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Cited by 29Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

Strain and temperature dependent aggregation of Candida auris is attenuated by inhibition of surface amyloid proteins

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Malavia-Jones, Dhara, Farrer, Rhys A., Stappers, Mark H.T., Edmondson, Matt B., Borman, Andrew M., Johnson, Elizabeth M., Lipke, Peter N., Gow, Neil A.R.·2023·The Cell Surface
DOI 10.1016/j.tcsw.2023.100110PMC PMC10407437
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Abstract

ABSTRACT Candida auris is a multi-drug resistant human fungal pathogen that has become a global threat to human health due to its drug resistant phenotype, persistence in the hospital environment and propensity for patient to patient spread. Isolates display variable aggregation that may affect the relative virulence of strains. Therefore, dissection of this phenotype has gained substantial interest in recent years. We studied eight clinical isolates from four different clades (I-IV); four of which had a strongly aggregating phenotype and four of which did not. Genome analysis identified polymorphisms associated with loss of cell surface proteins were enriched in weakly-aggregating strains. Additionally, we identified down-regulation of chitin synthase and chitinase genes involved in the synthesis and dissolution of the chitinous septum. Characterisation of the cells revealed no ultrastructural defects in cytokinesis or cell separation in aggregating isolates. Strongly and weakly aggregating strains did not differ in net surface charge or in cell surface hydrophobicity. The capacity for aggregation and for adhesion to polystyrene microspheres were also not correlated. However, aggregation and extracellular matrix formation were all increased at higher growth temperatures, and treatment with the amyloid protein inhibitor Thioflavin-T markedly attenuated aggregation. Genome analysis further indicated strain specific differences in the genome content of GPI-anchored proteins including those encoding genes with the potential to form amyloid proteins. Collectively our data suggests that aggregation is a complex strain and temperature dependent phenomenon that may be linked in part to the ability to form extracellular matrix and cell surface amyloids. HIGHLIGHTS The amyloid inhibitor Thioflavin-T inhibited C. auris aggregation. Aggregating isolates do not exhibit any defects in cell separation. Genomic differences were identified between strongly aggregating and weakly-aggregating strains of C. auris . Aggregation did not correlate with surface charge or hydrophobicity of yeast cells.

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  • Cell 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).”

    From Cell aggregation mediated by <i>ACE2</i> deletion in <i>Candida auris</i> modulates fungal colonization and host immune responses in the skin (2024) · cites this paper as [17]

    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

  • 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 [110]

    The Introduction reports that ACE2 deletion was associated with reduced expression of the chitinase CTS1, which might contribute to cell-separation defects and aggregation. But the Results found no correlation between CTS1 expression and aggregation, and the Discussion says cell-separation defects did not explain aggregation differences in the isolates studied. The claim presents a tentative mechanism as established and names the chitinase CST1 rather than CTS1. (LLM, conf=0.87)

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Research works printed but not linked: 64

  1. Arastehfar A. Shaban T. Zarrinfar H. Roudbary M. Ghazanfari M. Hedayati M.T. Sedaghat A. Ilkit M. Najafzadeh M.J. Perlin D.S. Candidemia among Iranian Patients with Severe COVID-19 Admitted to ICUs J. Fungi (Basel) 7 2021 PMC8068363 33917967
  2. Bing J. Guan Z. Zheng T. Zhang Z. Fan S. Ennis C.L. Nobile C.J. Huang G. Clinical isolates of Candida auris with enhanced adherence and biofilm formation due to genomic amplification of ALS4 PLoS Pathog. 19 2023 e1011239 36913408 PMC10035925
  3. Biswas C. Marcelino V.R. Van Hal S. Halliday C. Martinez E. Wang Q. Kidd S. Kennedy K. Marriott D. Morrissey C.O. Arthur I. Weeks K. Slavin M.A. Sorrell T.C. Sintchenko V. Meyer W. Chen S.C. Whole Genome Sequencing of Australian Candida glabrata Isolates Reveals Genetic Diversity and Novel Sequence Types Front. Microbiol. 9 2018 2946 30559734 PMC6287553
  4. Borman A.M. Szekely A. Johnson E.M. Comparative Pathogenicity of United Kingdom Isolates of the Emerging Pathogen Candida auris and Other Key Pathogenic Candida Species mSphere 2016 1 PMC4990711 27547827
  5. Brown J.L. Delaney C. Short B. Butcher M.C. McKloud E. Williams C. Kean R. Ramage G. Candida auris Phenotypic Heterogeneity Determines Pathogenicity In Vitro mSphere 5 2020 PMC7316489 32581078
  6. Chakrabarti A. Sood P. On the emergence, spread and resistance of Candida auris: host, pathogen and environmental tipping points J. Med. Microbiol. 70 2021 PMC8346726 33599604
  7. Chow N.A. de Groot T. Badali H. Abastabar M. Chiller T.M. Meis J.F. Potential Fifth Clade of Candida auris, Iran, 2018 Emerg. Infect. Dis. 25 2019 1780 2171 31310230 PMC6711235
  8. Chybowska A.D. Childers D.S. Farrer R.A. Nine Things Genomics Can Tell Us About Candida auris Front. Genet. 11 2020 351 32351544 PMC7174702
  9. Forgacs L. Borman A.M. Prepost E. Toth Z. Kardos G. Kovacs R. Szekely A. Nagy F. Kovacs I. Majoros L. Comparison of in vivo pathogenicity of four Candida auris clades in a neutropenic bloodstream infection murine model Emerg. Microb. Infect. 9 2020 1160 2119 PMC7448943 32486923
  10. Forsberg K. Woodworth K. Walters M. Berkow E.L. Jackson B. Chiller T. Vallabhaneni S. Erratum: Candida auris: The recent emergence of a multidrug-resistant fungal Pathogen Med. Mycol. 57 4 2019 e7 30085270
  11. Gautam, A., 2022. Phenol-Chloroform DNA Isolation Method. In: DNA and RNA Isolation Techniques for Non-Experts (Springer Naturevo).
  12. Govender P. Domingo J.L. Bester M.C. Pretorius I.S. Bauer F.F. Controlled expression of the dominant flocculation genes FLO1, FLO5, and FLO11 in Saccharomyces cerevisiae Appl. Environ. Microbiol. 74 2008 6041 6052 18708514 PMC2565957
  13. Gregori C. Glaser W. Frohner I.E. Reinoso-Martin C. Rupp S. Schuller C. Kuchler K. Efg1 Controls caspofungin-induced cell aggregation of Candida albicans through the adhesin Als1 Eukaryot. Cell 10 2011 1694 1704 22037180 PMC3232723
  14. Hobson R.P. Munro C.A. Bates S. MacCallum D.M. Cutler J.E. Heinsbroek S.E. Brown G.D. Odds F.C. Gow N.A. Loss of cell wall mannosylphosphate in Candida albicans does not influence macrophage recognition J. Biol. Chem. 279 2004 39628 39635 15271989
  15. 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 2008 1 15 17852717 PMC2742883
  16. Klein B.S. Tebbets B. Dimorphism and virulence in fungi Curr. Opin. Microbiol. 10 2007 314 319 17719267 PMC3412142
  17. Klotz S.A. Gaur N.K. De Armond R. Sheppard D. Khardori N. Edwards J.E. Jr. Lipke P.N. El-Azizi M. Candida albicans Als proteins mediate aggregation with bacteria and yeasts Med. Mycol. 45 2007 363 370 17510860
  18. Kumamoto C.A. Vinces M.D. Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence Cell. Microbiol. 7 2005 1546 1554 16207242
  19. Kumar R. Saraswat D. Tati S. Edgerton M. Novel Aggregation Properties of Candida albicans Secreted Aspartyl Proteinase Sap6 Mediate Virulence in Oral Candidiasis Infect. Immun. 83 2015 2614 2626 25870228 PMC4468525
  20. Kumar R. Breindel C. Saraswat D. Cullen P.J. Edgerton M. Candida albicans Sap6 amyloid regions function in cellular aggregation and zinc binding, and contribute to zinc acquisition Sci. Rep. 7 2017 2908 28588252 PMC5460171
  21. Li H. Handsaker B. Wysoker A. Fennell T. Ruan J. Homer N. Marth G. Abecasis G. Durbin R. 1000 Genome Project Data Processing Subgroup, The Sequence Alignment/Map format and SAMtools Bioinforma. Oxf. Engl. 25 2009 2078 2209 PMC2723002 19505943
  22. Li F. Palecek S.P. EAP1, a Candida albicans gene involved in binding human epithelial cells Eukaryot. Cell 2 2003 1266 1273 14665461 PMC326646
  23. Lipke P.N. Klotz S.A. Dufrene Y.F. Jackson D.N. Garcia-Sherman M.C. Amyloid-Like beta-Aggregates as Force-Sensitive Switches in Fungal Biofilms and Infections Microbiol. Mol. Biol. Rev. 82 2018 PMC5813885 29187516
  24. Lipke P.N. Mathelié-Guinlet M. Viljoen A. Dufrêne Y.F. A New Function for Amyloid-Like Interactions: Cross-Beta Aggregates of Adhesins form Cell-to-Cell Bonds Pathogens 10 8 2021 1013 34451476 PMC8398270
  25. Lockhart S.R. Etienne K.A. Vallabhaneni S. Farooqi J. Chowdhary A. Govender N.P. Colombo A.L. Calvo B. Cuomo C.A. Desjardins C.A. Berkow E.L. Castanheira M. Magobo R.E. Jabeen K. Asghar R.J. Meis J.F. Jackson B. Chiller T. Litvintseva A.P. Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses Clin. Infect. Dis. 64 2017 134 140 27988485 PMC5215215
  26. Lohse M.B. Johnson A.D. Temporal anatomy of an epigenetic switch in cell programming: the white-opaque transition of C. albicans Mol. Microbiol. 78 2010 331 343 20735781 PMC3057202
  27. McCreath K.J. Specht C.A. Robbins P.W. Molecular cloning and characterization of chitinase genes from Candida albicans PNAS 92 1995 2544 2548 7708682 PMC42254
  28. McKenna A. Hanna M. Banks E. Sivachenko A. Cibulskis K. Kernytsky A. Garimella K. Altshuler D. Gabriel S. Daly M. DePristo M.A. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data Genome Res. 20 9 2010 1297 1303 20644199 PMC2928508
  29. Mota S. Alves R. Carneiro C. Silva S. Brown A.J. Istel F. Kuchler K. Sampaio P. Casal M. Henriques M. Paiva S. Candida glabrata susceptibility to antifungals and phagocytosis is modulated by acetate Front. Microbiol. 6 2015 919 26388859 PMC4560035
  30. Mukaremera L. Lee K.K. Mora-Montes H.M. Gow N.A.R. Candida albicans Yeast, Pseudohyphal, and Hyphal Morphogenesis Differentially Affects Immune Recognition Front. Immunol. 8 2017 629 28638380 PMC5461353
  31. Munoz J.F. Gade L. Chow N.A. Loparev V.N. Juieng P. Berkow E.L. Farrer R.A. Litvintseva A.P. Cuomo C.A. Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species Nat. Commun. 9 2018 5346 30559369 PMC6297351
  32. Munoz J.F. Welsh R.M. Shea T. Batra D. Gade L. Howard D. Rowe L.A. Meis J.F. Litvintseva A.P. Cuomo C.A. Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris Genetics 218 2021 PMC8128392 33769478
  33. Nguyen V.Q. Sil A. Temperature-induced switch to the pathogenic yeast form of Histoplasma capsulatum requires Ryp1, a conserved transcriptional regulator PNAS 105 2008 4880 4885 18339808 PMC2290814
  34. Nobile C.J. Mitchell A.P. Regulation of cell-surface genes and biofilm formation by the C. albicans transcription factor Bcr1p Curr. Biol. 15 2005 1150 1155 15964282
  35. Pelletier C. Brown A.J.P. Lorenz A. Candida auris undergoes adhesin-dependent and -independent cellular aggregation Biorxiv. this 2023 10.1101/2023.04.21.537817 PMC10957086 38466738 · DOI
  36. Petersen T.N. Brunak S. von Heijne G. Nielsen H. SignalP 4.0: discriminating signal peptides from transmembrane regions Nat. Methods 8 2011 785 786 21959131
  37. Pierantoni D. Corte L. Casadevall A. Robert V. Cardinali G. Tascini C. How does temperature trigger biofilm adhesion and growth in Candida albicans and two non-Candida albicans Candida species? Mycoses 64 2021 1412 1421 33894074 PMC8597170
  38. Pierleoni A. Martelli P.L. Casadio R. PredGPI: a GPI-anchor predictor BMC Bioinf. 9 2008 392 PMC2571997 18811934
  39. Ramsook C.B. Tan C. Garcia M.C. Fung R. Soybelman G. Henry R. Litewka A. O'Meally S. Otoo H.N. Khalaf R.A. Dranginis A.M. Gaur N.K. Klotz S.A. Rauceo J.M. Jue C.K. Lipke P.N. Yeast cell adhesion molecules have functional amyloid-forming sequences Eukaryot. Cell 9 2010 393 404 20038605 PMC2837979
  40. Rauceo J.M. Gaur N.K. Lee K.G. Edwards J.E. Klotz S.A. Lipke P.N. Global cell surface conformational shift mediated by a Candida albicans adhesin Infect. Immun. 72 2004 4948 4955 15321986 PMC517415
  41. Rhodes J. Abdolrasouli A. Farrer R.A. Cuomo C.A. Aanensen D.M. Armstrong-James D. Fisher M.C. Schelenz S. Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris Emerg. Microb. Infect. 7 2018 43 PMC5874254 29593275
  42. Rosenberg M. Greenstein B.-N.-R. Barki M. Goldberg S. Hydrophobic Interactions as a Basis for Interfering with Microbial Adhesion Kahane I. Ofek I. Towards Anti-Adhesion Therapy for Microbial Diseases 1996 Boston MA Springer Nature
  43. San-Blas G. Travassos L.R. Fries B.C. Goldman D.L. Casadevall A. Carmona A.K. Barros T.F. Puccia R. Hostetter M.K. Shanks S.G. Copping V.M. Knox Y. Gow N.A. Fungal morphogenesis and virulence Med. Mycol. 38 Suppl 1 2000 79 86 11204167
  44. Satoh K. Makimura K. Hasumi Y. Nishiyama Y. Uchida K. Yamaguchi H. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital Microbiol. Immunol. 53 2009 41 44 19161556
  45. Schweizer A. Rupp S. Taylor B.N. Rollinghoff M. Schroppel K. The TEA/ATTS transcription factor CaTec1p regulates hyphal development and virulence in Candida albicans Mol. Microbiol. 38 2000 435 445 11069668
  46. Shapiro R.S. Cowen L.E. Thermal Control of Microbial Development and Virulence: Molecular Mechanisms of Microbial Temperature Sensing MBio 3 5 2012 PMC3518907 23033469
  47. Sherry L. Ramage G. Kean R. Borman A. Johnson E.M. Richardson M.D. Rautemaa-Richardson R. Biofilm-Forming Capability of Highly Virulent, Multidrug-Resistant Candida auris Emerg. Infect. Dis. 23 2017 328 331 28098553 PMC5324806
  48. Short B. Brown J. Delaney C. Sherry L. Williams C. Ramage G. Kean R. Candida auris exhibits resilient biofilm characteristics in vitro: implications for environmental persistence J. Hosp. Infect. 103 2019 92 96 31226270
  49. Silva-Dias A. Miranda I.M. Rocha R. Monteiro-Soares M. Salvador A. Rodrigues A.G. Pina-Vaz C. A novel flow cytometric protocol for assessment of yeast cell adhesion Cytometry A 81 2012 265 270 22076919
  50. Silva-Dias A. Miranda I.M. Branco J. Monteiro-Soares M. Pina-Vaz C. Rodrigues A.G. Adhesion, biofilm formation, cell surface hydrophobicity, and antifungal planktonic susceptibility: relationship among Candida spp Front. Microbiol. 6 2015 205 25814989 PMC4357307
  51. Soares E.V. Flocculation in Saccharomyces cerevisiae: a review J. Appl. Microbiol. 110 2011 1 18 21114594
  52. Sonneborn A. Tebarth B. Ernst J.F. Control of white-opaque phenotypic switching in Candida albicans by the Efg1p morphogenetic regulator Infect. Immun. 67 1999 4655 4660 10456912 PMC96790
  53. Stamatakis A. RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models Bioinformatics 22 2006 2688 2690 16928733
  54. Sudbery P. Gow N. Berman J. The distinct morphogenic states of Candida albicans Trends Microbiol. 12 2004 317 324 15223059
  55. Szekely A. Borman A.M. Johnson E.M. Land G.A. Candida auris Isolates of the Southern Asian and South African Lineages Exhibit Different Phenotypic and Antifungal Susceptibility Profiles In Vitro J. Clin. Microbiol. 57 5 2019 PMC6498034 30867237
  56. Touhami A. Hoffmann B. Vasella A. Denis F.A. Dufrene Y.F. Aggregation of yeast cells: direct measurement of discrete lectin-carbohydrate interactions Microbiology (Reading) 149 2003 2873 3288 14523119
  57. Umeyama T. Kaneko A. Watanabe H. Hirai A. Uehara Y. Niimi M. Azuma M. Deletion of the CaBIG1 gene reduces beta-1,6-glucan synthesis, filamentation, adhesion, and virulence in Candida albicans Infect. Immun. 74 2006 2373 2381 16552067 PMC1418944
  58. Van Mulders S.E. Christianen E. Saerens S.M. Daenen L. Verbelen P.J. Willaert R. Verstrepen K.J. Delvaux F.R. Phenotypic diversity of Flo protein family-mediated adhesion in Saccharomyces cerevisiae FEMS Yeast Res. 9 2009 178 190 19087208
  59. Vendele I. Willment J.A. Silva L.M. Palma A.S. Chai W. Liu Y. Feizi T. Spyrou M. Stappers M.H.T. Brown G.D. Gow N.A.R. Hohl T.M. Mannan detecting C-type lectin receptor probes recognise immune epitopes with diverse chemical, spatial and phylogenetic heterogeneity in fungal cell walls PLoS Pathog. 16 1 2020 e1007927 31999794 PMC7012452
  60. Wilcocks K.L. Smart K.A. The importance of surface charge and hydrophobicity for the flocculation of chain-forming brewing yeast strains and resistance of these parameters to acid washing FEMS Microbiol. Lett. 134 1995 293 297 8586282
  61. Yang Z. PAML 4: phylogenetic analysis by maximum likelihood Mol. Biol. Evol. 24 2007 1586 1591 17483113
  62. Yang Z. Nielsen R. Estimating synonymous and nonsynonymous substitution rates under realistic evolutionary models Mol. Biol. Evol. 17 2000 32 43 10666704
  63. Yue H. Bing J. Zheng Q. Zhang Y. Hu T. Du H. Wang H. Huang G. Filamentation in Candida auris, an emerging fungal pathogen of humans: passage through the mammalian body induces a heritable phenotypic switch Emerg. Microb. Infect. 7 1 2018 1 13 PMC6258701 30482894
  64. Zhao X. Oh S.H. Yeater K.M. Hoyer L.L. Analysis of the Candida albicans Als2p and Als4p adhesins suggests the potential for compensatory function within the Als family Microbiology (Reading) 151 2005 1619 1630 15870470 PMC2583123

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Authors
Malavia-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.
Affiliations
  • University of Exeter (GB)
  • City University of New York (US)
Corresponding author
Gow, Neil A.R.
ORCID
Venue
The Cell Surface
Publisher
Elsevier BV
Published
2023-12
Volume
10
Pages
100110
ISSN
2468-2330 (ISSN-L)
DOI
10.1016/j.tcsw.2023.100110
PMC
PMC10407437
OpenAlex
W4385216504
Cited by
29
References
10
Citations by year
2026: 11 · 2025: 6 · 2024: 10 · 2023: 2
FWCI
6.00
Type
journal article
Language
en
Open access
Licence
Locations
  • The Cell Surface (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-sa)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Medical Research Council (225303/Z/22/Z, MR/N006364/2, MR/M026663/2)
  • Wellcome Trust (101873, 215599, 200208, 224323)
  • NIHR Imperial Biomedical Research Centre
  • National Institute for Health and Care Research
  • NIHR Leicester Biomedical Research Centre
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 aggregation, thioflavin T, extracellular matrix synthesis, chitin synthase, GPI-anchored proteins, cell surface hydrophobicity, surface charge, temperature dependence, strain differences, virulence, multidrug resistance, cell isolation

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