{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T08:20:33Z","timestamp":1771748433692,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,2,16]],"date-time":"2019-02-16T00:00:00Z","timestamp":1550275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010127","name":"J\u00fcrgen Manchot Stiftung","doi-asserted-by":"publisher","award":["MOI III"],"award-info":[{"award-number":["MOI III"]}],"id":[{"id":"10.13039\/100010127","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human retinal pigment epithelial (hRPE) cells are important for the establishment and maintenance of the immune privilege of the eye. They function as target cells for human cytomegalovirus (hCMV), but are able to restrict viral replication. hCMV causes opportunistic posterior uveitis such as retinitis and chorioretinitis. Both mainly occur in severely immunocompromised patients and rarely manifest in immunocompetent individuals. In this study, hRPE cells were infected with hCMV in vitro and activated with proinflammatory cytokines. The enzymatic activities of indoleamine 2,3-dioxygenase-1 (IDO1) and inducible nitric oxide synthase (iNOS) were determined. The antimicrobial capacity of both molecules was analyzed in co-infection experiments using Staphylococcus aureus (S. aureus) and Toxoplasma gondii (T. gondii), causing uveitis in patients. We show that an hCMV infection of hRPE cells blocks IDO1 and iNOS mediated antimicrobial defense mechanisms necessary for the control of S. aureus and T. gondii. hCMV also inhibits immune suppressive effector mechanisms in hRPE. The interferon gamma-induced IDO1 dependent immune regulation was severely blocked, as detected by the loss of T cell inhibition. We conclude that an active hCMV infection in the eye might favor the replication of pathogens causing co-infections in immunosuppressed individuals. An hCMV caused blockade of IDO1 might weaken the eye\u2019s immune privilege and favor the development of post-infectious autoimmune uveitis.<\/jats:p>","DOI":"10.3390\/ijms20040858","type":"journal-article","created":{"date-parts":[[2019,2,17]],"date-time":"2019-02-17T22:11:50Z","timestamp":1550441510000},"page":"858","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["hCMV-Mediated Immune Escape Mechanisms Favor Pathogen Growth and Disturb the Immune Privilege of the Eye"],"prefix":"10.3390","volume":"20","author":[{"given":"Katrin","family":"Spekker-Bosker","sequence":"first","affiliation":[{"name":"Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4779-5424","authenticated-orcid":false,"given":"Christoph-Martin","family":"Ufermann","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Maywald","sequence":"additional","affiliation":[{"name":"Institute of Virology, Heinrich-Heine-University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"},{"name":"Bavarian Nordic GmbH, 82152 Martinsried, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Institute of Virology, Heinrich-Heine-University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Domr\u00f6se","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Woite","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6083-7991","authenticated-orcid":false,"given":"Walter","family":"D\u00e4ubener","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4106-3695","authenticated-orcid":false,"given":"Silvia Kathrin","family":"Eller","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/rmv.655","article-title":"Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection","volume":"20","author":"Cannon","year":"2010","journal-title":"Rev. Med. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lachmann, R., Loenenbach, A., Waterboer, T., Brenner, N., Pawlita, M., Michel, A., Thamm, M., Poethko-M\u00fcller, C., Wichmann, O., and Wiese-Posselt, M. (2018). Cytomegalovirus (CMV) seroprevalence in the adult population of Germany. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0200267"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Melendez-Munoz, R., Marchalik, R., Jerussi, T., Dimitrova, D., Nussenblatt, V., Beri, A., Rai, K., Wilder, J.S., Barrett, A.J., and Battiwalla, M. (2018). Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution. Biol. Blood Marrow Transpl.","DOI":"10.1016\/j.bbmt.2018.10.011"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1053\/j.semperi.2018.02.002","article-title":"Congenital cytomegalovirus infection","volume":"42","author":"Fowler","year":"2018","journal-title":"Semin. Perinatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1097\/ICU.0000000000000481","article-title":"Cytomegalovirus keratitis","volume":"29","author":"Faith","year":"2018","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1097\/ICU.0000000000000531","article-title":"Opportunistic ocular infections in the setting of HIV","volume":"29","author":"Laovirojjanakul","year":"2018","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1016\/j.bbmt.2018.03.028","article-title":"Control of Cytomegalovirus Viremia after Allogeneic Stem Cell Transplantation: A Review on CMV-Specific T Cell Reconstitution","volume":"24","author":"Marijt","year":"2018","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nikitina, E., Larionova, I., Choinzonov, E., and Kzhyshkowska, J. (2018). Monocytes and Macrophages as Viral Targets and Reservoirs. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092821"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1084\/jem.20151899","article-title":"Inflammatory monocytes and NK cells play a crucial role in DNAM-1-dependent control of cytomegalovirus infection","volume":"213","author":"Kaynan","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/eye.2011.327","article-title":"Cytomegalovirus and the eye","volume":"26","author":"Carmichael","year":"2012","journal-title":"Eye"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Keino, H., Horie, S., and Sugita, S. (2018). Immune Privilege and Eye-Derived T-Regulatory Cells. Immunol. Res., 1679197.","DOI":"10.1155\/2018\/1679197"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4188","DOI":"10.1128\/iai.64.10.4188-4196.1996","article-title":"Mechanisms of interferon-induced inhibition of Toxoplasma gondii replication in human retinal pigment epithelial cells","volume":"64","author":"Nagineni","year":"1996","journal-title":"Infect. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"957","DOI":"10.4049\/jimmunol.162.2.957","article-title":"Role of IFN-gamma-induced indoleamine 2,3 dioxygenase and inducible nitric oxide synthase in the replication of human cytomegalovirus in retinal pigment epithelial cells","volume":"162","author":"Bodaghi","year":"1999","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1160\/TH09-04-0250","article-title":"Antimicrobial and immunoregulatory effector mechanisms in human endothelial cells. Indoleamine 2,3-dioxygenase versus inducible nitric oxide synthase","volume":"102","author":"Schmidt","year":"2009","journal-title":"Thromb. Haemost."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Heseler, K., Schmidt, S.K., Spekker, K., Sinzger, C., Sorg, R.V., Quambusch, M., Zimmermann, A., Meisel, R., and D\u00e4ubener, W. (2013). Cytomegalovirus impairs the induction of indoleamine 2,3-dioxygenase mediated antimicrobial and immunoregulatory effects in human fibroblasts. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064442"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1099\/vir.0.061994-0","article-title":"Checks and balances between human cytomegalovirus replication and indoleamine-2,3-dioxygenase","volume":"95","author":"Zimmermann","year":"2014","journal-title":"J. Gen. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1159\/000363141","article-title":"Ocular toxoplasmosis: Recent aspects of pathophysiology and clinical implications","volume":"52","author":"Pleyer","year":"2014","journal-title":"Ophthalmic Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.ijmm.2014.09.002","article-title":"Animals are key to human toxoplasmosis","volume":"304","author":"Schares","year":"2014","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5530","DOI":"10.4049\/jimmunol.181.8.5530","article-title":"Inhibition of IFN-gamma-induced STAT1 tyrosine phosphorylation by human CMV is mediated by SHP2","volume":"181","author":"Baron","year":"2008","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1084\/jem.187.5.675","article-title":"Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak\/Stat pathway","volume":"187","author":"Miller","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4654","DOI":"10.1167\/iovs.07-0286","article-title":"Interaction of retinal pigmented epithelial cells and CD4 T cells leads to T-cell anergy","volume":"48","author":"Gregerson","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6926","DOI":"10.1167\/iovs.13-12703","article-title":"Suppression of IL-22-producing T helper 22 cells by RPE cells via PD-L1\/PD-1 interactions","volume":"54","author":"Sugita","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3109\/09273940903326203","article-title":"The role of indoleamine 2,3-dioxygenase in retinal pigment epithelial cell-mediated immune modulation","volume":"18","author":"Park","year":"2010","journal-title":"Ocul. Immunol. Inflamm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1080\/02713680590934120","article-title":"The immune privilege of the eye: Human retinal pigment epithelial cells selectively modulate T-cell activation in vitro","volume":"30","author":"Kaestel","year":"2005","journal-title":"Curr. Eye Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1084\/jem.189.9.1363","article-title":"Inhibition of T cell proliferation by macrophage tryptophan catabolism","volume":"189","author":"Munn","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5615","DOI":"10.1128\/IAI.67.11.5615-5620.1999","article-title":"Interleukin-1 inhibits gamma interferon-induced bacteriostasis in human uroepithelial cells","volume":"67","author":"Hucke","year":"1999","journal-title":"Infect. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1128\/IAI.72.5.2723-2730.2004","article-title":"Nitric oxide-mediated regulation of gamma interferon-induced bacteriostasis: Inhibition and degradation of human indoleamine 2,3-dioxygenase","volume":"72","author":"Hucke","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3073","DOI":"10.1172\/JCI42440","article-title":"A look at autoimmunity and inflammation in the eye","volume":"120","author":"Caspi","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.survophthal.2016.12.008","article-title":"Viral posterior uveitis","volume":"62","author":"Lee","year":"2017","journal-title":"Surv. Ophthalmol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0022-1759(94)90207-0","article-title":"A new, simple bioassay for human IFN-gamma","volume":"168","author":"Wanagat","year":"1994","journal-title":"J. Immunol. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.4049\/jimmunol.141.7.2407","article-title":"Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production","volume":"141","author":"Ding","year":"1988","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1099\/0022-1317-80-11-2867","article-title":"Modification of human cytomegalovirus tropism through propagation in vitro is associated with changes in the viral genome","volume":"80","author":"Sinzger","year":"1999","journal-title":"J. Gen. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1099\/vir.0.83286-0","article-title":"Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40\/E","volume":"89","author":"Sinzger","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1099\/vir.0.2008\/001669-0","article-title":"Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation","volume":"89","author":"Le","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1111\/j.1550-7408.1977.tb04774.x","article-title":"Specific labeling of intracellular Toxoplasma gondii with uracil","volume":"24","author":"Pfefferkorn","year":"1977","journal-title":"J. Protozool."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1574-695X.2007.00374.x","article-title":"Antimicrobial and immunoregulatory effects mediated by human lung cells: Role of IFN-gamma-induced tryptophan degradation","volume":"52","author":"Heseler","year":"2008","journal-title":"FEMS Immunol. Med. Microbiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/4\/858\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:32:37Z","timestamp":1760185957000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/4\/858"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,16]]},"references-count":36,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["ijms20040858"],"URL":"https:\/\/doi.org\/10.3390\/ijms20040858","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,16]]}}}