{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T06:03:29Z","timestamp":1774073009814,"version":"3.50.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014538","name":"Lembaga Pengelola Dana Pendidikan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014538","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Ophthalmol."],"abstract":"<jats:p><jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>Mtb<\/jats:italic>) can infect the retinal pigment epithelium (RPE) cells. Current <jats:italic>in vitro<\/jats:italic> research models for ocular tuberculosis (OTB) only rely on RPE cell culture approaches. Until now it remains unclear why only a minority of patients with active systemic tuberculosis (TB) develops concurrent OTB. There is significant variation in the clinical manifestations of OTB, which is potentially influenced by ethnic differences and diversity in mycobacterial strains. To better understand the immunopathobiology of OTB, particularly an individual\u2019s susceptibility to <jats:italic>Mtb<\/jats:italic>-infection and the specific host response, cell culture systems utilizing induced pluripotent stem cells (iPSC)-derived RPE cells offer a promising <jats:italic>in vitro<\/jats:italic> model to better mimic the disease. With this technology, RPE cells can be generated from specific patients of interest, enabling to test hypotheses in a bench to bedside or reverse manner. In this current study, we explore the utility of iPSC-derived RPE cells as an <jats:italic>in vitro<\/jats:italic> model for OTB. Such an approach would overcome drawbacks associated with the currently commonly used \u201cgeneral\u201d RPE cell lines as disease model. The application of iPSC-derived RPE cells offers promising options for the identification of novel biomarkers and to study individualized drug screening methods for host-directed therapy of OTB, in order to restore and maintain vision in OTB patients with sight-threatening disease.<\/jats:p>","DOI":"10.3389\/fopht.2025.1610215","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T04:14:10Z","timestamp":1749010450000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploiting induced pluripotent stem cell-derived retinal pigment epithelium to unravel host-pathogen interaction in ocular tuberculosis: a reverse translational in vitro model"],"prefix":"10.3389","volume":"5","author":[{"given":"Ikhwanuliman","family":"Putera","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanne van","family":"de Meerendonk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole M.A.","family":"Nagtzaam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rina","family":"La Distia Nora","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saskia M.","family":"Rombach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jurriaan E.M.","family":"de Steenwinkel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes R.","family":"Vingerling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Willem A.","family":"Dik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. Martin","family":"van Hagen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"B1","volume-title":"Global tuberculosis report 2024","year":"2024"},{"key":"B2","doi-asserted-by":"publisher","first-page":"20130428","DOI":"10.1098\/rstb.2013.0428","article-title":"Human genetics of tuberculosis: a long and winding road","volume":"369","author":"Abel","year":"2014","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1869-5760-3-1","article-title":"Prevalence of presumed ocular tuberculosis among pulmonary tuberculosis patients in a tertiary hospital in the Philippines","volume":"3","author":"Lara","year":"2013","journal-title":"J Ophthalmic Inflammation Infect"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s10792-021-01718-z","article-title":"Incidence of ocular inflammation among patients with active tuberculosis or nontuberculous mycobacterial infections in a tertiary hospital in Japan","volume":"41","author":"Ohara","year":"2021","journal-title":"Int Ophthalmol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/BF00130924","article-title":"Ocular morbidity in patients with active systemic tuberculosis","volume":"19","author":"Biswas","year":"1995","journal-title":"Int Ophthalmol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9394(67)92860-7","article-title":"Ophthalmologic experience in a tuberculosis sanatorium","volume":"64","author":"Donahue","year":"1967","journal-title":"Am J Ophthalmol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2017.231","article-title":"Tuberculosis and other causes of uveitis in Indonesia","volume":"32","author":"La Distia Nora","year":"2018","journal-title":"Eye (Lond)"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/ceo.13847","article-title":"Clinics of ocular tuberculosis: A review","volume":"49","author":"Betzler","year":"2021","journal-title":"Clin Exp Ophthalmol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2021.03.040","article-title":"Classification criteria for tubercular uveitis","volume":"228","year":"2021","journal-title":"Am J Ophthalmol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1080\/09273948.2018.1489061","article-title":"The collaborative ocular tuberculosis study (COTS)-1: A multinational description of the spectrum of choroidal involvement in 245 patients with tubercular uveitis","volume":"28","author":"Agrawal","year":"2020","journal-title":"Ocul Immunol Inflammation"},{"key":"B11","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1080\/09273948.2024.2359614","article-title":"Clinical features and predictors of treatment outcome in patients with ocular tuberculosis from the Netherlands and Indonesia: the oculaR TB in low versus high endemic countries (ORTEC) study","volume":"33","author":"Putera","year":"2025","journal-title":"Ocul Immunol Inflammation"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.17-23246","article-title":"Retinal Pigment Epithelial Cells Control Early Mycobacterium tuberculosis Infection via Interferon Signaling","volume":"59","author":"La Distia Nora","year":"2018","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2014.270","article-title":"Replication of Mycobacterium tuberculosis in retinal pigment epithelium","volume":"132","author":"Nazari","year":"2014","journal-title":"JAMA Ophthalmol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9394(24)90818-X","article-title":"Changes in eyes of rabbits following injection of dead tubercle bacilli into common carotid artery","volume":"7","author":"Finnoff","year":"1924","journal-title":"Am J Ophthalmology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e0194982","DOI":"10.1371\/journal.pone.0194982","article-title":"A zebrafish model for ocular tuberculosis","volume":"13","author":"Takaki","year":"2018","journal-title":"PloS One"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-022-01419-x","article-title":"Mendelian susceptibility to mycobacterial disease (MSMD): clinical, immunological, and genetic features of 22 patients from 15 moroccan kindreds","volume":"43","author":"Errami","year":"2023","journal-title":"J Clin Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s44368-024-00006-z","article-title":"Mendelian susceptibility to mycobacterial disease: a rare genetic disorder that demands attention","volume":"1","author":"Ye","year":"2024","journal-title":"Discover Immunity"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.4103\/lungindia.lungindia_146_15","article-title":"Host genetics and tuberculosis: Theory of genetic polymorphism and tuberculosis","volume":"36","author":"Aravindan","year":"2019","journal-title":"Lung India"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/stcltm\/szae097","article-title":"iPSC-derived retinal pigment epithelium: an in vitro platform to reproduce key cellular phenotypes and pathophysiology of retinal degenerative diseases","volume":"14","author":"Li","year":"2025","journal-title":"Stem Cells Transl Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/cts.2018.11.issue-2","article-title":"It\u2019s time to reverse our thinking: the reverse translation research paradigm","volume":"11","author":"Shakhnovich","year":"2018","journal-title":"Clin Transl Sci"},{"key":"B21","doi-asserted-by":"publisher","first-page":"100074","DOI":"10.1016\/j.hsr.2022.100074","article-title":"Optimizing drug discovery: An opportunity and application with reverse translational research","volume":"6","author":"Musyuni","year":"2023","journal-title":"Health Sci Review"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.v103.2","article-title":"Reverse translation for assessment of confidence in animal models of multiple sclerosis for drug discovery","volume":"103","author":"t Hart","year":"2018","journal-title":"Clin Pharmacol Ther"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e001225","DOI":"10.1136\/bmjresp-2022-001225","article-title":"BTS clinical statement for the diagnosis and management of ocular tuberculosis","volume":"9","author":"Kon","year":"2022","journal-title":"BMJ Open Respir Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2010.08.011","article-title":"Ocular tuberculosis: a clinicopathologic and molecular study","volume":"118","author":"Wroblewski","year":"2011","journal-title":"Ophthalmology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00330","article-title":"Transcriptional Profile of Mycobacterium tuberculosis in an in vitro Model of Intraocular Tuberculosis","volume":"8","author":"Abhishek","year":"2018","journal-title":"Front Cell Infect Microbiol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2041731416650838","DOI":"10.1177\/2041731416650838","article-title":"Methods for culturing retinal pigment epithelial cells: a review of current protocols and future recommendations","volume":"7","author":"Fronk","year":"2016","journal-title":"J Tissue Eng"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.2010.187930","article-title":"The neonatal Fc receptor is expressed by human retinal pigment epithelial cells and is downregulated by tumour necrosis factor-alpha","volume":"95","author":"van Bilsen","year":"2011","journal-title":"Br J Ophthalmol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"101189","DOI":"10.1016\/j.preteyeres.2023.101189","article-title":"The immune response in tubercular uveitis and its implications for treatment: From anti-tubercular treatment to host-directed therapies","volume":"95","author":"Putera","year":"2023","journal-title":"Prog Retin Eye Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/stem.2010","article-title":"Concise review: making stem cells retinal: methods for deriving retinal pigment epithelium and implications for patients with ocular disease","volume":"33","author":"Leach","year":"2015","journal-title":"Stem Cells"},{"key":"B30","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1186\/s13287-022-02894-0","article-title":"Human-induced pluripotent stem cells-derived retinal pigmented epithelium, a new horizon for cells-based therapies for age-related macular degeneration","volume":"13","author":"Dehghan","year":"2022","journal-title":"Stem Cell Res Ther"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1422818112","article-title":"Small-molecule-directed, efficient generation of retinal pigment epithelium from human pluripotent stem cells","volume":"112","author":"Maruotti","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B32","doi-asserted-by":"publisher","first-page":"109999","DOI":"10.1016\/j.exer.2024.109999","article-title":"RNASeq profiling of retinal pigment epithelial cells derived from induced pluripotent stem cells revealed 3 genes involved in lipid homeostasis in age-related macular degeneration","volume":"246","author":"Voisin","year":"2024","journal-title":"Exp Eye Res"},{"key":"B33","doi-asserted-by":"publisher","first-page":"108576","DOI":"10.1016\/j.exer.2021.108576","article-title":"Altered transcriptome and disease-related phenotype emerge only after fibroblasts harvested from patients with age-related macular degeneration are differentiated into retinal pigment epithelium","volume":"207","author":"Cai","year":"2021","journal-title":"Exp Eye Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1136\/bjo-2024-325207","article-title":"Relapse in ocular tuberculosis: relapse rate, risk factors and clinical management in a non-endemic country","volume":"108","author":"Putera","year":"2024","journal-title":"Br J Ophthalmol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00749-08","article-title":"New drugs against tuberculosis: problems, progress, and evaluation of agents in clinical development","volume":"53","author":"van den Boogaard","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2022.02.002","article-title":"Why 90% of clinical drug development fails and how to improve it","volume":"12","author":"Sun","year":"2022","journal-title":"Acta Pharm Sin B"},{"key":"B37","doi-asserted-by":"publisher","first-page":"295","DOI":"10.31887\/DCNS.2006.8.3\/mspedding","article-title":"New directions for drug discovery","volume":"8","author":"Spedding","year":"2006","journal-title":"Dialogues Clin Neurosci"},{"key":"B38","doi-asserted-by":"publisher","first-page":"101248","DOI":"10.1016\/j.preteyeres.2024.101248","article-title":"Pluripotent stem cell-derived models of retinal disease: Elucidating pathogenesis, evaluating novel treatments, and estimating toxicity","volume":"100","author":"Kurzawa-Akanbi","year":"2024","journal-title":"Prog Retin Eye Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.pharmthera.2017.02.026","article-title":"Drug discovery using induced pluripotent stem cell models of neurodegenerative and ocular diseases","volume":"177","author":"Hung","year":"2017","journal-title":"Pharmacol Ther"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2392","DOI":"10.3390\/ijms25042392","article-title":"Induced pluripotent stem cells in drug discovery and neurodegenerative disease modelling","volume":"25","author":"Beghini","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abl4370","article-title":"Development of iPSC-based clinical trial selection platform for patients with ultrarare diseases","volume":"8","author":"Sequiera","year":"2022","journal-title":"Sci Adv"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2019.10.002","article-title":"Drug discovery platform targeting M. tuberculosis with human embryonic stem cell-derived macrophages","volume":"13","author":"Han","year":"2019","journal-title":"Stem Cell Reports"},{"key":"B43","doi-asserted-by":"publisher","first-page":"591","DOI":"10.3390\/ijms23020591","article-title":"10-DEBC Hydrochloride as a Promising New Agent against Infection of Mycobacterium abscessus","volume":"23","author":"Lee","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.910040","article-title":"Transcriptional comparison of adult human primary Retinal Pigment Epithelium, human pluripotent stem cell-derived Retinal Pigment Epithelium, and ARPE19 cells","volume":"10","author":"Markert","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2020.08.002","article-title":"Transcriptomic profiling of human pluripotent stem cell-derived retinal pigment epithelium over time","volume":"19","author":"Lidgerwood","year":"2021","journal-title":"Genomics Proteomics Bioinf"}],"container-title":["Frontiers in Ophthalmology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fopht.2025.1610215\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T04:14:11Z","timestamp":1749010451000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fopht.2025.1610215\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,4]]},"references-count":45,"alternative-id":["10.3389\/fopht.2025.1610215"],"URL":"https:\/\/doi.org\/10.3389\/fopht.2025.1610215","relation":{},"ISSN":["2674-0826"],"issn-type":[{"value":"2674-0826","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,4]]},"article-number":"1610215"}}