{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T21:32:43Z","timestamp":1768080763088,"version":"3.49.0"},"reference-count":52,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,3]],"date-time":"2018-10-03T00:00:00Z","timestamp":1538524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CL 459\/3-1"],"award-info":[{"award-number":["CL 459\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Rubella virus (RV) infection impacts cellular metabolic activity in a complex manner with strain-specific nutritional requirements. Here we addressed whether this differential metabolic influence was associated with differences in oxidative stress induction and subsequently with innate immune response activation. The low passaged clinical isolates of RV examined in this study induced oxidative stress as validated through generation of the reactive oxygen species (ROS) cytoplasmic hydrogen peroxide and mitochondrial superoxide. The addition of the cytoplasmic and mitochondrial ROS scavengers N-acetyl-l-cysteine and MitoTEMPO, respectively, reduced RV-associated cytopathogenicity and caspase activation. While the degree of oxidative stress induction varied among RV clinical isolates, the level of innate immune response and interferon-stimulated gene activation was comparable. The type III IFNs were highly upregulated in all cell culture systems tested. However, only pre-stimulation with IFN \u03b2 slightly reduced RV replication indicating that RV appears to have evolved the ability to counteract innate immune response mechanisms. Through the data presented, we showed that the ability of RV to induce oxidative stress was independent of its capacity to stimulate and counteract the intrinsic innate immune response.<\/jats:p>","DOI":"10.3390\/v10100540","type":"journal-article","created":{"date-parts":[[2018,10,4]],"date-time":"2018-10-04T02:19:49Z","timestamp":1538619589000},"page":"540","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Rubella Virus Strain-Associated Differences in the Induction of Oxidative Stress Are Independent of Their Interferon Activation"],"prefix":"10.3390","volume":"10","author":[{"given":"Sarah","family":"Zobel","sequence":"first","affiliation":[{"name":"Institute of Virology, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mechthild","family":"Lorenz","sequence":"additional","affiliation":[{"name":"Institute of Virology, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giada","family":"Frascaroli","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Experimental Virology, Heinrich Pette Institute, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janik","family":"B\u00f6hnke","sequence":"additional","affiliation":[{"name":"Institute of Virology, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole C.","family":"Bilz","sequence":"additional","affiliation":[{"name":"Institute of Virology, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan L.","family":"Stanifer","sequence":"additional","affiliation":[{"name":"Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8614-4993","authenticated-orcid":false,"given":"Steeve","family":"Boulant","sequence":"additional","affiliation":[{"name":"Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany"},{"name":"Research Group \u201cCellular Polarity and Viral Infection\u201d (F140), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Bergs","sequence":"additional","affiliation":[{"name":"Institute of Virology, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5129-0875","authenticated-orcid":false,"given":"Uwe G.","family":"Liebert","sequence":"additional","affiliation":[{"name":"Institute of Virology, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4962-6568","authenticated-orcid":false,"given":"Claudia","family":"Claus","sequence":"additional","affiliation":[{"name":"Institute of Virology, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0095-5108(18)30710-3","article-title":"Maternal rubella and the congenital rubella syndrome","volume":"15","author":"Freij","year":"1988","journal-title":"Clin. Perinatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1002\/pd.4467","article-title":"Rubella and pregnancy: Diagnosis, management and outcomes","volume":"34","author":"Bouthry","year":"2014","journal-title":"Prenat. Diagn."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lazar, M., Abernathy, E., Chen, M.H., Icenogle, J., Janta, D., Stanescu, A., Pistol, A., Santibanez, S., Mankertz, A., and Hubschen, J.M. (2016). Epidemiological and molecular investigation of a rubella outbreak, romania, 2011 to 2012. Euro Surveill., 21.","DOI":"10.2807\/1560-7917.ES.2016.21.38.30345"},{"key":"ref_4","first-page":"2","article-title":"Ongoing outbreak of rubella among young male adults in Poland: Increased risk of congenital rubella infections","volume":"18","author":"Czarkowski","year":"2013","journal-title":"Eurosurveillance"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1006\/viro.1998.9562","article-title":"Rubella virus-induced apoptosis varies among cell lines and is modulated by bcl-xl and caspase inhibitors","volume":"255","author":"Duncan","year":"1999","journal-title":"Virology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.virol.2007.08.003","article-title":"Analysis of gene expression in fetal and adult cells infected with rubella virus","volume":"370","author":"Adamo","year":"2008","journal-title":"Virology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.jviromet.2007.08.021","article-title":"An indirect immunocolorimetric assay to detect rubella virus infected cells","volume":"146","author":"Chen","year":"2007","journal-title":"J. Virol. Methods"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Perelygina, L., Zheng, Q., Metcalfe, M., and Icenogle, J. (2013). Persistent infection of human fetal endothelial cells with rubella virus. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073014"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1099\/jgv.0.000226","article-title":"Semliki forest virus and sindbis virus, but not vaccinia virus, require glycolysis for optimal replication","volume":"96","author":"Findlay","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e00934-18","DOI":"10.1128\/JVI.00934-18","article-title":"Rubella viruses shift cellular bioenergetics to a more oxidative and glycolytic phenotype with a strain-specific requirement for glutamine","volume":"92","author":"Bilz","year":"2018","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8481","DOI":"10.1128\/JVI.00533-13","article-title":"Activity increase in respiratory chain complexes by rubella virus with marginal induction of oxidative stress","volume":"87","author":"Claus","year":"2013","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5569","DOI":"10.1128\/JVI.74.12.5569-5576.2000","article-title":"Rubella virus capsid associates with host cell protein p32 and localizes to mitochondria","volume":"74","author":"Beatch","year":"2000","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ilkow, C.S., Goping, I.S., and Hobman, T.C. (2011). The rubella virus capsid is an anti-apoptotic protein that attenuates the pore-forming ability of bax. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1001291"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6108","DOI":"10.3390\/v7122928","article-title":"Activation of the mitochondrial apoptotic signaling platform during rubella virus infection","volume":"7","author":"Claus","year":"2015","journal-title":"Viruses"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.3389\/fmicb.2016.01233","article-title":"Interplay between inflammation and cellular stress triggered by flaviviridae viruses","volume":"7","author":"Valadao","year":"2016","journal-title":"Front. Microbiol"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Olagnier, D., Peri, S., Steel, C., van Montfoort, N., Chiang, C., Beljanski, V., Slifker, M., He, Z., Nichols, C.N., and Lin, R. (2014). Cellular oxidative stress response controls the antiviral and apoptotic programs in dengue virus-infected dendritic cells. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004566"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.jhep.2006.01.037","article-title":"Oxidative stress inhibits IFN-alpha-induced antiviral gene expression by blocking the JAK-STAT pathway","volume":"45","author":"Cippitelli","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2900","DOI":"10.1128\/JVI.05738-11","article-title":"Sensing of rna viruses: A review of innate immune receptors involved in recognizing RNA virus invasion","volume":"86","author":"Jensen","year":"2012","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1146\/annurev-immunol-032713-120231","article-title":"Interferon-stimulated genes: A complex web of host defenses","volume":"32","author":"Schneider","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.ebiom.2015.11.050","article-title":"Immunolocalization and distribution of rubella antigen in fatal congenital rubella syndrome","volume":"3","author":"Lazar","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.1111\/j.1440-1843.2006.00805.x","article-title":"Functional heterogeneity of colony-stimulating factor-induced human monocyte-derived macrophages","volume":"11","author":"Akagawa","year":"2006","journal-title":"Respirology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1128\/JVI.01585-12","article-title":"Human cytomegalovirus infection of M1 and M2 macrophages triggers inflammation and autologous t-cell proliferation","volume":"87","author":"Bayer","year":"2013","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s00705-016-3131-1","article-title":"A sensitive one-step taqman amplification approach for detection of rubella virus clade I and II genotypes in clinical samples","volume":"162","author":"Claus","year":"2017","journal-title":"Arch. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cicinnati, V.R., Shen, Q.L., Sotiropoulos, G.C., Radtke, A., Gerken, G., and Beckebaum, S. (2008). Validation of putative reference genes for gene expression studies in human hepatocellular carcinoma using real-time quantitative RT-PCR. BMC Cancer, 8.","DOI":"10.1186\/1471-2407-8-350"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1248\/jhs.51.185","article-title":"Increased expression of cyclin-dependent kinase-interacting protein p21 during tamoxifen-induced hepatocarcinogenesis in female rats","volume":"51","author":"Kasahara","year":"2005","journal-title":"J. Health Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"423.e25","DOI":"10.1016\/j.cell.2017.11.018","article-title":"Intrinsic immunity shapes viral resistance of stem cells","volume":"172","author":"Wu","year":"2018","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1099\/jgv.0.000680","article-title":"Genetic diversity of currently circulating rubella viruses: A need to define more precise viral groups","volume":"98","author":"Rivailler","year":"2017","journal-title":"J. Gen. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.freeradbiomed.2008.09.022","article-title":"p21(Cip1) protects against oxidative stress by suppressing er-dependent activation of mitochondrial death pathways","volume":"46","author":"Vitiello","year":"2009","journal-title":"Free Radic. Boil. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1006\/viro.1998.9395","article-title":"Rubella virus induces apoptosis in culture cells","volume":"250","author":"Pugachev","year":"1998","journal-title":"Virology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1038\/nprot.2007.327","article-title":"Simultaneous detection of apoptosis and mitochondrial superoxide production in live cells by flow cytometry and confocal microscopy","volume":"2","author":"Mukhopadhyay","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1196\/annals.1443.020","article-title":"Toll-like receptor and RIG-I-like receptor signaling","volume":"1143","author":"Kawai","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1436.e1411","DOI":"10.1016\/j.jaci.2016.06.030","article-title":"Rubella persistence in epidermal keratinocytes and granuloma m2 macrophages in patients with primary immunodeficiencies","volume":"138","author":"Perelygina","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2515S","DOI":"10.1093\/jn\/131.9.2515S","article-title":"Why is l-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection?","volume":"131","author":"Newsholme","year":"2001","journal-title":"J. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Neu, C., Sedlag, A., Bayer, C., Forster, S., Crauwels, P., Niess, J.H., van Zandbergen, G., Frascaroli, G., and Riedel, C.U. (2013). CD14-dependent monocyte isolation enhances phagocytosis of Listeria monocytogenes by proinflammatory, GM-CSF-derived macrophages. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066898"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.1099\/jgv.0.000240","article-title":"Susceptibility of bone marrow-derived macrophages to influenza virus infection is dependent on macrophage phenotype","volume":"96","author":"Campbell","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6237","DOI":"10.4049\/jimmunol.0803447","article-title":"M1 and M2a polarization of human monocyte-derived macrophages inhibits HIV-1 replication by distinct mechanisms","volume":"182","author":"Cassol","year":"2009","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1097\/QAD.0b013e328361d059","article-title":"M1 polarization of human monocyte-derived macrophages restricts pre and postintegration steps of HIV-1 replication","volume":"27","author":"Cassetta","year":"2013","journal-title":"Aids"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.1128\/JVI.02492-10","article-title":"Involvement of p32 and microtubules in alteration of mitochondrial functions by rubella virus","volume":"85","author":"Claus","year":"2011","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/1423-0127-16-98","article-title":"The specificity of neuroprotection by antioxidants","volume":"16","author":"Liu","year":"2009","journal-title":"J. Biomed. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Levitz, R., Gao, Y., Dozmorov, I., Song, R., Wakeland, E.K., and Kahn, J.S. (2017). Distinct patterns of innate immune activation by clinical isolates of respiratory syncytial virus. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184318"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4812","DOI":"10.4049\/jimmunol.0903952","article-title":"Influenza A virus protein PB1-F2 exacerbates IFN-beta expression of human respiratory epithelial cells","volume":"185","author":"Bouguyon","year":"2010","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1099\/jgv.0.000782","article-title":"Influenza virus protein PB1-F2 interacts with CALCOCO2 (NDP52) to modulate innate immune response","volume":"98","author":"Leymarie","year":"2017","journal-title":"J. Gen. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1136\/bmj.1.5847.197","article-title":"Interferon studies with Japanese and U.S. Rubella virus strains","volume":"1","author":"Potter","year":"1973","journal-title":"Br. Med. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1128\/iai.2.2.132-138.1970","article-title":"Effect of exogenous interferon on rubella virus production in carrier cultures of cells defective in interferon production","volume":"2","author":"Mifune","year":"1970","journal-title":"Infect. Immun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.virol.2012.04.003","article-title":"Characterization of cell lines stably transfected with rubella virus replicons","volume":"429","author":"Tzeng","year":"2012","journal-title":"Virology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10792","DOI":"10.1128\/JVI.01235-14","article-title":"Dual modulation of type i interferon response by bluetongue virus","volume":"88","author":"Doceul","year":"2014","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jhep.2018.02.021","article-title":"Hepatitis D virus replication is sensed by MDA5 and induces IFN-beta\/lambda responses in hepatocytes","volume":"69","author":"Zhang","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.antiviral.2016.10.006","article-title":"HDV RNA replication is associated with hbv repression and interferon-stimulated genes induction in super-infected hepatocytes","volume":"136","author":"Alfaiate","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.virol.2010.06.043","article-title":"Three-dimensional structure of rubella virus factories","volume":"405","author":"Fontana","year":"2010","journal-title":"Virology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1099\/vir.0.18785-0","article-title":"Time-course induction of apoptosis by wild-type and attenuated strains of rubella virus","volume":"84","author":"Cooray","year":"2003","journal-title":"J. Gen. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0065-3527(08)60328-0","article-title":"Molecular biology of rubella virus","volume":"44","author":"Frey","year":"1994","journal-title":"Adv. In Virus Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1021\/acsinfecdis.7b00103","article-title":"Infection of iPSC lines with miscarriage-associated coxsackievirus and measles virus and teratogenic rubella virus as a model for viral impairment of early human embryogenesis","volume":"3","author":"Hubner","year":"2017","journal-title":"ACS Infect. Dis."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/10\/10\/540\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:23:50Z","timestamp":1760196230000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/10\/10\/540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,3]]},"references-count":52,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["v10100540"],"URL":"https:\/\/doi.org\/10.3390\/v10100540","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,3]]}}}