{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:19:11Z","timestamp":1790115551228,"version":"4.0.1"},"reference-count":46,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Croatian Science Foundation research project","doi-asserted-by":"publisher","award":["IP-2020-02-8921"],"award-info":[{"award-number":["IP-2020-02-8921"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pterygium is a condition affecting the ocular surface, marked by a triangular-shaped growth of fibrotic tissue extending from the nasal conjunctiva toward the corneal center, potentially causing visual impairment. While ultraviolet (UV )light exposure is the primary risk factor for pterygium, its underlying cause remains unclear. In order to better understand the true genesis of pterygium development, we investigated pterygium tissue and compared it with healthy conjunctiva controls. Given the eye\u2019s direct environmental exposure, we analyzed the microbiota composition using metagenomic sequencing of pterygium tissue to identify microbes potentially associated with this condition. Metagenomic sequencing revealed a higher prevalence of the fungus Malassezia restricta in five pterygium samples, confirmed by in situ hybridization. The CHIT1 gene, which plays a role in antifungal defenses, displayed the highest expression in five pterygium tissue samples compared to healthy conjunctiva controls, suggesting the potential involvement of Malassezia restricta in pterygium development. Gene expression profiling of pterygium highlighted an IL-33 and IL-4 gene expression signature, along with an increased presence of M2 macrophages, emphasizing their role in promoting fibrosis\u2014a hallmark feature of pterygium. The detection of Malassezia restricta in the pterygium samples and associated molecular changes provides novel insights into the ocular microbiome and raises the possibility of Malassezia\u2019s involvement in pterygium pathology.<\/jats:p>","DOI":"10.3390\/ijms26072976","type":"journal-article","created":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T08:42:35Z","timestamp":1742892155000},"page":"2976","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Potential Role of Malassezia restricta in Pterygium Development"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0735-5598","authenticated-orcid":false,"given":"Martina","family":"Paradzik Simunovic","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7023-9381","authenticated-orcid":false,"given":"Marina","family":"Degoricija","sequence":"additional","affiliation":[{"name":"Laboratory for Cancer Research, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia"},{"name":"Department of Medical Chemistry and Biochemistry, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7840-9979","authenticated-orcid":false,"given":"Jelena","family":"Korac-Prlic","sequence":"additional","affiliation":[{"name":"Laboratory for Cancer Research, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mladen","family":"Lesin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Stanic","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8467-6061","authenticated-orcid":false,"given":"Livia","family":"Puljak","sequence":"additional","affiliation":[{"name":"Center for Evidence-Based Medicine and Healthcare, Catholic University of Croatia, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Olujic","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josipa","family":"Marin Lovric","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Vucinovic","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zana","family":"Ljubic","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Thissen","sequence":"additional","affiliation":[{"name":"Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1131-9784","authenticated-orcid":false,"given":"Car","family":"Reen Kok","sequence":"additional","affiliation":[{"name":"Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Jaing","sequence":"additional","affiliation":[{"name":"Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kajo","family":"Bucan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janos","family":"Terzic","sequence":"additional","affiliation":[{"name":"Laboratory for Cancer Research, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.survophthal.2018.03.001","article-title":"Prevalence and Risk Factors of Pterygium: A Systematic Review and Meta-Analysis","volume":"63","author":"Rezvan","year":"2018","journal-title":"Surv. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e003787","DOI":"10.1136\/bmjopen-2013-003787","article-title":"Geographical Prevalence and Risk Factors for Pterygium: A Systematic Review and Meta-Analysis","volume":"3","author":"Liu","year":"2013","journal-title":"BMJ Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.ajpath.2010.10.037","article-title":"Ophthalmic Pterygium: A Stem Cell Disorder with Premalignant Features","volume":"178","author":"Chui","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Suarez, M.F., Echenique, J., L\u00f3pez, J.M., Medina, E., Ir\u00f3s, M., Serra, H.M., and Fini, M.E. (2021). Transcriptome Analysis of Pterygium and Pinguecula Reveals Evidence of Genomic Instability Associated with Chronic Inflammation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222112090"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"528","DOI":"10.5935\/0004-2749.20190103","article-title":"Mechanisms and Biomarker Candidates in Pterygium Development","volume":"82","author":"Wanzeler","year":"2019","journal-title":"Arq. Bras. Oftalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1097\/ICO.0000000000002721","article-title":"Comparison of Pterygium Recurrence Rates Between Attending Physicians and Supervised Trainee Residents","volume":"41","author":"Thompson","year":"2022","journal-title":"Cornea"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.survophthal.2021.03.010","article-title":"The Ocular Microbiome and Microbiota and Their Effects on Ocular Surface Pathophysiology and Disorders","volume":"66","author":"Aragona","year":"2021","journal-title":"Surv. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1080\/07853890.2021.1925150","article-title":"Influence of Gut Microbiota on Eye Diseases: An Overview","volume":"53","author":"Napolitano","year":"2021","journal-title":"Ann. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Campagnoli, L.I.M., Varesi, A., Barbieri, A., Marchesi, N., and Pascale, A. (2023). Targeting the Gut\u2013Eye Axis: An Emerging Strategy to Face Ocular Diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713338"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jtos.2014.10.003","article-title":"Barrier Function in the Ocular Surface: From Conventional Paradigms to New Opportunities","volume":"13","author":"Leong","year":"2015","journal-title":"Ocul. Surf."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1136\/bjo.51.7.483","article-title":"Evaluation of Conjunctival and Nasal Bacterial Cultures before Intra-Ocular Operations","volume":"51","author":"Nolan","year":"1967","journal-title":"Br. J. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5408","DOI":"10.1167\/iovs.10-6939","article-title":"Diversity of Bacteria at Healthy Human Conjunctiva","volume":"52","author":"Dong","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4268","DOI":"10.1167\/iovs.18-24651","article-title":"Identification and Visualization of a Distinct Microbiome in Ocular Surface Conjunctival Tissue","volume":"59","author":"Ozkan","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"539","DOI":"10.3892\/ijmm.2013.1438","article-title":"Viral Involvement in the Pathogenesis and Clinical Features of Ophthalmic Pterygium (Review)","volume":"32","author":"Chalkia","year":"2013","journal-title":"Int. J. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/eye.2011.312","article-title":"Association of Human Papilloma Virus with Pterygia and Ocular-Surface Squamous Neoplasia","volume":"26","year":"2012","journal-title":"Eye"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/mlf2.12064","article-title":"Human Skin Bacterial Microbiota Homeostasis: A Delicate Balance between Health and Disease","volume":"2","author":"Zhu","year":"2023","journal-title":"mLife"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1136\/gutjnl-2021-326789","article-title":"Gut Microbiome and Health: Mechanistic Insights","volume":"71","author":"Tilg","year":"2022","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1097\/APO.0000000000000330","article-title":"Ocular Surface Microbiome in Health and Disease","volume":"9","author":"Gomes","year":"2020","journal-title":"Asia Pac. J. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"637","DOI":"10.4014\/jmb.2012.12048","article-title":"Skin Commensal Fungus Malassezia and Its Lipases","volume":"31","author":"Park","year":"2021","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/s41586-019-1608-2","article-title":"The Fungal Mycobiome Promotes Pancreatic Oncogenesis via Activation of MBL","volume":"574","author":"Aykut","year":"2019","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Abdillah, A., and Ranque, S. (2021). Chronic Diseases Associated with Malassezia Yeast. J. Fungi, 7.","DOI":"10.20944\/preprints202109.0416.v1"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Soret, P., Vandenborght, L.E., Francis, F., Coron, N., Enaud, R., Avalos, M., Schaeverbeke, T., Berger, P., Fayon, M., and Thiebaut, R. (2020). Respiratory Mycobiome and Suggestion of Inter-Kingdom Network during Acute Pulmonary Exacerbation in Cystic Fibrosis. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-60015-4"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.chom.2019.01.007","article-title":"Malassezia Is Associated with Crohn\u2019s Disease and Exacerbates Colitis in Mouse Models","volume":"25","author":"Limon","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ccell.2022.01.003","article-title":"Fungal Mycobiome Drives IL-33 Secretion and Type 2 Immunity in Pancreatic Cancer","volume":"40","author":"Alam","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.immuni.2017.07.014","article-title":"Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression","volume":"47","author":"Zhu","year":"2017","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1016\/j.immuni.2021.09.010","article-title":"IL-33-Induced Metabolic Reprogramming Controls the Differentiation of Alternatively Activated Macrophages and the Resolution of Inflammation","volume":"54","author":"Faas","year":"2021","journal-title":"Immunity"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Hassanshahi, A., Moradzad, M., Ghalamkari, S., Fadaei, M., Cowin, A.J., and Hassanshahi, M. (2022). Macrophage-Mediated Inflammation in Skin Wound Healing. Cells, 11.","DOI":"10.3390\/cells11192953"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/s41420-024-02247-1","article-title":"Macrophages in Organ Fibrosis: From Pathogenesis to Therapeutic Targets","volume":"10","author":"Jiang","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/ni.3417","article-title":"Acidic Chitinase Primes the Protective Immune Response to Gastrointestinal Nematodes","volume":"17","author":"Vannella","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Anwar, W., Amin, H., Khan, H.A.A., Akhter, A., Bashir, U., Anjum, T., Kalsoom, R., Javed, M.A., and Zohaib, K.A. (2023). Chitinase of Trichoderma Longibrachiatum for Control of Aphis Gossypii in Cotton Plants. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-39965-y"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Choudhary, V., Choudhary, M., and Bollag, W.B. (2024). Exploring Skin Wound Healing Models and the Impact of Natural Lipids on the Healing Process. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25073790"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1165\/rcmb.2019-0098ED","article-title":"Lipid Metabolism: A New Player in the Conundrum of Lung Fibrosis","volume":"61","author":"Summer","year":"2019","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.jtos.2024.01.013","article-title":"Single-Cell RNA Sequencing Reveals the Complex Cellular Niche of Pterygium","volume":"32","author":"Zhang","year":"2024","journal-title":"Ocul. Surf."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Mayslich, C., Grange, P.A., Dupin, N., and Br\u00fcggemann, H. (2021). Cutibacterium acnes as an Opportunistic Pathogen: An Update of Its Virulence-Associated Factors. Microorganisms, 9.","DOI":"10.3390\/microorganisms9020303"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.ophtha.2020.07.030","article-title":"Evaluation of Metagenomic Deep Sequencing as a Diagnostic Test for Infectious Keratitis","volume":"128","author":"Lalitha","year":"2021","journal-title":"Ophthalmology"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ram\u00edrez-Soto, M.C., and Bonifaz, A. (2022). Ocular Fungal Infections. J. Fungi, 8.","DOI":"10.3390\/jof8101078"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e020714","DOI":"10.1136\/bmjopen-2017-020714","article-title":"Cauterisation versus Fibrin Glue for Conjunctival Autografting in Primary Pterygium Surgery (CAGE CUP): Study Protocol of a Randomised Controlled Trial","volume":"8","author":"Olujia","year":"2018","journal-title":"BMJ Open"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1007\/s10792-018-0957-4","article-title":"YKL-40 Expression in Pterygium: A Potential Role in the Pathogenesis","volume":"39","author":"Kurt","year":"2019","journal-title":"Int. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lee, K., Zhang, I., Kyman, S., Kask, O., and Kathryn, E. (2020). Co-Infection of Malassezia sympodialis with Bacterial Pathobionts Pseudomonas aeruginosa or Staphylococcus aureus Leads to Distinct Sinonasal Inflammatory Responses in a Murine Acute Sinusitis Model. Front. Cell Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.00472"},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining Cell Type Abundance and Expression from Bulk Tissues with Digital Cytometry","volume":"37","author":"Newman","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e107","DOI":"10.1002\/imt2.107","article-title":"Ultrafast One-Pass FASTQ Data Preprocessing, Quality Control, and Deduplication Using Fastp","volume":"2","author":"Chen","year":"2023","journal-title":"iMeta"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1101\/gr.210641.116","article-title":"Centrifuge: Rapid and Sensitive Classification of Metagenomic Sequences","volume":"26","author":"Kim","year":"2016","journal-title":"Genome Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Mart\u00ed, J.M. (2019). Recentrifuge: Robust Comparative Analysis and Contamination Removal for Metagenomics. PLoS Comput. Biol., 15.","DOI":"10.1371\/journal.pcbi.1007131"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"McMurdie, P.J., and Holmes, S. (2013). Phyloseq: An R Package for Reproducible Interactive Analysis and Graphics of Microbiome Census Data. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061217"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1111\/j.1654-1103.2003.tb02228.x","article-title":"VEGAN, a Package of R Functions for Community Ecology","volume":"14","author":"Dixon","year":"2003","journal-title":"J. Veg. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/2976\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:59:49Z","timestamp":1760029189000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/2976"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,25]]},"references-count":46,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26072976"],"URL":"https:\/\/doi.org\/10.3390\/ijms26072976","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,25]]}}}