{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:33:03Z","timestamp":1760059983764,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Drug resistance in Candida may result in either a fitness cost or a fitness advantage. Candida auris, whose intrinsic drug resistance remains unclear, has emerged as a significant human pathogen. We aimed to investigate whether Candida fitness, including early interaction with the host innate immune system, depends on the antifungal susceptibility phenotype and putative-associated resistance mutations. We compared interleukin-1\u03b2, interleukin-6, interleukin-8, and tumor necrosis factor \u03b1 production by human colorectal adenocarcinoma cells stimulated by fluconazole-susceptible and fluconazole-resistant strains of Candida albicans, C. parapsilosis, C. tropicalis, and C. glabrata, as well as fluconazole-resistant C. auris strains. Sensitive Candida strains induced lower cytokine levels compared with C. auris and resistant strains, except for TNF a. Resistant strains induced cytokine levels like C. auris, except for higher IL-1\u03b2 and lower TNF-\u03b1. Susceptible strains exhibited cytokine profiles distinct from those of resistant strains. C. auris induced cytokine levels comparable to resistant strains but displayed profiles resembling those of susceptible strains. This study highlights the relationship among antifungal susceptibility, fungal fitness and host early immunity. C. auris behavior appears to be between fluconazole-sensitive and fluconazole-resistant strains. Understanding these dynamics may enhance the knowledge of the survival and reproduction of resistant Candida and the epidemiology of fungal infections.<\/jats:p>","DOI":"10.3390\/microorganisms13081777","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:55:37Z","timestamp":1753872937000},"page":"1777","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of Drug Resistance in Candida Inflammation and Fitness"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6517-0321","authenticated-orcid":false,"given":"Gabriella","family":"Piatti","sequence":"first","affiliation":[{"name":"Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16126 Genoa, Italy"},{"name":"Unit of Microbiology, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Vitale","sequence":"additional","affiliation":[{"name":"Unit of Microbiology, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Maria","family":"Schito","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16126 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanna","family":"Penco","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DiMeS), University of Genoa, 16126 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1623-1116","authenticated-orcid":false,"given":"Daniele","family":"Saverino","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DiMeS), University of Genoa, 16126 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"165rv113","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden killers: Human fungal infections","volume":"4","author":"Brown","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3000605221131122","DOI":"10.1177\/03000605221131122","article-title":"Characteristics, risk factors, and outcomes of bloodstream Candida infections in the intensive care unit: A retrospective cohort study","volume":"51","author":"Hohmann","year":"2023","journal-title":"J. Int. Med. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1612661","DOI":"10.1080\/21688370.2019.1612661","article-title":"Candida albicans interactions with the host: Crossing the intestinal epithelial barrier","volume":"7","author":"Basmaciyan","year":"2019","journal-title":"Tissue Barriers."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"a019687","DOI":"10.1101\/cshperspect.a019687","article-title":"Host cell invasion by medically important fungi","volume":"5","author":"Sheppard","year":"2014","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1080\/21505594.2016.1138201","article-title":"Innate immune cell response upon Candida albicans infection","volume":"7","author":"Qin","year":"2016","journal-title":"Virulence"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e0051623","DOI":"10.1128\/iai.00516-23","article-title":"Controlling Candida: Immune regulation of commensal fungi in the gut","volume":"92","author":"Jensen","year":"2024","journal-title":"Infect. Immun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00281-014-0462-4","article-title":"Pattern recognition receptors in antifungal immunity","volume":"37","author":"Plato","year":"2015","journal-title":"Semin. Immunopathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nrmicro1815","article-title":"An integrated model of the recognition of Candida albicans by the innate immune system","volume":"6","author":"Netea","year":"2008","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1111\/mpp.12127","article-title":"Ergosterol, an orphan fungal microbe-associated molecular pattern (MAMP)","volume":"15","author":"Klemptner","year":"2014","journal-title":"Mol. Plant Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1093\/jxb\/erq047","article-title":"Ergosterol triggers characteristic elicitation steps in Beta vulgaris leaf tissues","volume":"61","author":"Rossard","year":"2010","journal-title":"J. Exper. Botany."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kazan, K., and Gardiner, D.M. (2017). Targeting pathogen sterols: Defence and counterdefence?. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006297"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e383","DOI":"10.1016\/S1473-3099(17)30316-X","article-title":"The global problem of antifungal resistence: Prevalence, mechanisms, and management","volume":"12","author":"Perlin","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.mib.2018.02.005","article-title":"Antifungal drug resistance: Evolution, mechanisms and impact","volume":"45","author":"Revie","year":"2018","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/infdis\/jir355","article-title":"At what cost echinocandin resistance?","volume":"204","author":"Clancy","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_15","first-page":"753","article-title":"Molecular evolution of antifungal drug resistance","volume":"71","author":"Robbins","year":"2017","journal-title":"Microbiol. Spectr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1128\/AAC.05720-11","article-title":"Azole resistance by loss of function of the sterol \u03945,6-desaturase gene (ERG3) in Candida albicans does not necessarily decrease virulence","volume":"56","author":"Coste","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1128\/EC.00215-12","article-title":"Gain-of-function mutations in UPC2 are a frequent cause of ERG11 upregulation in azole-resistant clinical isolates of Candida albicans","volume":"11","author":"Flowers","year":"2012","journal-title":"Eukaryot. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1128\/CMR.00017-07","article-title":"Clinical significance of human immunodeficiency virus type 1 replication fitness","volume":"20","author":"Dykes","year":"2007","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Goig, G.A., Windels, E.M., Loiseau, C., Stritt, C., Biru, L., Borrell, S., Brites, D., and Gagneux, S. (2025). Ecology, global diversity and evolutionary mechanisms in the Mycobacterium tuberculosis complex. Nat. Rev. Microbiol., epub ahead of print.","DOI":"10.1038\/s41579-025-01159-w"},{"key":"ref_20","first-page":"1456","article-title":"Infectiousness, reproductive fitness and evolution of drug-resistant Mycobacterium tuberculosis","volume":"13","author":"Borrell","year":"2009","journal-title":"Int. J. Tuberc. Lung. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1128\/JB.183.10.2971-2978.2001","article-title":"Divergence in fitness and evolution of drug resistance in experimental populations of Candida albicans","volume":"183","author":"Cowen","year":"2001","journal-title":"J. Bacteriol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nrmicro1179","article-title":"Evolution of antifungal-drug resistance: Mechanisms and pathogen fitness","volume":"3","author":"Anderson","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1093\/infdis\/jir351","article-title":"Fitness and virulence costs of Candida albicans FKS1 Hot Spot Mutations associated with echinocandin resistance","volume":"204","author":"Lewis","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_24","unstructured":"CLSI (2022). Performance Standards for Antifungal Susceptibility Testing of Yeasts, Clinical and Laboratory Standards Institute. [3rd ed.]. CLSI supplement M27M44S."},{"key":"ref_25","unstructured":"NCCLS (2002). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, NCCLS. [2nd ed.]. Approved standard, NCCLS document M27-A2."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"783","DOI":"10.2147\/IDR.S197531","article-title":"Differential recognition of Candida tropicalis, Candida guilliermondii, Candida krusei, and Candida auris by human innate immune cells","volume":"12","author":"Franco","year":"2019","journal-title":"Infect. Drug Resist."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Estrada-Mata, E., Navarro-Arias, M.J., P\u00e9rez-Garc\u00eda, L.A., Mellado-Mojica, E., L\u00f3pez, M.G., Csonka, K., Gacser, A., and Mora-Montes, H.M. (2016). Members of the Candida parapsilosis complex and Candida albicans are differentially recognized by human peripheral blood mononuclear cells. Front. Microbiol., 6.","DOI":"10.3389\/fmicb.2015.01527"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wachtler, B., Citiulo, F., Jablonowski, N., F\u00f6rster, S., Dalle, F., Schaller, M., Wilson, D., and Hube, B. (2012). Candida albicans-epithelial interactions: Dissecting the roles of active penetration, induced endocytosis and host factors on the infection process. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0036952"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.micinf.2016.05.005","article-title":"TLR2 modulates gut colonization and dissemination of Candida albicans in a murine model","volume":"18","author":"Prieto","year":"2016","journal-title":"Microbes Infect."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Singh-Babak, S.D., Babak, T., Diezmann, S., Hill, J.A., Xie, J.L., Chen, Y.L., Poutanen, S.M., Rennie, R.P., Heitman, J., and Cowen, L.E. (2012). Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002718"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1128\/JB.182.6.1515-1522.2000","article-title":"Evolution of drug resistance in experimental population of Candida albicans","volume":"182","author":"Cowen","year":"2000","journal-title":"J. Bacteriol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Vincent, B.M., Lancaster, A.K., Scherz-Shouval, R., Whitesell, L., and Lindquist, S. (2013). Fitness trade-offs restrict the evolution of resistance to amphotericin B. PLoS Biol., 11.","DOI":"10.1371\/journal.pbio.1001692"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.mib.2006.07.002","article-title":"The biological cost of mutational antibiotoc resistance: Any practical conclusion?","volume":"9","author":"Andersson","year":"2006","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Selmecki, A.M., Dulmage, K., Cowen, L.E., Anderson, J.B., and Berman, J. (2009). Acquisition of aneuploidy provides increased fitness during the evolution of antifungal resistance. PLoS Genet., 5.","DOI":"10.1371\/journal.pgen.1000705"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1179\/1973947813Y.0000000100","article-title":"Antifungal resistance does not necessarily affect Candida glabrata fitness","volume":"26","author":"Borghi","year":"2014","journal-title":"J. Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nrmicro2711","article-title":"Candida albicans morphogenesis and host defence: Discriminating invasion from colonization","volume":"10","author":"Gow","year":"2013","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.micres.2017.02.002","article-title":"Candida albicans infection and intestinal immunity","volume":"198","author":"Tong","year":"2017","journal-title":"Microbiol. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"891.e5","DOI":"10.1016\/j.cmi.2016.07.025","article-title":"Discontinuation of echinocandin and azole treatments led to the disappearance of an FKS alteration but not azole resistance during clonal Candida glabrata persistent candidaemia","volume":"22","author":"Imbert","year":"2016","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1016\/j.micinf.2005.12.031","article-title":"Fitness of antimicrobial-resistant Campylobacter and Salmonella","volume":"8","author":"Zang","year":"2006","journal-title":"Microbes Infect."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"102091","DOI":"10.1016\/j.tube.2021.102091","article-title":"Drug resistance, fitness and compensatory mutations in Mycobacterium tuberculosis","volume":"129","author":"Guo","year":"2021","journal-title":"Tuberculosis"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Du, H., Bing, J., Hu, T., Ennis, C.L., Nobile, C.J., and Huang, G. (2020). Candida auris: Epidemiology, biology, antifungal resistance, and virulence. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008921"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.nmni.2016.07.003","article-title":"Whole genome sequencing of emerging multidrug resistant Candida auris isolates in India demonstrates low genetic variation","volume":"13","author":"Sharma","year":"2016","journal-title":"New Microbes New Infect."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Chatterjee, S., Alampalli, S.V., Nageshan, R.K., Chettiar, S.T., Joshi, S., and Tatu, U.S. (2015). Draft genome of a commonly misdiagnosed multidrug resistant pathogen Candida auris. BMC Genom., 16.","DOI":"10.1186\/s12864-015-1863-z"},{"key":"ref_44","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":"Lockhart","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"a019752","DOI":"10.1101\/cshperspect.a019752","article-title":"Mechanisms of antifungal drug resistance","volume":"5","author":"Cowen","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/8\/1777\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:18:44Z","timestamp":1760033924000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/8\/1777"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["microorganisms13081777"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms13081777","relation":{},"ISSN":["2076-2607"],"issn-type":[{"type":"electronic","value":"2076-2607"}],"subject":[],"published":{"date-parts":[[2025,7,30]]}}}