{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T11:46:14Z","timestamp":1793015174208,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012076","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T00:00:00Z","timestamp":1710979200000}}],"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T00:00:00Z","timestamp":1710115200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019690","name":"Medical Research Council Centre for Medical Mycology","doi-asserted-by":"publisher","award":["MR\/P501955\/1"],"award-info":[{"award-number":["MR\/P501955\/1"]}],"id":[{"id":"10.13039\/501100019690","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019690","name":"Medical Research Council Centre for Medical Mycology","doi-asserted-by":"publisher","award":["MR\/N006364\/2"],"award-info":[{"award-number":["MR\/N006364\/2"]}],"id":[{"id":"10.13039\/501100019690","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    <jats:italic>Candida auris<\/jats:italic>\n                    is a fungal pathogen of humans responsible for nosocomial infections with high mortality rates. High levels of resistance to antifungal drugs and environmental persistence mean these infections are difficult to treat and eradicate from a healthcare setting. Understanding the life cycle and the genetics of this fungus underpinning clinically relevant traits, such as antifungal resistance and virulence, is of the utmost importance to develop novel treatments and therapies. Epidemiological and genomic studies have identified five geographical clades (I-V), which display phenotypic and genomic differences. Aggregation of cells, a phenotype primarily of clade III strains, has been linked to reduced virulence in some infection models. The aggregation phenotype has thus been associated with conferring an advantage for (skin) colonisation rather than for systemic infection. However, strains with different clade affiliations were compared to infer the effects of different morphologies on virulence. This makes it difficult to distinguish morphology-dependent causes from clade-specific or even strain-specific genetic factors. Here, we identify two different types of aggregation: one induced by antifungal treatment which is a result of a cell separation defect; and a second which is controlled by growth conditions and only occurs in strains with the ability to aggregate. The latter aggregation type depends on an ALS-family adhesin which is differentially expressed during aggregation in an aggregative\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>auris<\/jats:italic>\n                    strain. Finally, we demonstrate that macrophages cannot clear aggregates, suggesting that aggregation might after all provide a benefit during systemic infection and could facilitate long-term persistence in the host.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012076","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T13:41:39Z","timestamp":1710164499000},"page":"e1012076","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":46,"title":["Candida auris undergoes adhesin-dependent and -independent cellular aggregation"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5581-3442","authenticated-orcid":true,"given":"Chloe","family":"Pelletier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakinah","family":"Alsayegh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1406-4251","authenticated-orcid":true,"given":"Alistair J. P.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1925-3713","authenticated-orcid":true,"given":"Alexander","family":"Lorenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,3,11]]},"reference":[{"key":"ppat.1012076.ref001","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1348-0421.2008.00083.x","article-title":"Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital","volume":"53","author":"K Satoh","year":"2009","journal-title":"Microbiol Immunol"},{"key":"ppat.1012076.ref002","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.mib.2019.05.008","article-title":"Global epidemiology of emerging Candida auris","volume":"52","author":"J Rhodes","year":"2019","journal-title":"Curr Opin Microbiol"},{"key":"ppat.1012076.ref003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/mmy\/myy054","article-title":"Candida auris: The recent emergence of a multidrug-resistant fungal pathogen","volume":"57","author":"K Forsberg","year":"2019","journal-title":"Med Mycol"},{"key":"ppat.1012076.ref004","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1007\/s40475-023-00293-w","article-title":"A fungus for our time: Candida auris emerges into the anthropocene","volume":"10","author":"JC Stephenson","year":"2023","journal-title":"Curr Trop Med Rep"},{"key":"ppat.1012076.ref005","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1093\/cid\/ciw691","article-title":"Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses","volume":"64","author":"SR Lockhart","year":"2017","journal-title":"Clinical Infectious Diseases"},{"key":"ppat.1012076.ref006","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.3201\/eid2509.190686","article-title":"Potential fifth clade of Candida auris, Iran, 2018","volume":"25","author":"NA Chow","year":"2019","journal-title":"Emerg Infect Dis"},{"key":"ppat.1012076.ref007","doi-asserted-by":"crossref","first-page":"280","DOI":"10.3390\/jof7040280","article-title":"Candidemia among Iranian patients with severe COVID-19 admitted to ICUs","volume":"7","author":"A Arastehfar","year":"2021","journal-title":"Journal of Fungi"},{"key":"ppat.1012076.ref008","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nrmicro.2016.157","article-title":"Candida albicans cell-type switching and functional plasticity in the mammalian host","volume":"15","author":"SM Noble","year":"2017","journal-title":"Nat Rev Microbiol"},{"key":"ppat.1012076.ref009","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.3390\/pathogens10111463","article-title":"On and Off: epigenetic regulation of C. albicans morphological switches.","volume":"10","author":"E Iracane","year":"2021","journal-title":"Pathogens"},{"key":"ppat.1012076.ref010","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1111\/j.1462-5822.2005.00616.x","article-title":"Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence","volume":"7","author":"CA Kumamoto","year":"2005","journal-title":"Cell Microbiol"},{"key":"ppat.1012076.ref011","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/nature17625","article-title":"Candidalysin is a fungal peptide toxin critical for mucosal infection","volume":"532","author":"DL Moyes","year":"2016","journal-title":"Nature"},{"key":"ppat.1012076.ref012","first-page":"188","article-title":"Filamentation in Candida auris, an emerging fungal pathogen of humans: passage through the mammalian body induces a heritable phenotypic switch","volume":"7","author":"H Yue","year":"2018","journal-title":"Emerg Microbes Infect"},{"key":"ppat.1012076.ref013","doi-asserted-by":"crossref","first-page":"e00151","DOI":"10.1128\/mSphere.00151-20","article-title":"Pseudohyphal growth of the emerging pathogen Candida auris is triggered by genotoxic stress through the S phase checkpoint.","volume":"5","author":"G Bravo Ruiz","year":"2020","journal-title":"mSphere."},{"key":"ppat.1012076.ref014","doi-asserted-by":"crossref","first-page":"e00189","DOI":"10.1128\/mSphere.00189-16","article-title":"Comparative pathogenicity of United Kingdom isolates of the emerging pathogen Candida auris and other key pathogenic Candida species.","volume":"1","author":"AM Borman","year":"2016","journal-title":"mSphere"},{"key":"ppat.1012076.ref015","doi-asserted-by":"crossref","first-page":"7197","DOI":"10.1038\/s41467-021-27545-5","article-title":"Forward and reverse genetic dissection of morphogenesis identifies filament-competent Candida auris strains.","volume":"12","author":"DJ Santana","year":"2021","journal-title":"Nat Commun."},{"key":"ppat.1012076.ref016","doi-asserted-by":"crossref","first-page":"5264","DOI":"10.1016\/j.csbj.2021.09.007","article-title":"Transcriptional and translational landscape of Candida auris in response to caspofungin.","volume":"19","author":"D Zamith-Miranda","year":"2021","journal-title":"Comput Struct Biotechnol J"},{"key":"ppat.1012076.ref017","doi-asserted-by":"crossref","first-page":"e02055","DOI":"10.1128\/JCM.02055-18","article-title":"Candida auris isolates of the Southern Asian and South African lineages exhibit different phenotypic and antifungal susceptibility profiles in vitro","volume":"57","author":"A Szekely","year":"2019","journal-title":"J Clin Microbiol"},{"key":"ppat.1012076.ref018","doi-asserted-by":"crossref","first-page":"e1011239","DOI":"10.1371\/journal.ppat.1011239","article-title":"Clinical isolates of Candida auris with enhanced adherence and biofilm formation due to genomic amplification of ALS4.","volume":"19","author":"J Bing","year":"2023","journal-title":"PLoS Pathog"},{"key":"ppat.1012076.ref019","first-page":"1160","article-title":"Comparison of in vivo pathogenicity of four Candida auris clades in a neutropenic bloodstream infection murine model","volume":"9","author":"L Forg\u00e1cs","year":"2020","journal-title":"Emerg Infect Dis"},{"key":"ppat.1012076.ref020","doi-asserted-by":"crossref","first-page":"126621","DOI":"10.1016\/j.micres.2020.126621","article-title":"What do we know about the biology of the emerging fungal pathogen of humans Candida auris?","volume":"242","author":"G Bravo Ruiz","year":"2021","journal-title":"Microbiol Res"},{"key":"ppat.1012076.ref021","doi-asserted-by":"crossref","first-page":"100110","DOI":"10.1016\/j.tcsw.2023.100110","article-title":"Strain and temperature dependent aggregation of Candida auris is attenuated by inhibition of surface amyloid proteins","volume":"10","author":"D Malavia-Jones","year":"2023","journal-title":"The Cell Surface"},{"key":"ppat.1012076.ref022","doi-asserted-by":"crossref","first-page":"382","DOI":"10.3390\/tropicalmed8080382","article-title":"Cell aggregation capability of clinical isolates from Candida auris and Candida haemulonii species complex","volume":"8","author":"LS Ramos","year":"2023","journal-title":"Trop Med Infect Dis"},{"key":"ppat.1012076.ref023","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jhin.2019.06.006","article-title":"Candida auris exhibits resilient biofilm characteristics in vitro: implications for environmental persistence","volume":"103","author":"B Short","year":"2019","journal-title":"Journal of Hospital Infection"},{"key":"ppat.1012076.ref024","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1111\/myc.12947","article-title":"Biofilm formation by Candida auris isolated from colonising sites and candidemia cases.","volume":"62","author":"R Singh","year":"2019","journal-title":"Mycoses."},{"key":"ppat.1012076.ref025","doi-asserted-by":"crossref","DOI":"10.1093\/femspd\/ftaa067","article-title":"The Galleria mellonella infection model as a system to investigate the virulence of Candida auris strains","volume":"78","author":"D Romera","year":"2020","journal-title":"Pathog Dis."},{"key":"ppat.1012076.ref026","article-title":"Rapamycin and Torin2 inhibit Candida auris TOR: Insights through growth profiling, docking, and MD simulations","author":"B Biswas","year":"2022","journal-title":"J Biomol Struct Dyn"},{"key":"ppat.1012076.ref027","doi-asserted-by":"crossref","first-page":"280","DOI":"10.3389\/fmicb.2016.00280","article-title":"Candida albicans Agglutinin-like sequence (Als) family vignettes: a review of Als protein structure and function.","volume":"7","author":"LL Hoyer","year":"2016","journal-title":"Front Microbiol"},{"key":"ppat.1012076.ref028","doi-asserted-by":"crossref","first-page":"5346","DOI":"10.1038\/s41467-018-07779-6","article-title":"Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species.","volume":"9","author":"JF Mu\u00f1oz","year":"2018","journal-title":"Nat Commun"},{"key":"ppat.1012076.ref029","doi-asserted-by":"crossref","DOI":"10.1093\/genetics\/iyab029","article-title":"Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris","volume":"218","author":"JF Mu\u00f1oz","year":"2021","journal-title":"Genetics"},{"key":"ppat.1012076.ref030","doi-asserted-by":"crossref","first-page":"e1007460","DOI":"10.1371\/journal.ppat.1007460","article-title":"The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection","volume":"15","author":"S Singh","year":"2019","journal-title":"PLoS Pathog"},{"key":"ppat.1012076.ref031","doi-asserted-by":"crossref","DOI":"10.1093\/genetics\/iyad024","article-title":"Parallel expansion and divergence of an adhesin family in pathogenic yeasts","volume":"223","author":"RA Smoak","year":"2023","journal-title":"Genetics"},{"key":"ppat.1012076.ref032","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1126\/science.adf8972","article-title":"A Candida auris\u2013specific adhesin, Scf1, governs surface association, colonization, and virulence","volume":"381","author":"DJ Santana","year":"2023","journal-title":"Science."},{"key":"ppat.1012076.ref033","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1128\/EC.00279-10","article-title":"Candida albicans Als3, a multifunctional adhesin and invasin","volume":"10","author":"Y Liu","year":"2011","journal-title":"Eukaryot Cell"},{"key":"ppat.1012076.ref034","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3390\/jof4040119","article-title":"Adhesins of yeasts: protein structure and interactions","volume":"4","author":"R. Willaert","year":"2018","journal-title":"Journal of Fungi"},{"key":"ppat.1012076.ref035","first-page":"e00279","article-title":"A Zinc Cluster transcription factor contributes to the intrinsic fluconazole resistance of Candida auris.","volume":"5","author":"E-M Mayr","year":"2020","journal-title":"mSphere"},{"key":"ppat.1012076.ref036","doi-asserted-by":"crossref","DOI":"10.1128\/Spectrum.00013-21","article-title":"Characterization of the differential pathogenicity of Candida auris in a Galleria mellonella infection model.","volume":"9","author":"V Garcia-Bustos","year":"2021","journal-title":"Microbiol Spectr"},{"key":"ppat.1012076.ref037","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1111\/j.1462-5822.2012.01813.x","article-title":"Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen","volume":"14","author":"V. Ene I","year":"2012","journal-title":"Cell Microbiol"},{"key":"ppat.1012076.ref038","doi-asserted-by":"crossref","first-page":"11704","DOI":"10.1038\/ncomms11704","article-title":"Hsf1 and Hsp90 orchestrate temperature-dependent global transcriptional remodelling and chromatin architecture in Candida albicans.","volume":"7","author":"MD Leach","year":"2016","journal-title":"Nat Commun"},{"key":"ppat.1012076.ref039","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1128\/EC.05085-11","article-title":"Coevolution of morphology and virulence in Candida species","volume":"10","author":"DS Thompson","year":"2011","journal-title":"Eukaryot Cell"},{"key":"ppat.1012076.ref040","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.tim.2014.07.001","article-title":"Metabolism impacts upon Candida immunogenicity and pathogenicity at multiple levels","volume":"22","author":"AJP Brown","year":"2014","journal-title":"Trends Microbiol"},{"key":"ppat.1012076.ref041","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.tim.2022.01.010","article-title":"New tools for the new bug Candida auris","volume":"30","author":"A Lorenz","year":"2022","journal-title":"Trends Microbiol"},{"key":"ppat.1012076.ref042","doi-asserted-by":"crossref","first-page":"3553","DOI":"10.1038\/s41467-022-31201-x","article-title":"Innate immune responses against the fungal pathogen Candida auris.","volume":"13","author":"Y Wang","year":"2022","journal-title":"Nat Commun"},{"key":"ppat.1012076.ref043","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/978-1-0716-2417-3_15","article-title":"High-pressure freezing and transmission electron microscopy to visualize the ultrastructure of the C. auris cell wall","volume":"2517","author":"G Milne","year":"2022","journal-title":"Methods in Molecular Biology"},{"key":"ppat.1012076.ref044","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis.","volume":"9","author":"J Schindelin","year":"2012","journal-title":"Nat Methods"},{"key":"ppat.1012076.ref045","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nmeth1005-731","article-title":"The External RNA Controls ConsortiumThe External RNA Controls Consortium: a progress report.","volume":"2","year":"2005","journal-title":"Nat Methods"},{"key":"ppat.1012076.ref046","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: a fast spliced aligner with low memory requirements.","volume":"12","author":"D Kim","year":"2015","journal-title":"Nat Methods"},{"key":"ppat.1012076.ref047","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1186\/s12864-015-1863-z","article-title":"Draft genome of a commonly misdiagnosed multidrug resistant pathogen Candida auris","volume":"16","author":"S Chatterjee","year":"2015","journal-title":"BMC Genomics"},{"key":"ppat.1012076.ref048","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"H Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ppat.1012076.ref049","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Y Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ppat.1012076.ref050","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"MD Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ppat.1012076.ref051","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1186\/1471-2105-10-421","article-title":"BLAST+: architecture and applications","volume":"10","author":"C Camacho","year":"2009","journal-title":"BMC Bioinformatics"},{"key":"ppat.1012076.ref052","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/978-1-0716-2417-3_8","article-title":"Genetic transformation of Candida auris via homology-directed repair using a standard lithium acetate protocol","volume":"2517","author":"G Bravo Ruiz","year":"2022","journal-title":"Methods in Molecular Biology"},{"key":"ppat.1012076.ref053","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/yea.1813","article-title":"Transformation of Candida albicans with a synthetic hygromycin B resistance gene","volume":"27","author":"LR Basso","year":"2010","journal-title":"Yeast"},{"key":"ppat.1012076.ref054","doi-asserted-by":"crossref","first-page":"e8668","DOI":"10.1371\/journal.pone.0008668","article-title":"The identification of markers of macrophage differentiation in PMA-stimulated THP-1 cells and monocyte-derived macrophages.","volume":"5","author":"M Daigneault","year":"2010","journal-title":"PLoS One."}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1012076","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T00:00:00Z","timestamp":1710979200000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012076","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T14:01:56Z","timestamp":1711029716000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012076"}},"subtitle":[],"editor":[{"given":"Scott G.","family":"Filler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,3,11]]},"references-count":54,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1012076","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.04.21.537817","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,11]]}}}