{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T05:06:19Z","timestamp":1771650379376,"version":"3.50.1"},"reference-count":86,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T00:00:00Z","timestamp":1624233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI116812"],"award-info":[{"award-number":["R01 AI116812"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005640","name":"Flight Attendant Medical Research Institute","doi-asserted-by":"publisher","award":["160020"],"award-info":[{"award-number":["160020"]}],"id":[{"id":"10.13039\/100005640","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The recently discovered exchange protein directly activated by cAMP (EPAC), compared with protein kinase A (PKA), is a fairly new family of cAMP effectors. Soon after the discovery, EPAC has shown its significance in many diseases including its emerging role in infectious diseases. In a recent study, we demonstrated that EPAC, but not PKA, is a promising therapeutic target to regulate respiratory syncytial virus (RSV) replication and its associated inflammation. In mammals, there are two isoforms of EPAC\u2014EPAC1 and EPAC2. Unlike other viruses, including Middle East respiratory syndrome coronavirus (MERS-CoV) and Ebola virus, which use EPAC1 to regulate viral replication, RSV uses EPAC2 to control its replication and associated cytokine\/chemokine responses. To determine whether EPAC2 protein has a broad impact on other respiratory viral infections, we used an EPAC2-specific inhibitor, MAY0132, to examine the functions of EPAC2 in human metapneumovirus (HMPV) and adenovirus (AdV) infections. HMPV is a negative-sense single-stranded RNA virus belonging to the family Pneumoviridae, which also includes RSV, while AdV is a double-stranded DNA virus. Treatment with an EPAC1-specific inhibitor was also included to investigate the impact of EPAC1 on these two viruses. We found that the replication of HMPV, AdV, and RSV and the viral-induced immune mediators are significantly impaired by MAY0132, while an EPAC1-specific inhibitor, CE3F4, does not impact or slightly impacts, demonstrating that EPAC2 could serve as a novel common therapeutic target to control these viruses, all of which do not have effective treatment and prevention strategies.<\/jats:p>","DOI":"10.3390\/v13061179","type":"journal-article","created":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T04:21:21Z","timestamp":1624249281000},"page":"1179","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Broad Impact of Exchange Protein Directly Activated by cAMP 2 (EPAC2) on Respiratory Viral Infections"],"prefix":"10.3390","volume":"13","author":[{"given":"Eun-Jin","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenzhe","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Cong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqi","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sha","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pingyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Toxicology, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adarsh","family":"Suresh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"},{"name":"Department of Kinesiology, Rice University, Houston, TX 77005, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uneeb Mohammad","family":"Ullah","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"},{"name":"College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2811-1090","authenticated-orcid":false,"given":"Jia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Toxicology, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"},{"name":"Sealy Center for Molecular Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA"},{"name":"The Institute of Translational Sciences, The University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6884-2584","authenticated-orcid":false,"given":"Xiaoyong","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX 77555-0372, USA"},{"name":"Sealy Center for Molecular Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA"},{"name":"The Institute of Translational Sciences, The University of Texas Medical Branch, Galveston, TX 77555, USA"},{"name":"The Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,21]]},"reference":[{"key":"ref_1","unstructured":"Forum of International Respiratory Societies (2017). The Global Impact of Respiratory Disease, European Respiratory Society."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Wardlaw, T.M., Johansson, E.W., Hodge, M., World Health Organization, and UNICEF (2006). Pneumonia: The Forgotten Killer of Children.","DOI":"10.1016\/S0140-6736(06)69334-3"},{"key":"ref_3","unstructured":"Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J.L., and Loscalzo, J. (2014). Infections Due to DNA and RNA Respiratory Viruses. Harrison\u2019s Principles of Internal Medicine, McGraw-Hill Education. [19th ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding","volume":"395","author":"Lu","year":"2020","journal-title":"Lancet"},{"key":"ref_5","unstructured":"World Health Organization (2020). Disease Outbreak News. Novel Coronavirus\u2014China, WHO."},{"key":"ref_6","unstructured":"World Health Organization (2020). WHO Coronavirus (COVID-19) Dashboard, WHO."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12889-021-10708-w","article-title":"Health, psychosocial, and economic impacts of the COVID-19 pandemic on people with chronic conditions in India: A mixed methods study","volume":"21","author":"Singh","year":"2021","journal-title":"BMC Public Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1086\/367901","article-title":"Human Metapneumovirus Infections in Young and Elderly Adults","volume":"187","author":"Falsey","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1086\/379771","article-title":"Human Metapneumovirus-Associated Lower Respiratory Tract Infections among Hospitalized Human Immunodeficiency Virus Type 1 (HIV-1)-Infected and HIV-1-Uninfected African Infants","volume":"37","author":"Madhi","year":"2003","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.1128\/JCM.41.7.3043-3045.2003","article-title":"High Prevalence of Human Metapneumovirus Infection in Young Children and Genetic Heterogeneity of the Viral Isolates","volume":"41","author":"Viazov","year":"2003","journal-title":"J. Clin. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S215","DOI":"10.1097\/01.inf.0000144668.81573.6d","article-title":"Human Metapneumovirus as a Major Cause of Human Respiratory Tract Disease","volume":"23","author":"Crowe","year":"2004","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1056\/NEJMoa1204630","article-title":"Burden of Human Metapneumovirus Infection in Young Children","volume":"368","author":"Edwards","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1056\/NEJMoa0804877","article-title":"The Burden of Respiratory Syncytial Virus Infection in Young Children","volume":"360","author":"Hall","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"010426","DOI":"10.7189\/jogh.10.010426","article-title":"The role of viral co-infections in the severity of acute respiratory infections among children infected with respiratory syncytial virus (RSV): A systematic review and meta-analysis","volume":"10","author":"Li","year":"2020","journal-title":"J. Glob. Health"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1086\/426457","article-title":"Dual Infection of Infants by Human Metapneumovirus and Human Respiratory Syncytial Virus Is Strongly Associated with Severe Bronchiolitis","volume":"191","author":"Semple","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"629971","DOI":"10.3389\/fmicb.2021.629971","article-title":"The Epidemiology, Molecular, and Clinical of Human Adenoviruses in Children Hospitalized with Acute Respiratory Infections","volume":"12","author":"Wen","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.3201\/eid2206.151898","article-title":"Human Adenovirus Associated with Severe Respiratory Infection, Oregon, USA, 2013\u20132014","volume":"22","author":"Scott","year":"2016","journal-title":"Emerg. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Alharbi, S., Van Caeseele, P., Consunji-Araneta, R., Zoubeidi, T., Fanella, S., Souid, A.-K., and Alsuwaidi, A.R. (2012). Epidemiology of severe pediatric adenovirus lower respiratory tract infections in Manitoba, Canada, 1991\u20132005. BMC Infect. Dis., 12.","DOI":"10.1186\/1471-2334-12-55"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1086\/522188","article-title":"Genotype prevalence and risk factors for severe clinical adenovirus infection, United States 2004\u20132006","volume":"45","author":"Gray","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1128\/CMR.00052-07","article-title":"Adenoviruses in Immunocompromised Hosts","volume":"21","year":"2008","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1080\/21645515.2017.1337614","article-title":"Product review on the monoclonal antibody palivizumab for prevention of respiratory syncytial virus infection","volume":"13","author":"Resch","year":"2017","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/24884","article-title":"Epac is a Rap1 gua-nine-nucleotide-exchange factor directly activated by cyclic AMP","volume":"396","author":"Zwartkruis","year":"1998","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1126\/science.282.5397.2275","article-title":"A family of cAMP-binding proteins that directly activate Rap1","volume":"282","author":"Kawasaki","year":"1998","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1161\/CIRCRESAHA.107.164947","article-title":"Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy","volume":"102","author":"Metrich","year":"2008","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s11010-017-2959-3","article-title":"Role of exchange protein directly activated by cAMP (EPAC1) in breast cancer cell migration and apoptosis","volume":"430","author":"Kumar","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24248","DOI":"10.1074\/jbc.M109.094581","article-title":"Differential Roles of Epac in Regulating Cell Death in Neuronal and Myocardial Cells","volume":"285","author":"Suzuki","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.nbd.2019.02.019","article-title":"Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db\/db mouse model of type 2 diabetes","volume":"127","author":"Griggs","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3902","DOI":"10.1128\/JVI.03001-13","article-title":"Blocking of Exchange Proteins Directly Activated by cAMP Leads to Reduced Replication of Middle East Respiratory Syndrome Coronavirus","volume":"88","author":"Tao","year":"2014","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12931-019-1260-2","article-title":"Exchange protein directly activated by cAMP (Epac) protects against airway inflammation and airway remodeling in asthmatic mice","volume":"20","author":"Chen","year":"2019","journal-title":"Respir. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.tips.2015.02.003","article-title":"The future of EPAC-targeted therapies: Agonism versus antagonism","volume":"36","author":"Parnell","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Xu, Y., Schwede, F., Wienk, H., Tengholm, A., and Rehmann, H. (2019). A Membrane Permeable Prodrug of S223 for Selective Epac2 Activation in Living Cells. Cells, 8.","DOI":"10.3390\/cells8121589"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1161\/CIRCRESAHA.115.306529","article-title":"Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease","volume":"118","author":"Fazal","year":"2016","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1128\/JVI.01200-18","article-title":"Exchange Proteins Directly Activated by cAMP and Their Roles in Respiratory Syncytial Virus Infection","volume":"92","author":"Choi","year":"2018","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1093\/jmcb\/mjy045","article-title":"IFN-stimulated P2Y13 protects mice from viral infection by suppressing the cAMP\/EPAC1 signaling pathway","volume":"11","author":"Zhang","year":"2018","journal-title":"J. Mol. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Drelich, A., Judy, B., He, X., Chang, Q., Yu, S., Li, X., Lu, F., Wakamiya, M., Popov, V., and Zhou, J. (2018). Exchange Protein Directly Activated by cAMP Modulates Ebola Virus Uptake into Vascular Endothelial Cells. Viruses, 10.","DOI":"10.3390\/v10100563"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.bbrc.2013.09.107","article-title":"The (R)-enantiomer of CE3F4 is a preferential inhibitor of human exchange protein directly activated by cyclic AMP isoform 1 (Epac1)","volume":"440","author":"Courilleau","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5163","DOI":"10.1016\/j.bmcl.2017.10.056","article-title":"Structure-activity relationships of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of exchange proteins directly activated by cAMP (EPACs)","volume":"27","author":"Liu","year":"2017","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Bao, X., Liu, T., Shan, Y., Li, K., Garofalo, R.P., and Casola, A. (2008). Human Metapneumovirus Glycoprotein G Inhibits Innate Immune Responses. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.1000077"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.virol.2007.12.024","article-title":"Identification of human metapneu-movirus-induced gene networks in airway epithelial cells by microarray analysis","volume":"374","author":"Bao","year":"2008","journal-title":"Virology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8224","DOI":"10.1128\/JVI.02584-07","article-title":"Human metapneumovirus small hydrophobic protein inhibits NF-kappaB transcriptional activity","volume":"82","author":"Bao","year":"2008","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1074\/mcp.M117.067116","article-title":"Identifying Host Factors Associated with DNA Replicated During Virus Infection","volume":"16","author":"Reyes","year":"2017","journal-title":"Mol. Cell. Proteom."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.virol.2010.09.016","article-title":"IKKepsilon modulates RSV-induced NF-kappaB-dependent gene transcription","volume":"408","author":"Bao","year":"2010","journal-title":"Virology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1021\/acsmedchemlett.5b00477","article-title":"Functionalized N,N-Diphenylamines as Potent and Selective EPAC2 Inhibitors","volume":"7","author":"Wild","year":"2016","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"13049","DOI":"10.1128\/JVI.01248-12","article-title":"Human Metapneumovirus M2-2 Protein Inhibits Innate Cellular Signaling by Targeting MAVS","volume":"86","author":"Ren","year":"2012","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5557","DOI":"10.1128\/JVI.00264-15","article-title":"Role of Hydrogen Sulfide in Paramyxovirus Infections","volume":"89","author":"Li","year":"2015","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1165\/rcmb.2005-0287OC","article-title":"Differential Response of Dendritic Cells to Human Metapneumovirus and Respiratory Syncytial Virus","volume":"34","author":"Casola","year":"2006","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14992","DOI":"10.1128\/JVI.79.23.14992-14997.2005","article-title":"Human Metapneumovirus Induces a Profile of Lung Cytokines Distinct from That of Respiratory Syncytial Virus","volume":"79","author":"Casola","year":"2005","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1465-9921-8-6","article-title":"Human metapneumovirus induces more severe disease and stronger innate immune response in BALB\/c mice as compared with respiratory syncytial virus","volume":"8","author":"Huck","year":"2007","journal-title":"Respir. Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Malmo, J., Moe, N., Krokstad, S., Ryan, L., Loevenich, S., Johnsen, I.B., Espevik, T., Nordb\u00f8, S.A., D\u00f8llner, H., and Anthonsen, M.W. (2016). Cytokine Profiles in Human Metapneumovirus Infected Children: Identification of Genes Involved in the Antiviral Response and Pathogenesis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155484"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/pr.2015.113","article-title":"Prem-ature infants have impaired airway antiviral IFNgamma responses to human metapneumovirus compared to respiratory syncytial virus","volume":"78","author":"Pancham","year":"2015","journal-title":"Pediatr. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1099\/vir.0.81541-0","article-title":"Induction of cytokine expression by herpes simplex virus in human monocyte-derived macrophages and dendritic cells is dependent on virus replication and is counteracted by ICP27 targeting NF-kappaB and IRF-3","volume":"87","author":"Melchjorsen","year":"2006","journal-title":"J. Gen. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1165\/rcmb.2013-0354OC","article-title":"Rhinovirus-Induced Macrophage Cytokine Expression Does Not Require Endocytosis or Replication","volume":"50","author":"Saba","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Forbester, J.L., Clement, M., Wellington, D., Yeung, A., Dimonte, S., Marsden, M., Chapman, L., Coomber, E.L., Tolley, C., and Lees, E. (2020). IRF5 Promotes Influenza Virus-Induced Inflam-matory Responses in Human Induced Pluripotent Stem Cell-Derived Myeloid Cells and Murine Models. J. Virol., 94.","DOI":"10.1128\/JVI.00121-20"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.jcv.2017.03.003","article-title":"Serum IFN-gamma-induced protein 10 (IP-10) as a biomarker for severity of acute respiratory infection in healthy adults","volume":"90","author":"Hayney","year":"2017","journal-title":"J. Clin. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1189\/jlb.0606412","article-title":"Human rhinovirus induces robust IP-10 release by monocytic cells, which is independent of viral replication but linked to type I interferon receptor ligation and STAT1 activation","volume":"80","author":"Bates","year":"2006","journal-title":"J. Leukoc. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"L18","DOI":"10.1152\/ajplung.2001.280.1.L18","article-title":"Reovirus triggers cell type-specific proinflammatory responses dependent on the autocrine action of IFN-beta","volume":"280","author":"Hamamdzic","year":"2001","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/0042-6822(83)90325-2","article-title":"Structure and function of adenovirus DNA binding protein: Comparison of the amino acid sequences of the Ad5 and Ad12 proteins derived from the nucleotide sequence of the corre-sponding genes","volume":"128","author":"Kruijer","year":"1983","journal-title":"Virology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S1386-6532(01)00159-7","article-title":"Cytokines and chemokines in respiratory secretion and severity of disease in infants with respiratory syncytial virus (RSV) infection","volume":"21","author":"Hornsleth","year":"2001","journal-title":"J. Clin. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9590","DOI":"10.1128\/JVI.00740-12","article-title":"Vaccination with Adenovirus Serotypes 35, 26, and 48 Elicits Higher Levels of Innate Cytokine Responses than Adenovirus Serotype 5 in Rhesus Monkeys","volume":"86","author":"Teigler","year":"2012","journal-title":"J. Virol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1165\/ajrcmb.21.4.3677","article-title":"Type-Specific Induction of Interleukin-8 by Adenovirus","volume":"21","author":"Booth","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11241","DOI":"10.1128\/JVI.00721-06","article-title":"Interaction of Adenovirus Type 5 Fiber with the Coxsackievirus and Adenovirus Receptor Activates Inflammatory Response in Human Respiratory Cells","volume":"80","author":"Tamanini","year":"2006","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"a000034","DOI":"10.1101\/cshperspect.a000034","article-title":"The NF-kappaB family of transcription factors and its regulation","volume":"1","author":"Oeckinghaus","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Song, K., and Li, S. (2021). The Role of Ubiquitination in NF-kappaB Signaling during Virus Infection. Viruses, 13.","DOI":"10.3390\/v13020145"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.virol.2007.06.023","article-title":"Airway epithelial cell response to human metapneumovirus infection","volume":"368","author":"Bao","year":"2007","journal-title":"J. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7267","DOI":"10.1128\/JVI.00142-10","article-title":"Respiratory syncytial virus-mediated NF-kappa B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKK beta","volume":"84","author":"Yoboua","year":"2010","journal-title":"J. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1124\/pr.110.003707","article-title":"Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions","volume":"65","author":"Schmidt","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1016\/j.bmcl.2017.02.065","article-title":"Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets","volume":"27","author":"Wang","year":"2017","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"44192","DOI":"10.1074\/jbc.M112.422956","article-title":"Identification of a tetrahydroquinoline analog as a pharmacological inhibitor of the cAMP-binding protein Epac","volume":"287","author":"Courilleau","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_69","first-page":"1766","article-title":"Identification of a pharmacological inhibitor of Epac1 that protects the heart against acute and chronic models of cardiac stress","volume":"115","author":"Laudette","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1128\/CMR.7.2.143","article-title":"Mixed viral infections: Detection and management","volume":"7","author":"Waner","year":"1994","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.jcv.2008.03.012","article-title":"Multiple simultaneous viral infections in infants with acute respiratory tract infections in Spain","volume":"42","author":"Calvo","year":"2008","journal-title":"J. Clin. Virol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/ppul.21552","article-title":"Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis","volume":"47","author":"Brand","year":"2012","journal-title":"Pediatr. Pulmonol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1093\/infdis\/jis934","article-title":"Epidemiology of Multiple Respiratory Viruses in Childcare Attendees","volume":"207","author":"Martin","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/j.1750-2659.2011.00265.x","article-title":"Multiple versus single virus respiratory infections: Viral load and clinical disease severity in hospitalized children","volume":"6","author":"Martin","year":"2012","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Pinky, L., and Dobrovolny, H.M. (2016). Coinfections of the Respiratory Tract: Viral Competition for Resources. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155589"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/ppul.25166","article-title":"Childhood bronchiolitis obliterans in Hong Kong-case series over a 20-year period","volume":"56","author":"Chan","year":"2021","journal-title":"Pediatr. Pulmonol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1017\/S0950268814000302","article-title":"Single, dual and multiple respiratory virus infections and risk of hospi-talization and mortality","volume":"143","author":"Goka","year":"2015","journal-title":"Epidemiol. Infect."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1097\/INF.0b013e31815b4935","article-title":"The Impact of Dual Viral Infection in Infants Admitted to a Pediatric Intensive Care Unit Associated with Severe Bronchiolitis","volume":"27","author":"Richard","year":"2008","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11908-020-0711-8","article-title":"Respiratory Virus Co-infection in Acute Respiratory Infections in Children","volume":"22","author":"Meskill","year":"2020","journal-title":"Curr. Infect. Dis. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1002\/jmv.10255","article-title":"Simultaneous detection of influenza A, B, and C viruses, respiratory syncytial virus, and adenoviruses in clinical samples by multiplex reverse transcription nested-PCR assay","volume":"69","author":"Coiras","year":"2003","journal-title":"J. Med. Virol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Liu, T., Zhang, L., Joo, D., and Sun, S.C. (2017). NF-kappaB signaling in inflammation. Signal Transduct. Target Ther., 2.","DOI":"10.1038\/sigtrans.2017.23"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1099\/vir.0.2008\/000778-0","article-title":"Role of retinoic acid inducible gene-I in human metapneu-movirus-induced cellular signalling","volume":"89 Pt 8","author":"Liao","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/35099560","article-title":"Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3","volume":"413","author":"Alexopoulou","year":"2001","journal-title":"Nature"},{"key":"ref_84","first-page":"101","article-title":"Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses","volume":"441","author":"Kato","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/ni1087","article-title":"The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses","volume":"5","author":"Yoneyama","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"37427","DOI":"10.1074\/jbc.M605311200","article-title":"The Functional Effects of Physical Interactions among Toll-like Receptors 7, 8, and 9","volume":"281","author":"Wang","year":"2006","journal-title":"J. Biol. Chem."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/6\/1179\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:19:49Z","timestamp":1760163589000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/6\/1179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,21]]},"references-count":86,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["v13061179"],"URL":"https:\/\/doi.org\/10.3390\/v13061179","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,21]]}}}