{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:11:25Z","timestamp":1788455485071,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014Next Generation EU","award":["E53D23001460006"],"award-info":[{"award-number":["E53D23001460006"]}]},{"name":"European Union\u2014Next Generation EU","award":["1R15AI169393"],"award-info":[{"award-number":["1R15AI169393"]}]},{"name":"National Institutes of Health, USA","award":["E53D23001460006"],"award-info":[{"award-number":["E53D23001460006"]}]},{"name":"National Institutes of Health, USA","award":["1R15AI169393"],"award-info":[{"award-number":["1R15AI169393"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>The complosome controls different activities in innate immune cells and epithelial cells; however, its role in the response of VECs to Candida remains untested. In this in vitro study, we compared two clinical vaginal strains of C. albicans, namely, a Colonizing strain from a healthy woman and a strain from a patient with vulvovaginal candidiasis (VVC), for their ability to activate the complosome and release anaphylatoxins in vaginal epithelial cells (VECs). Our results show the following: (i) both strains triggered the cleavage of C3 into C3a and C3b within VECs, while infection with the Colonizing strain led to greater release of the anaphylatoxin C3a; (ii) infection with the VVC isolate led to a strong reduction in both C5 and C5a in VECs, while no increase in C5a release was observed after infection with either strain; (iii) cathepsin-family gene expression and cathepsin D activity were reduced in VECs infected with the VVC strain but not in those infected with the Colonizing strain; (iv) infection with the Colonizing strain induced a significant increase in intracellular C5aR1 while intracellular C3aR levels remained unchanged. Collectively, our data suggests the propensity of this VVC strain to inactivate the C5\/C5aR1 axis and to reduce the C3\/C3aR axis, dampening the activity of the complosome in VECs. These effects exerted by the VVC strain suggest a novel strategy of immune evasion by C. albicans and may open new perspectives for finding new therapeutic targets against vaginal fungal infections.<\/jats:p>","DOI":"10.3390\/jof11070501","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T06:01:33Z","timestamp":1751522493000},"page":"501","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Vaginal Clinical Isolates of Candida albicans Differentially Modulate Complosome Activation in Vaginal Epithelial Cells"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9448-7344","authenticated-orcid":false,"given":"Samyr","family":"Kenno","sequence":"first","affiliation":[{"name":"Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Pedretti","sequence":"additional","affiliation":[{"name":"Department of Clinical, Medical, Surgical and Health Sciences, University of Trieste, 34100 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1369-0955","authenticated-orcid":false,"given":"Luca","family":"Spaggiari","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41124 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9845-7399","authenticated-orcid":false,"given":"Andrea","family":"Ardizzoni","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manola","family":"Comar","sequence":"additional","affiliation":[{"name":"Department of Clinical, Medical, Surgical and Health Sciences, University of Trieste, 34100 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8955-7654","authenticated-orcid":false,"given":"Wilfried","family":"Posch","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medizinische Universit\u00e4t Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3223-7021","authenticated-orcid":false,"given":"Robert Treyde","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Department of Molecular and Biomedical Sciences, University of Maine, Orono, ME 04473, USA"},{"name":"Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04473, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuele","family":"Peppoloni","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5299-8197","authenticated-orcid":false,"given":"Eva","family":"Pericolini","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104471","DOI":"10.1016\/j.micpath.2020.104471","article-title":"Recurrent Vulvovaginal Candida spp. Isolates Phenotypically Express Less Virulence Traits","volume":"148","author":"Rolo","year":"2020","journal-title":"Microb. Pathog."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"d\u2019Enfert, C., Kaune, A.-K., Alaban, L.-R., Chakraborty, S., Cole, N., Delavy, M., Kosmala, D., Marsaux, B., Fr\u00f3is-Martins, R., and Morelli, M. (2021). The Impact of the Fungus-Host-Microbiota Interplay upon Candida Albicans Infections: Current Knowledge and New Perspectives. FEMS Microbiol. Rev., 45.","DOI":"10.1093\/femsre\/fuaa060"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ardizzoni, A., Wheeler, R.T., and Pericolini, E. (2021). It Takes Two to Tango: How a Dysregulation of the Innate Immunity, Coupled With Candida Virulence, Triggers VVC Onset. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.692491"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"iv28","DOI":"10.1136\/sti.2006.023168","article-title":"Vulvovaginal Candidiasis","volume":"82","author":"White","year":"2006","journal-title":"Sex. Transm. Infect."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Pericolini, E., Perito, S., Castagnoli, A., Gabrielli, E., Mencacci, A., Blasi, E., Vecchiarelli, A., and Wheeler, R.T. (2018). Epitope Unmasking in Vulvovaginal Candidiasis Is Associated with Hyphal Growth and Neutrophilic Infiltration. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0201436"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e00107-23","DOI":"10.1128\/mbio.00107-23","article-title":"A New Phenotype in Candida-Epithelial Cell Interaction Distinguishes Colonization- versus Vulvovaginal Candidiasis-Associated Strains","volume":"14","author":"Sala","year":"2023","journal-title":"MBio"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"110183","DOI":"10.1016\/j.celrep.2021.110183","article-title":"Estrogen Promotes Innate Immune Evasion of Candida Albicans through Inactivation of the Alternative Complement System","volume":"38","author":"Kumwenda","year":"2022","journal-title":"Cell Rep."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kenno, S., Speth, C., Rambach, G., Binder, U., Chatterjee, S., Caramalho, R., Haas, H., Lass-Fl\u00f6rl, C., Shaughnessy, J., and Ram, S. (2019). Candida Albicans Factor H Binding Molecule Hgt1p\u2014A Low Glucose-Induced Transmembrane Protein Is Trafficked to the Cell Wall and Impairs Phagocytosis and Killing by Human Neutrophils. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.03319"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.molimm.2017.07.010","article-title":"The Secreted Candida Albicans Protein Pra1 Disrupts Host Defense by Broadly Targeting and Blocking Complement C3 and C3 Activation Fragments","volume":"93","author":"Luo","year":"2018","journal-title":"Mol. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Harpf, V., Rambach, G., W\u00fcrzner, R., Lass-Fl\u00f6rl, C., and Speth, C. (2020). Candida and Complement: New Aspects in an Old Battle. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01471"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Heggi, M.T., Nour El-Din, H.T., Morsy, D.I., Abdelaziz, N.I., and Attia, A.S. (2024). Microbial Evasion of the Complement System: A Continuous and Evolving Story. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1281096"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"D\u00fchring, S., Germerodt, S., Skerka, C., Zipfel, P.F., Dandekar, T., and Schuster, S. (2015). Host-Pathogen Interactions between the Human Innate Immune System and Candida Albicans\u2014Understanding and Modeling Defense and Evasion Strategies. Front. Microbiol., 6.","DOI":"10.3389\/fmicb.2015.00625"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Merle, N.S., Church, S.E., Fremeaux-Bacchi, V., and Roumenina, L.T. (2015). Complement System Part I Molecular Mechanisms of Activation and Regulation. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00262"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/cei.12952","article-title":"Production of Complement Components by Cells of the Immune System","volume":"188","author":"Lubbers","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s00441-010-1034-0","article-title":"The Complement System","volume":"343","author":"Sarma","year":"2011","journal-title":"Cell Tissue Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.1016\/j.molimm.2009.04.027","article-title":"The Role of the Anaphylatoxins in Health and Disease","volume":"46","author":"Klos","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"110081","DOI":"10.1016\/j.intimp.2023.110081","article-title":"The Anaphylatoxin C5a: Structure, Function, Signaling, Physiology, Disease, and Therapeutics","volume":"118","author":"Ghosh","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/s41577-023-00926-1","article-title":"A Guide to Complement Biology, Pathology and Therapeutic Opportunity","volume":"24","author":"Mastellos","year":"2024","journal-title":"Nat. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2802","DOI":"10.1016\/j.cell.2023.04.031","article-title":"C5a-Licensed Phagocytes Drive Sterilizing Immunity during Systemic Fungal Infection","volume":"186","author":"Desai","year":"2023","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41581-023-00704-1","article-title":"Complosome\u2014The Intracellular Complement System","volume":"19","author":"West","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Xiao, F., Guo, J., Tomlinson, S., Yuan, G., and He, S. (2023). The Role of the Complosome in Health and Disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1146167"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/j.1365-3083.1990.tb03196.x","article-title":"Synthesis of C3, C5, C6, C7, C8, and C9 by Human Fibroblasts","volume":"32","author":"Garred","year":"1990","journal-title":"Scand. J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1016\/j.jaci.2021.03.038","article-title":"C5aR Inhibition of Nonimmune Cells Suppresses Inflammation and Maintains Epithelial Integrity in SARS-CoV-2\u2013Infected Primary Human Airway Epithelia","volume":"147","author":"Posch","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2250042","DOI":"10.1002\/eji.202250042","article-title":"Complement, Complosome, and Complotype: A Perspective","volume":"53","author":"Singh","year":"2023","journal-title":"Eur. J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2314627121","DOI":"10.1073\/pnas.2314627121","article-title":"Cell-Intrinsic C5a Synergizes with Dectin-1 in Macrophages to Mediate Fungal Killing","volume":"121","author":"Li","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1038\/s41375-025-02613-7","article-title":"Complosome as a New Intracellular Regulatory Network in Both Normal and Malignant Hematopoiesis","volume":"39","author":"Ratajczak","year":"2025","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eabf2489","DOI":"10.1126\/sciimmunol.abf2489","article-title":"Mitochondrial C5aR1 Activity in Macrophages Controls IL-1\u03b2 Production Underlying Sterile Inflammation","volume":"6","author":"Niyonzima","year":"2021","journal-title":"Sci. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e1424","DOI":"10.1002\/ctm2.1424","article-title":"C5-C5aR1-mediated Immune Responses during Fungal Infection: Clinical and Translational Implications","volume":"13","author":"Desai","year":"2023","journal-title":"Clin. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.mucimm.2024.05.006","article-title":"Local Complement Activation and Modulation in Mucosal Immunity","volume":"17","author":"Kulkarni","year":"2024","journal-title":"Mucosal Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kohli, A., Islam, A., Moyes, D.L., Murciano, C., Shen, C., Challacombe, S.J., and Naglik, J.R. (2014). Oral and Vaginal Epithelial Cell Lines Bind and Transfer Cell-Free Infectious HIV-1 to Permissive Cells but Are Not Productively Infected. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098077"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lafon, E., Diem, G., Witting, C., Zaderer, V., Bellmann-Weiler, R.M., Reindl, M., Bauer, A., Griesmacher, A., Fux, V., and Hoermann, G. (2021). Potent SARS-CoV-2-Specific T Cell Immunity and Low Anaphylatoxin Levels Correlate With Mild Disease Progression in COVID-19 Patients. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.684014"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/s41596-019-0128-8","article-title":"Protocol Update for Large-Scale Genome and Gene Function Analysis with the PANTHER Classification System (v.14.0)","volume":"14","author":"Mi","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: A Web Server for Functional Enrichment Analysis and Functional Annotation of Gene Lists (2021 Update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/pro.4218","article-title":"PANTHER: Making Genome-scale Phylogenetics Accessible to All","volume":"31","author":"Thomas","year":"2022","journal-title":"Protein Sci."},{"key":"ref_35","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":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2014A Python Framework to Work with High-Throughput Sequencing Data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_37","first-page":"D682","article-title":"Ensembl 2020","volume":"48","author":"Yates","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2350813","DOI":"10.1002\/eji.202350813","article-title":"Intracellular Complement and Immunometabolism: The Advantages of Compartmentalization","volume":"54","author":"King","year":"2024","journal-title":"Eur. J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12974-016-0485-y","article-title":"Complement Component C3a Plays a Critical Role in Endothelial Activation and Leukocyte Recruitment into the Brain","volume":"13","author":"Wu","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.mib.2020.05.005","article-title":"Soluble Mediators in Anti-Fungal Immunity","volume":"58","author":"Aimanianda","year":"2020","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1038\/s41564-024-01780-0","article-title":"Manipulation of Host Phagocytosis by Fungal Pathogens and Therapeutic Opportunities","volume":"9","author":"Jia","year":"2024","journal-title":"Nat. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.molimm.2020.03.008","article-title":"The Responses of the Gut Microbiota to MBL Deficiency","volume":"122","author":"Wu","year":"2020","journal-title":"Mol. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/mi.2015.100","article-title":"Role of Mannose-Binding Lectin in Intestinal Homeostasis and Fungal Elimination","volume":"9","author":"Choteau","year":"2016","journal-title":"Mucosal Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2206713","DOI":"10.1002\/advs.202206713","article-title":"Sequence Variation of Candida Albicans Sap2 Enhances Fungal Pathogenicity via Complement Evasion and Macrophage M2-Like Phenotype Induction","volume":"10","author":"Lin","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ishii, M., Beeson, G., Beeson, C., and Rohrer, B. (2021). Mitochondrial C3a Receptor Activation in Oxidatively Stressed Epithelial Cells Reduces Mitochondrial Respiration and Metabolism. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.628062"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/s41564-021-00875-2","article-title":"Candida Pathogens Induce Protective Mitochondria-Associated Type I Interferon Signalling and a Damage-Driven Response in Vaginal Epithelial Cells","volume":"6","author":"Pekmezovic","year":"2021","journal-title":"Nat. Microbiol."}],"container-title":["Journal of Fungi"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2309-608X\/11\/7\/501\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:03:46Z","timestamp":1760033026000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2309-608X\/11\/7\/501"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,3]]},"references-count":47,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["jof11070501"],"URL":"https:\/\/doi.org\/10.3390\/jof11070501","relation":{},"ISSN":["2309-608X"],"issn-type":[{"value":"2309-608X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,3]]}}}