{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:33:04Z","timestamp":1784259184013,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013947","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000}}],"reference-count":101,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA268976"],"award-info":[{"award-number":["R01 CA268976"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012787","name":"Office of the Vice Chancellor for Research and Graduate Education, University of Wisconsin-Madison","doi-asserted-by":"publisher","award":["Funding from the Wisconsin Alumni Research Foundation"],"award-info":[{"award-number":["Funding from the Wisconsin Alumni Research Foundation"]}],"id":[{"id":"10.13039\/100012787","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Careful regulation of type I interferons (IFN) like IFN-\u03b2 is vital for balancing tissue damage and protection against infections. Heterogeneity in type I IFN expression among virally infected cells is a common phenomenon that may help limit IFN responses, but the source of this heterogeneity is poorly understood. We previously found that during Kaposi\u2019s sarcoma-associated herpesvirus replication, type I IFN induction was limited to a small percentage of infected cells. This heterogeneity was not explained by viral gene expression. Here, we used a fluorescent reporter and fluorescence activated cell sorting to investigate the source of the heterogeneity. Surprisingly, the canonical IFN induction pathway culminating in the activation of the IRF3 transcription factor was similarly activated between cells that made high vs. low\/no IFN-\u03b2. In contrast, the activation or expression of the two other IFN transcription factors, the NF-\u03baB subunit RelA and the AP-1 subunit ATF2, correlated with IFN-\u03b2 induction. Our results suggest that during viral infection, activation of IRF3 does not automatically result in IFN responses at the level of individual cells, but that other factors, such as NF-\u03baB and AP-1, are limiting for type I IFN induction.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013947","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:43:12Z","timestamp":1770835392000},"page":"e1013947","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Interferon-\u03b2 induction heterogeneity during KSHV infection is correlated to levels and activation of the transcription factors ATF2 and RelA, and not IRF3"],"prefix":"10.1371","volume":"22","author":[{"given":"Machika","family":"Kaku","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1791-0663","authenticated-orcid":true,"given":"Marta Maria","family":"Gaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"issue":"7344","key":"ppat.1013947.ref001","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature09907","article-title":"A diverse range of gene products are effectors of the type I interferon antiviral response","volume":"472","author":"JW Schoggins","year":"2011","journal-title":"Nature"},{"issue":"6","key":"ppat.1013947.ref002","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.coviro.2011.10.008","article-title":"Interferon-stimulated genes and their antiviral effector functions","volume":"1","author":"JW Schoggins","year":"2011","journal-title":"Curr Opin Virol"},{"issue":"12","key":"ppat.1013947.ref003","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.4049\/jimmunol.1800764","article-title":"The Goldilocks Zone of Type I IFNs: Lessons from Human Genetics","volume":"201","author":"J Taft","year":"2018","journal-title":"J Immunol"},{"issue":"2","key":"ppat.1013947.ref004","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nri3133","article-title":"Immunomodulatory functions of type I interferons","volume":"12","author":"JM Gonz\u00e1lez-Navajas","year":"2012","journal-title":"Nat Rev Immunol"},{"issue":"3","key":"ppat.1013947.ref005","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1189\/jlb.0703321","article-title":"Shielding the double-edged sword: negative regulation of the innate immune system","volume":"75","author":"KS Kobayashi","year":"2004","journal-title":"J Leukoc Biol"},{"key":"ppat.1013947.ref006","article-title":"Caspase-mediated regulation and cellular heterogeneity of the cGAS\/STING pathway in kaposi\u2019s sarcoma-associated herpesvirus infection","author":"T Tabtieng","year":"2022","journal-title":"mBio"},{"key":"ppat.1013947.ref007","doi-asserted-by":"crossref","DOI":"10.1128\/jvi.00505-22","article-title":"In vivo profiling of individual multiciliated cells during acute influenza A virus infection","volume":"96","author":"CE Hamele","year":"2022","journal-title":"J Virol"},{"issue":"3","key":"ppat.1013947.ref008","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s41587-021-01059-3","article-title":"Functional single-cell genomics of human cytomegalovirus infection","volume":"40","author":"MY Hein","year":"2022","journal-title":"Nat Biotechnol"},{"issue":"1","key":"ppat.1013947.ref009","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1009292","article-title":"Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium","volume":"17","author":"JK Fiege","year":"2021","journal-title":"PLoS Pathog"},{"issue":"7","key":"ppat.1013947.ref010","article-title":"Single cell heterogeneity in influenza A virus gene expression shapes the innate antiviral response to infection","volume":"16","author":"J Sun","year":"2020","journal-title":"PLoS Pathog"},{"issue":"14","key":"ppat.1013947.ref011","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00500-19","article-title":"Single-cell virus sequencing of influenza infections that trigger innate immunity","volume":"93","author":"AB Russell","year":"2019","journal-title":"J Virol"},{"key":"ppat.1013947.ref012","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.46339","article-title":"HSV-1 single-cell analysis reveals the activation of anti-viral and developmental programs in distinct sub-populations","volume":"8","author":"N Drayman","year":"2019","journal-title":"Elife"},{"issue":"6","key":"ppat.1013947.ref013","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01778-18","article-title":"West nile virus-inclusive single-cell rna sequencing reveals heterogeneity in the type I interferon response within single cells","volume":"93","author":"JT O\u2019Neal","year":"2019","journal-title":"J Virol"},{"key":"ppat.1013947.ref014","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.32303","article-title":"Extreme heterogeneity of influenza virus infection in single cells","volume":"7","author":"AB Russell","year":"2018","journal-title":"Elife"},{"issue":"3","key":"ppat.1013947.ref015","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1099\/jgv.0.000687","article-title":"Single-cell studies of IFN-\u03b2 promoter activation by wild-type and NS1-defective influenza A viruses","volume":"98","author":"MJ Killip","year":"2017","journal-title":"J Gen Virol"},{"issue":"9","key":"ppat.1013947.ref016","doi-asserted-by":"crossref","first-page":"4632","DOI":"10.1128\/JVI.00014-14","article-title":"An unbiased genetic screen reveals the polygenic nature of the influenza virus anti-interferon response","volume":"88","author":"M P\u00e9rez-Cidoncha","year":"2014","journal-title":"J Virol"},{"issue":"12","key":"ppat.1013947.ref017","doi-asserted-by":"crossref","first-page":"6925","DOI":"10.1128\/JVI.00283-13","article-title":"Visualizing the beta interferon response in mice during infection with influenza A viruses expressing or lacking nonstructural protein 1","volume":"87","author":"C Kallfass","year":"2013","journal-title":"J Virol"},{"issue":"2","key":"ppat.1013947.ref018","article-title":"Role of cell-to-cell variability in activating a positive feedback antiviral response in human dendritic cells","volume":"6","author":"J Hu","year":"2011","journal-title":"PLoS One"},{"issue":"15","key":"ppat.1013947.ref019","doi-asserted-by":"crossref","first-page":"5232","DOI":"10.1093\/nar\/gkm557","article-title":"Chromosome-specific and noisy IFNB1 transcription in individual virus-infected human primary dendritic cells","volume":"35","author":"J Hu","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"ppat.1013947.ref020","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/msb.2012.17","article-title":"Multi-layered stochasticity and paracrine signal propagation shape the type-I interferon response","volume":"8","author":"U Rand","year":"2012","journal-title":"Mol Syst Biol"},{"issue":"1","key":"ppat.1013947.ref021","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.1001249","article-title":"Stochastic expression of the interferon-\u03b2 gene","volume":"10","author":"M Zhao","year":"2012","journal-title":"PLoS Biol"},{"key":"ppat.1013947.ref022","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00078-18","article-title":"Caspase-dependent suppression of type I interferon signaling promotes Kaposi\u2019s sarcoma-associated herpesvirus lytic replication","volume":"92","author":"T Tabtieng","year":"2018","journal-title":"J Virol"},{"issue":"6","key":"ppat.1013947.ref023","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.cell.2007.05.019","article-title":"An atomic model of the interferon-beta enhanceosome","volume":"129","author":"D Panne","year":"2007","journal-title":"Cell"},{"key":"ppat.1013947.ref024","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1101\/sqb.1998.63.609","article-title":"Structure and function of the interferon-beta enhanceosome","volume":"63","author":"T Maniatis","year":"1998","journal-title":"Cold Spring Harb Symp Quant Biol"},{"issue":"1","key":"ppat.1013947.ref025","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cell.2008.05.052","article-title":"Virus infection induces NF-kappaB-dependent interchromosomal associations mediating monoallelic IFN-beta gene expression","volume":"134","author":"E Apostolou","year":"2008","journal-title":"Cell"},{"issue":"7","key":"ppat.1013947.ref026","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1182\/blood.V88.7.2648.bloodjournal8872648","article-title":"Establishment and characterization of a primary effusion (body cavity-based) lymphoma cell line (BC-3) harboring kaposi\u2019s sarcoma-associated herpesvirus (KSHV\/HHV-8) in the absence of Epstein-Barr virus","volume":"88","author":"L Arvanitakis","year":"1996","journal-title":"Blood"},{"issue":"17","key":"ppat.1013947.ref027","doi-asserted-by":"crossref","first-page":"16739","DOI":"10.1074\/jbc.M414139200","article-title":"Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes","volume":"280","author":"K Li","year":"2005","journal-title":"J Biol Chem"},{"key":"ppat.1013947.ref028","article-title":"RO 90-7501 enhances TLR3 and RLR agonist induced antiviral response","volume":"7","author":"F Guo","year":"2012","journal-title":"PLoS One"},{"issue":"6253","key":"ppat.1013947.ref029","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1126\/science.aab3628","article-title":"Transmission of innate immune signaling by packaging of cGAMP in viral particles","volume":"349","author":"M Gentili","year":"2015","journal-title":"Science"},{"issue":"10","key":"ppat.1013947.ref030","doi-asserted-by":"crossref","first-page":"2887","DOI":"10.1039\/b901966a","article-title":"The fluorescent protein palette: tools for cellular imaging","volume":"38","author":"RN Day","year":"2009","journal-title":"Chem Soc Rev"},{"issue":"9","key":"ppat.1013947.ref031","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/dvg.20335","article-title":"A global double-fluorescent Cre reporter mouse","volume":"45","author":"MD Muzumdar","year":"2007","journal-title":"Genesis"},{"issue":"1","key":"ppat.1013947.ref032","doi-asserted-by":"crossref","first-page":"12088","DOI":"10.1038\/s41598-018-30623-2","article-title":"Strong increase in the autofluorescence of cells signals struggle for survival","volume":"8","author":"J Surre","year":"2018","journal-title":"Sci Rep"},{"key":"ppat.1013947.ref033","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S0021-9258(17)30079-0","article-title":"Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples. NADH and flavoprotein fluorescence signals","volume":"254","author":"B Chance","year":"1979","journal-title":"J Biol Chem"},{"key":"ppat.1013947.ref034","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01019-12","article-title":"Construction and manipulation of a new Kaposi\u2019s sarcoma-associated herpesvirus bacterial artificial chromosome clone","volume":"86","author":"KF Brulois","year":"2012","journal-title":"J Virol"},{"key":"ppat.1013947.ref035","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1099\/vir.0.81619-0","article-title":"An essential role of ERK signalling in TPA-induced reactivation of Kaposi\u2019s sarcoma-associated herpesvirus","volume":"87","author":"A Cohen","year":"2006","journal-title":"J Gen Virol"},{"issue":"3","key":"ppat.1013947.ref036","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/nm0396-342","article-title":"Lytic growth of Kaposi\u2019s sarcoma-associated herpesvirus (human herpesvirus 8) in culture","volume":"2","author":"R Renne","year":"1996","journal-title":"Nat Med"},{"issue":"6","key":"ppat.1013947.ref037","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1093\/oxfordjournals.jbchem.a003294","article-title":"Protein kinase C delta (PKC delta): activation mechanisms and functions","volume":"132","author":"U Kikkawa","year":"2002","journal-title":"J Biochem"},{"key":"ppat.1013947.ref038","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.yjmcc.2011.07.013","article-title":"PKC-delta and PKC-epsilon: foes of the same family or strangers?","volume":"51","author":"N Duquesnes","year":"2011","journal-title":"J Mol Cell Cardiol"},{"key":"ppat.1013947.ref039","first-page":"9","article-title":"Establishment and characterization of an Epstein-Barr virus (EBC)-negative lymphoblastoid B cell line (BJA-B) from an exceptional, EBV-genome-negative African Burkitt\u2019s lymphoma","volume":"22","author":"J Menezes","year":"1975","journal-title":"Biomedicine"},{"key":"ppat.1013947.ref040","first-page":"11","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus-encoded LANA can induce chromosomal instability through targeted degradation of the mitotic checkpoint kinase Bub1","volume":"88","author":"Z Sun","year":"2014","journal-title":"J Virol"},{"key":"ppat.1013947.ref041","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1003672","article-title":"Molecular basis for oligomeric-DNA binding and episome maintenance by KSHV LANA","volume":"9","author":"JF Domsic","year":"2013","journal-title":"PLoS Pathog"},{"issue":"4","key":"ppat.1013947.ref042","first-page":"10","article-title":"Positive feedback regulation of type I IFN production by the IFN-inducible DNA sensor cGAS","volume":"194","author":"F Ma","year":"2015"},{"issue":"10","key":"ppat.1013947.ref043","doi-asserted-by":"crossref","first-page":"7576","DOI":"10.1074\/jbc.M608618200","article-title":"Viral infections activate types I and III interferon genes through a common mechanism","volume":"282","author":"K Onoguchi","year":"2007","journal-title":"J Biol Chem"},{"key":"ppat.1013947.ref044","first-page":"9","article-title":"IFN regulatory factor family members differentially regulate the expression of type III IFN (IFN-lambda) genes","volume":"179","author":"PI Osterlund","year":"2007","journal-title":"Immunity"},{"issue":"13","key":"ppat.1013947.ref045","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Y Hao","year":"2021","journal-title":"Cell"},{"issue":"2","key":"ppat.1013947.ref046","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.jmb.2008.03.050","article-title":"Contribution of Ser386 and Ser396 to activation of interferon regulatory factor 3","volume":"379","author":"W Chen","year":"2008","journal-title":"J Mol Biol"},{"issue":"2","key":"ppat.1013947.ref047","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/0092-8674(89)90966-5","article-title":"The involvement of NF-kappa B in beta-interferon gene regulation reveals its role as widely inducible mediator of signal transduction","volume":"57","author":"MJ Lenardo","year":"1989","journal-title":"Cell"},{"issue":"4","key":"ppat.1013947.ref048","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S1097-2765(00)80051-9","article-title":"Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo","volume":"1","author":"MG Wathelet","year":"1998","journal-title":"Mol Cell"},{"issue":"8","key":"ppat.1013947.ref049","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1089\/jir.2010.0063","article-title":"Mechanisms of type III interferon expression","volume":"30","author":"MB Iversen","year":"2010","journal-title":"J Interferon Cytokine Res"},{"issue":"5","key":"ppat.1013947.ref050","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1006\/smim.1999.0192","article-title":"On the stochastic regulation of interleukin-2 transcription","volume":"11","author":"GA Holl\u00e4nder","year":"1999","journal-title":"Semin Immunol"},{"issue":"2","key":"ppat.1013947.ref051","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S1074-7613(04)00025-1","article-title":"Probabilistic regulation of IL-4 production in Th2 cells: accessibility at the Il4 locus","volume":"20","author":"L Guo","year":"2004","journal-title":"Immunity"},{"issue":"6","key":"ppat.1013947.ref052","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s10875-005-8218-5","article-title":"Probabilistic regulation of IL-4 production","volume":"25","author":"L Guo","year":"2005","journal-title":"J Clin Immunol"},{"key":"ppat.1013947.ref053","doi-asserted-by":"crossref","first-page":"5","DOI":"10.4049\/jimmunol.165.6.2982","article-title":"Coordinate regulation of the IL-4, IL-13, and IL-5 cytokine cluster in Th2 clones revealed by allelic expression patterns","volume":"165","author":"BL Kelly","year":"2000","journal-title":"J Immunol"},{"key":"ppat.1013947.ref054","doi-asserted-by":"crossref","first-page":"7","DOI":"10.4049\/jimmunol.177.8.5358","article-title":"Stochastic monoallelic expression of IL-10 in T cells","volume":"177","author":"DP Calado","year":"2006","journal-title":"J Immunol"},{"issue":"7213","key":"ppat.1013947.ref055","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nature07317","article-title":"STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling","volume":"455","author":"H Ishikawa","year":"2008","journal-title":"Nature"},{"issue":"1","key":"ppat.1013947.ref056","doi-asserted-by":"crossref","first-page":"107492","DOI":"10.1016\/j.celrep.2020.03.056","article-title":"TBK1 and IKK\u03b5 act redundantly to mediate STING-Induced NF-\u03baB responses in myeloid cells","volume":"31","author":"KR Balka","year":"2020","journal-title":"Cell Rep"},{"key":"ppat.1013947.ref057","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1074\/jbc.274.43.30353","article-title":"IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain","volume":"274","author":"H Sakurai","year":"1999","journal-title":"J Biol Chem"},{"key":"ppat.1013947.ref058","doi-asserted-by":"crossref","first-page":"9","DOI":"10.4049\/jimmunol.172.10.6336","article-title":"Transient and selective NF-kappa B p65 serine 536 phosphorylation induced by T cell costimulation is mediated by I kappa B kinase beta and controls the kinetics of p65 nuclear import","volume":"172","author":"I Mattioli","year":"2004","journal-title":"J Immunol"},{"key":"ppat.1013947.ref059","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1074\/jbc.M409825200","article-title":"Constitutive and interleukin-1-inducible phosphorylation of p65 NF-{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription","volume":"279","author":"H Buss","year":"2004","journal-title":"J Biol Chem"},{"issue":"12","key":"ppat.1013947.ref060","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.4049\/jimmunol.2400227","article-title":"Regulation and dynamics of IFN-\u03b2 expression revealed with a knockin reporter mouse","volume":"213","author":"NJ Parekh","year":"2024","journal-title":"J Immunol"},{"issue":"7505","key":"ppat.1013947.ref061","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/nature13437","article-title":"Single-cell RNA-seq reveals dynamic paracrine control of cellular variation","volume":"510","author":"AK Shalek","year":"2014","journal-title":"Nature"},{"issue":"1","key":"ppat.1013947.ref062","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.virol.2006.03.022","article-title":"Sendai virus defective-interfering genomes and the activation of interferon-beta","volume":"351","author":"L Strahle","year":"2006","journal-title":"Virology"},{"key":"ppat.1013947.ref063","article-title":"Single-cell heterogeneity in interferon induction potential is heritable and governed by variation in cell state","author":"EA Thayer","year":"2025","journal-title":"bioRxiv"},{"key":"ppat.1013947.ref064","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1099\/0022-1317-56-1-175","article-title":"The characteristics required for a Sendai virus preparation to induce high levels of interferon in human lymphoblastoid cells","volume":"56","author":"MD Johnston","year":"1981","journal-title":"J Gen Virol"},{"issue":"363","key":"ppat.1013947.ref065","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2005728","article-title":"Single-cell analysis shows that paracrine signaling by first responder cells shapes the interferon-\u03b2 response to viral infection","volume":"8","author":"S Patil","year":"2015","journal-title":"Sci Signal"},{"issue":"3","key":"ppat.1013947.ref066","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.4049\/jimmunol.1202326","article-title":"Biphasic RLR-IFN-\u03b2 response controls the balance between antiviral immunity and cell damage","volume":"190","author":"S-Y Hwang","year":"2013","journal-title":"J Immunol"},{"issue":"5","key":"ppat.1013947.ref067","article-title":"Identification of individual interferon-producing cells by in situ hybridization","volume":"82","author":"R Zawatzky","year":"1985","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"3","key":"ppat.1013947.ref068","first-page":"801","article-title":"Activation of the human beta-interferon gene requires an interferon-inducible factor","volume":"6","author":"T Enoch","year":"1986","journal-title":"Mol Cell Biol"},{"issue":"1","key":"ppat.1013947.ref069","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1003847","article-title":"KSHV 2.0: a comprehensive annotation of the Kaposi\u2019s sarcoma-associated herpesvirus genome using next-generation sequencing reveals novel genomic and functional features","volume":"10","author":"C Arias","year":"2014","journal-title":"PLoS Pathog"},{"key":"ppat.1013947.ref070","article-title":"Structural basis of higher order oligomerization of KSHV inhibitor of cGAS","volume":"199","author":"D Bhowmik","year":"2022","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"ppat.1013947.ref071","article-title":"Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS","volume":"133","author":"G Zhang","year":"2016","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"47","key":"ppat.1013947.ref072","article-title":"PPM1G restricts innate immune signaling mediated by STING and MAVS and is hijacked by KSHV for immune evasion","volume":"6","author":"K Yu","year":"2020","journal-title":"Sci Adv"},{"key":"ppat.1013947.ref073","article-title":"Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses","volume":"112","author":"Z Ma","year":"2015","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"ppat.1013947.ref074","first-page":"10","article-title":"Inhibition of interferon regulatory factor 7 (IRF7)-mediated interferon signal transduction by the Kaposi\u2019s Sarcoma-associated herpesvirus viral IRF homolog vIRF3","volume":"81","author":"CH Joo","year":"2007","journal-title":"J Virol"},{"issue":"3","key":"ppat.1013947.ref075","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.bbrc.2017.03.101","article-title":"KSHV-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits interferon alpha production","volume":"486","author":"S-W Hwang","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"issue":"35","key":"ppat.1013947.ref076","doi-asserted-by":"crossref","first-page":"23272","DOI":"10.1074\/jbc.M109.033290","article-title":"Identification of caspase-mediated decay of interferon regulatory factor-3, exploited by a Kaposi sarcoma-associated herpesvirus immunoregulatory protein","volume":"284","author":"C Arest\u00e9","year":"2009","journal-title":"J Biol Chem"},{"issue":"9","key":"ppat.1013947.ref077","doi-asserted-by":"crossref","first-page":"7334","DOI":"10.1128\/JVI.73.9.7334-7342.1999","article-title":"Functional analysis of human herpesvirus 8-encoded viral interferon regulatory factor 1 and its association with cellular interferon regulatory factors and p300","volume":"73","author":"L Bur\u00fdsek","year":"1999","journal-title":"J Virol"},{"issue":"7","key":"ppat.1013947.ref078","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1038\/sj.onc.1204163","article-title":"HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP\/p300 coactivators","volume":"20","author":"R Lin","year":"2001","journal-title":"Oncogene"},{"issue":"13","key":"ppat.1013947.ref079","doi-asserted-by":"crossref","first-page":"4814","DOI":"10.1128\/MCB.20.13.4814-4825.2000","article-title":"Assembly of a functional beta interferon enhanceosome is dependent on ATF-2-c-jun heterodimer orientation","volume":"20","author":"JV Falvo","year":"2000","journal-title":"Mol Cell Biol"},{"issue":"5","key":"ppat.1013947.ref080","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.molcel.2007.04.022","article-title":"Structure of IRF-3 bound to the PRDIII-I regulatory element of the human interferon-beta enhancer","volume":"26","author":"CR Escalante","year":"2007","journal-title":"Mol Cell"},{"issue":"3","key":"ppat.1013947.ref081","doi-asserted-by":"crossref","DOI":"10.1128\/jvi.00029-23","article-title":"NF\u03baB and Cyclic AMP response element sites mediate the valproic acid and ul138 responsiveness of the human cytomegalovirus major immediate early enhancer and promoter","volume":"97","author":"ER Albright","year":"2023","journal-title":"J Virol"},{"issue":"5882","key":"ppat.1013947.ref082","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1126\/science.1157535","article-title":"The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1","volume":"320","author":"Y Sancak","year":"2008","journal-title":"Science"},{"issue":"9","key":"ppat.1013947.ref083","article-title":"A third-generation lentivirus vector with a conditional packaging system","volume":"71","author":"T Dull","year":"1997","journal-title":"J Virol"},{"key":"ppat.1013947.ref084","doi-asserted-by":"crossref","first-page":"1267078","DOI":"10.3389\/fmicb.2023.1267078","article-title":"Modulation of Influenza A virus NS1 expression reveals prioritization of host response antagonism at single-cell resolution","volume":"14","author":"Q Yang","year":"2023","journal-title":"Front Microbiol"},{"key":"ppat.1013947.ref085","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0165-022X(00)00129-9","article-title":"Effect of experimental treatment on housekeeping gene expression: validation by real-time, quantitative RT-PCR","volume":"46","author":"TD Schmittgen","year":"2000","journal-title":"J Biochem Biophys Methods"},{"issue":"5","key":"ppat.1013947.ref086","article-title":"Antagonism of host antiviral responses by Kaposi\u2019s sarcoma-associated herpesvirus tegument protein ORF45","volume":"5","author":"FX Zhu","year":"2010","journal-title":"PLoS One"},{"issue":"5","key":"ppat.1013947.ref087","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1002\/glia.23301","article-title":"A single-cell analysis reveals multiple roles of oligodendroglial lineage cells during post-ischemic regeneration","volume":"66","author":"M Valny","year":"2018","journal-title":"Glia"},{"issue":"9","key":"ppat.1013947.ref088","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1128\/JVI.80.9.4501-4509.2006","article-title":"Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo","volume":"80","author":"N Ank","year":"2006","journal-title":"J Virol"},{"issue":"2","key":"ppat.1013947.ref089","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbagrm.2018.01.002","article-title":"Regulation of the ATF3 gene by a single promoter in response to amino acid availability and endoplasmic reticulum stress in human primary hepatocytes and hepatoma cells","volume":"1861","author":"JN Hayner","year":"2018","journal-title":"Biochim Biophys Acta Gene Regul Mech"},{"key":"ppat.1013947.ref090","doi-asserted-by":"crossref","first-page":"749673","DOI":"10.3389\/fonc.2021.749673","article-title":"Upregulation of HSPA1A\/HSPA1B\/HSPA7 and downregulation of HSPA9 were related to poor survival in colon cancer","volume":"11","author":"Y Guan","year":"2021","journal-title":"Front Oncol"},{"key":"ppat.1013947.ref091","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1113\/jphysiol.2003.044883","article-title":"IL-6 gene expression in human adipose tissue in response to exercise--effect of carbohydrate ingestion","volume":"550","author":"C Keller","year":"2003","journal-title":"J Physiol"},{"issue":"1","key":"ppat.1013947.ref092","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.molcel.2015.11.004","article-title":"KAP1 recruitment of the 7SK snRNP complex to promoters enables transcription elongation by RNA polymerase II","volume":"61","author":"RP McNamara","year":"2016","journal-title":"Mol Cell"},{"issue":"2","key":"ppat.1013947.ref093","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.virol.2009.01.031","article-title":"Genome-wide identification of binding sites for Kaposi\u2019s sarcoma-associated herpesvirus lytic switch protein, RTA","volume":"386","author":"J Chen","year":"2009","journal-title":"Virology"},{"issue":"5","key":"ppat.1013947.ref094","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1002680","article-title":"KSHV PAN RNA associates with demethylases UTX and JMJD3 to activate lytic replication through a physical interaction with the virus genome","volume":"8","author":"CC Rossetto","year":"2012","journal-title":"PLoS Pathog"},{"issue":"2","key":"ppat.1013947.ref095","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.molcel.2014.11.026","article-title":"Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes","volume":"57","author":"ZH Davis","year":"2015","journal-title":"Mol Cell"},{"issue":"18","key":"ppat.1013947.ref096","doi-asserted-by":"crossref","first-page":"9866","DOI":"10.1128\/JVI.01190-12","article-title":"Binding of cellular export factor REF\/Aly by Kaposi\u2019s sarcoma-associated herpesvirus (KSHV) ORF57 protein is not required for efficient KSHV lytic replication","volume":"86","author":"D-J Li","year":"2012","journal-title":"J Virol"},{"issue":"8","key":"ppat.1013947.ref097","doi-asserted-by":"crossref","first-page":"711","DOI":"10.3390\/v11080711","article-title":"The Kaposi\u2019s sarcoma-associated herpesvirus protein ORF42 is required for efficient virion production and expression of viral proteins","volume":"11","author":"M Butnaru","year":"2019","journal-title":"Viruses"},{"issue":"7","key":"ppat.1013947.ref098","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1038\/nprot.2008.108","article-title":"A universal real-time PCR assay for the quantification of group-M HIV-1 proviral load","volume":"3","author":"MS Malnati","year":"2008","journal-title":"Nat Protoc"},{"issue":"3","key":"ppat.1013947.ref099","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.bbrc.2012.05.121","article-title":"qPCR-based mitochondrial DNA quantification: influence of template DNA fragmentation on accuracy","volume":"423","author":"CB Jackson","year":"2012","journal-title":"Biochem Biophys Res Commun"},{"key":"ppat.1013947.ref100","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/978-1-0716-2079-3_11","article-title":"Detection of damage-activated metacaspase activity by western blot in plants","volume":"2447","author":"S Stael","year":"2022","journal-title":"Methods Mol Biol"},{"key":"ppat.1013947.ref101","first-page":"7","article-title":"Toward enhanced MIQE compliance: reference residual normalization of qPCR gene expression data","volume":"25","author":"RC Edmunds","year":"2014","journal-title":"J Biomol Tech"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1013947","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013947","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T18:49:57Z","timestamp":1771526997000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013947"}},"subtitle":[],"editor":[{"given":"Pinghui","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,2,11]]},"references-count":101,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1013947","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,11]]}}}