy of anidulafungin against mature Candida albicans biofilms in a novel rat model of catheter-associated candidiasis. Antimicrob. Agents Chemother. 54, 4474–4475 (2010). 20660685 PMC2944565 · DOI
  41. [52]Reuss, O., Vik, A., Kolter, R. & Morschhäuser, J. The SAT1 flipper, an optimized tool for gene disruption in Candida albicans. Gene 341, 119–127 (2004). 15474295 · DOI
  42. [53]Carolus, H., Sofras, D., Boccarella, G. & Sephton-Clark, P. Acquired amphotericin B resistance and fitness trade-off compensation in Candida auris. Preprint at 10.21203/rs.3.rs-3621420/v1 (2024). 39567662 · DOI
  43. [54]Alsteens, D., Van Dijck, P., Lipke, P. N. & Dufrêne, Y. F. Quantifying the forces driving cell−cell adhesion in a fungal pathogen. Langmuir 29, 13473–13480 (2013). 24152214 PMC3858841 · DOI
  44. [55]Alsteens, D. et al. Single-cell force spectroscopy of Als-mediated fungal adhesion. Anal. Methods 3, 3657–3662 (2013). PMC3743104 23956795 · DOI

Cited by

Sorted by citations

Authors
Wang, T. W., Sofras, D., Montelongo-Jauregui, D., Paiva, T. O., Carolus, H., Dufrêne, Y. F., Alfaifi, A. A., McCracken, C., Bruno, V. M., Van Dijck, P., & Jabra-Rizk, M. A.
Affiliations
  • University of Maryland, Baltimore (US)
  • KU Leuven (BE)
  • UCLouvain (BE)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-10-25
Volume
15
Issue
1
Pages
9212-9212
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-53588-5
PMC
PMC11511831
OpenAlex
W4403769442
Cited by
47
References
11
Citations by year
2026: 27 · 2025: 16 · 2024: 4
FWCI
16.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Digital Access to Libraries (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Lirias (submittedVersion, cc-by)
  • Lirias (submittedVersion, cc-by-nc-nd)
Funders
  • U.S. Department of Health and Human Services (R01AI130170)
  • Fonds De La Recherche Scientifique - FNRS
  • Fonds Wetenschappelijk Onderzoek (W000921N)
  • Vlaamse regering
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (R01AI130170, U19AI110820, AI-110820)
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, cell surface adhesins, functional redundancy, cell aggregation, cell-cell adhesion, biofilm formation, cell wall proteins, co-aggregation, catheter-related infection, knockout mutants, cell adhesion force, atomic force spectroscopy, transcriptional regulation, fungal virulence, nosocomial fungal infections

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