{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T21:51:44Z","timestamp":1762033904906,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T00:00:00Z","timestamp":1650931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM109007","P20GM103408"],"award-info":[{"award-number":["P20GM109007","P20GM103408"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"United States Department of Veterans Affairs","doi-asserted-by":"publisher","award":["CDA-2-069-09S"],"award-info":[{"award-number":["CDA-2-069-09S"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human adenoviruses (HAdV) express either one or two virus-associated RNAs (VA RNAI or VA RNAII). The structure of VA RNA resembles human precursor microRNAs (pre-miRNA), and, like human pre-miRNA, VA RNA can be processed by DICER into small RNAs that resemble human miRNA. VA RNA-derived miRNA (mivaRNA) can mimic human miRNA post-transcriptional gene repression by binding to complementary sequences in the 3\u2032 UTR of host mRNA. HAdV14 is a member of the B2 subspecies of species B adenovirus, and the emergent strain HAdV14p1 is associated with severe respiratory illness that can lead to acute respiratory distress syndrome. Utilizing small RNA sequencing, we identified four main mivaRNAs generated from the HAdV14\/p1 VA RNA gene, two from each of the 5\u2032 and 3\u2032 regions of the terminal stem. There were temporal expression changes in the abundance of 5\u2032 and 3\u2032 mivaRNAs, with 3\u2032 mivaRNAs more highly expressed early in infection and 5\u2032 mivaRNAs more highly expressed later in infection. In addition, there are differences in expression between the emergent and reference strains, with HAdV14 expressing more mivaRNAs early during infection and HAdV14p1 having higher expression later during infection. HAdV14\/p1 mivaRNAs were also shown to repress gene expression in a luciferase gene reporter system. Our results raise the question as to whether differential expression of mivaRNAs during HAdV14p1 infection could play a role in the increased pathogenesis associated with the emergent strain.<\/jats:p>","DOI":"10.3390\/v14050898","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T21:37:53Z","timestamp":1651009073000},"page":"898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Characterization of Viral miRNAs during Adenovirus 14 Infection and Their Differential Expression in the Emergent Strain Adenovirus 14p1"],"prefix":"10.3390","volume":"14","author":[{"given":"Eric R.","family":"McIndoo","sequence":"first","affiliation":[{"name":"Research Section, Boise VA Medical Center, Idaho Veterans Research and Education Foundation, Boise, ID 83642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hailey M.","family":"Burgoyne","sequence":"additional","affiliation":[{"name":"Research Section, Boise VA Medical Center, Idaho Veterans Research and Education Foundation, Boise, ID 83642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyung-Sup","family":"Shin","sequence":"additional","affiliation":[{"name":"College of Southern Nevada, Henderson, NV 89002, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1696-6531","authenticated-orcid":false,"given":"Jay R.","family":"Radke","sequence":"additional","affiliation":[{"name":"Research Section, Boise VA Medical Center, Idaho Veterans Research and Education Foundation, Boise, ID 83642, USA"},{"name":"Department of Biological Sciences, Boise State University, Boise, ID 83725, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1086\/522970","article-title":"Abrupt Emergence of Diverse Species B Adenoviruses at US Military Recruit Training Centers","volume":"196","author":"Metzgar","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_2","unstructured":"Centers for Disease Control and Prevention (CDC) (2007). Acute Respiratory Disease Associated with Adenovirus Serotype 14\u2014Four States, 2006\u20132007. MMWR Morb. Mortal. Wkly. Rep., 56, 1181\u20131184."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1111\/irv.12118","article-title":"Outbreak of Febrile Respiratory Illness Associated with Human Adenovirus Type 14p1 in Gansu Province, China","volume":"7","author":"Huang","year":"2013","journal-title":"Influ. Other Respir."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1093\/pubmed\/fdu009","article-title":"Prison and Community Outbreak of Severe Respiratory Infection Due to Adenovirus Type 14p1 in Tayside, UK","volume":"37","author":"Parcell","year":"2015","journal-title":"J. Public Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3201\/eid1901.120423","article-title":"Adenovirus Serotype 14 Infection, New Brunswick, Canada, 2011","volume":"19","author":"Girouard","year":"2013","journal-title":"Emerg. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.3201\/1708.101760","article-title":"Deaths Associated with Human Adenovirus-14p1 Infections, Europe, 2009\u20132010","volume":"17","author":"Carr","year":"2011","journal-title":"Emerg. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1086\/522969","article-title":"Emergence of Adenovirus Type 14 in US Military Recruits\u2014A New Challenge","volume":"196","author":"Binn","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Radke, J.R., Covert, H.J., Bauer, F., Ananthanarayanan, V., and Cook, J.L. (2020). Adenovirus 14p1 Immunopathogenesis during Lung Infection in the Syrian Hamster. Viruses, 12.","DOI":"10.3390\/v12060595"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/1465-9921-11-116","article-title":"Genome Sequences of Human Adenovirus 14 Isolates from Mild Respiratory Cases and a Fatal Pneumonia, Isolated during 2006-2007 Epidemics in North America","volume":"11","author":"Houng","year":"2010","journal-title":"Respir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Punga, T., Darweesh, M., and Akusj\u00e4rvi, G. (2020). Synthesis, Structure, and Function of Human Adenovirus Small Non-Coding RNAs. Viruses, 12.","DOI":"10.3390\/v12101182"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.virusres.2015.06.018","article-title":"Adenovirus VA RNA: An Essential Pro-Viral Non-Coding RNA","volume":"212","author":"Vachon","year":"2015","journal-title":"Virus Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.3389\/fmicb.2017.01324","article-title":"MicroRNAs as Important Players in Host\u2013Adenovirus Interactions","volume":"8","author":"Piedade","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/0092-8674(76)90209-9","article-title":"A New Species of Virus-Coded Low Molecular Weight RNA from Cells Infected with Adenovirus Type 2","volume":"7","author":"Pettersson","year":"1976","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/0092-8674(75)90013-6","article-title":"Genes for VA-RNA in Adenovirus 2","volume":"6","author":"Mathews","year":"1975","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5657","DOI":"10.1128\/jvi.65.11.5657-5662.1991","article-title":"Adenovirus Virus-Associated RNA and Translation Control","volume":"65","author":"Mathews","year":"1991","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5083","DOI":"10.1128\/jvi.70.8.5083-5099.1996","article-title":"Structure, Function, and Evolution of Adenovirus-Associated RNA: A Phylogenetic Approach","volume":"70","author":"Ma","year":"1996","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/0092-8674(82)90310-5","article-title":"Adenovirus VAI RNA Is Required for Efficient Translation of Viral MRNAs at Late Times after Infection","volume":"31","author":"Thimmappaya","year":"1982","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7377","DOI":"10.1093\/nar\/12.19.7377","article-title":"Adenovirus Mutants with DNA Sequence Perturbations in the Intragenic Promoter of VAI RNA Gene Allow the Enhanced Transcription of VAII RNA Gene in HeLa Cells","volume":"12","author":"Bhat","year":"1984","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1038\/s41467-019-10752-6","article-title":"Crystal Structure of an Adenovirus Virus-Associated RNA","volume":"10","author":"Hood","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1093\/nar\/gkn020","article-title":"Analysis of Adenovirus VA RNA I Structure and Stability Using Compensatory Base Pair Modifications","volume":"36","author":"Coventry","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6605","DOI":"10.1128\/jvi.67.11.6605-6617.1993","article-title":"Comparative Analysis of the Structure and Function of Adenovirus Virus-Associated RNAs","volume":"67","author":"Ma","year":"1993","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0092-8674(86)90383-1","article-title":"Adenovirus VAI RNA Antagonizes the Antiviral Action of Interferon by Preventing Activation of the Interferon-Induced EIF-2\u03b1 Kinase","volume":"45","author":"Kitajewski","year":"1986","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/0042-6822(88)90625-3","article-title":"Characterization of the Double-Stranded RNA Implicated in the Inhibition of Protein Synthesis in Cells Infected with a Mutant Adenovirus Defective for VA RNA","volume":"164","author":"Maran","year":"1988","journal-title":"Virology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/0092-8674(86)90460-5","article-title":"A Mechanism for the Control of Protein Synthesis by Adenovirus VA RNAI","volume":"44","author":"Mariano","year":"1986","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3454","DOI":"10.1074\/jbc.270.7.3454","article-title":"Activation of Interferon-Inducible 2\u2032\u22125\u2032 Oligoadenylate Synthetase by Adenoviral VAI RNA","volume":"270","author":"Desai","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1093\/nar\/gkp1028","article-title":"Adenovirus VA RNA-Derived MiRNAs Target Cellular Genes Involved in Cell Growth, Gene Expression and DNA Repair","volume":"38","author":"Aparicio","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kamel, W., Segerman, B., Punga, T., and Akusj\u00e4rvi, G. (2014). Small RNA Sequence Analysis of Adenovirus VA RNA-Derived MiRNAs Reveals an Unexpected Serotype-Specific Difference in Structure and Abundance. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105746"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.jmb.2012.06.017","article-title":"Regulation of the Interferon-Inducible 2\u2032\u20135\u2032-Oligoadenylate Synthetases by Adenovirus VAI RNA","volume":"422","author":"Meng","year":"2012","journal-title":"J. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/nar\/5.1.205","article-title":"Initiation of Transcription in Nuclei Isolated from Adenovirus Infected Cells","volume":"5","author":"Pettersson","year":"1978","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17286","DOI":"10.1073\/pnas.1009823107","article-title":"Induction of Type I Interferon by Adenovirus-Encoded Small RNAs","volume":"107","author":"Yamaguchi","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1126\/science.1132505","article-title":"5\u2032-Triphosphate RNA Is the Ligand for RIG-I","volume":"314","author":"Hornung","year":"2006","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1128\/JVI.02160-10","article-title":"Adenovirus Virus-Associated RNAs Induce Type I Interferon Expression through a RIG-I-Mediated Pathway","volume":"85","author":"Minamitani","year":"2011","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5505","DOI":"10.1074\/jbc.C200668200","article-title":"Exportin-5 Mediates Nuclear Export of Minihelix-Containing RNAs","volume":"278","author":"Gwizdek","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"25910","DOI":"10.1074\/jbc.M100493200","article-title":"Terminal Minihelix, a Novel RNA Motif That Directs Polymerase III Transcripts to the Cell Cytoplasm Terminal Minihelix and RNA Export","volume":"276","author":"Gwizdek","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6205","DOI":"10.1093\/emboj\/cdf613","article-title":"Exp5 Exports EEF1A via TRNA from Nuclei and Synergizes with Other Transport Pathways to Confine Translation to the Cytoplasm","volume":"21","author":"Bohnsack","year":"2002","journal-title":"EMBO J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1083\/jcb.200110082","article-title":"Exportin-5, a Novel Karyopherin, Mediates Nuclear Export of Double-Stranded RNA Binding Proteins","volume":"156","author":"Brownawell","year":"2002","journal-title":"J. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12868","DOI":"10.1128\/JVI.78.23.12868-12876.2004","article-title":"Adenovirus VA1 Noncoding RNA Can Inhibit Small Interfering RNA and MicroRNA Biogenesis","volume":"78","author":"Lu","year":"2004","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9556","DOI":"10.1128\/JVI.79.15.9556-9565.2005","article-title":"Suppression of RNA Interference by Adenovirus Virus-Associated RNA","volume":"79","author":"Andersson","year":"2005","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10540","DOI":"10.1128\/JVI.00885-07","article-title":"Adenovirus Virus-Associated RNAII-Derived Small RNAs Are Efficiently Incorporated into the RNA-Induced Silencing Complex and Associate with Polyribosomes","volume":"81","author":"Xu","year":"2007","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1128\/JVI.80.3.1376-1384.2006","article-title":"Adenovirus Virus-Associated RNA Is Processed to Functional Interfering RNAs Involved in Virus Production","volume":"80","author":"Aparicio","year":"2006","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/j.febslet.2006.01.085","article-title":"Sequence-specific Interference by Small RNAs Derived from Adenovirus VAI RNA","volume":"580","author":"Sano","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1128\/JVI.02336-14","article-title":"Identification of RISC-Associated Adenoviral MicroRNAs, a Subset of Their Direct Targets, and Global Changes in the Targetome upon Lytic Adenovirus 5 Infection","volume":"89","author":"Bellutti","year":"2014","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e01265-18","DOI":"10.1128\/JVI.01265-18","article-title":"A MicroRNA Derived from Adenovirus Virus-Associated RNAII Promotes Virus Infection via Post-Transcriptional Gene Silencing","volume":"93","author":"Wakabayashi","year":"2019","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.virusres.2009.03.011","article-title":"Genomic and Bioinformatics Analyses of HAdV-14p, Reference Strain of a Re-Emerging Respiratory Pathogen and Analysis of B1\/B2","volume":"143","author":"Seto","year":"2009","journal-title":"Virus Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.bbrc.2009.07.167","article-title":"2\u2032-5\u2032-Oligoadenylate Synthetase Is Activated by a Specific RNA Sequence Motif","volume":"388","author":"Kodym","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1093\/nar\/gku1289","article-title":"A Novel RNA Molecular Signature for Activation of 2\u2032-5\u2032 Oligoadenylate Synthetase-1","volume":"43","author":"Vachon","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/1471-2105-11-129","article-title":"RNAstructure: Software for RNA Secondary Structure Prediction and Analysis","volume":"11","author":"Reuter","year":"2010","journal-title":"BMC Bioinform."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.virol.2013.04.006","article-title":"Identification of Adenovirus-Encoded Small RNAs by Deep RNA Sequencing","volume":"442","author":"Zhao","year":"2013","journal-title":"Virology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.jcv.2012.03.006","article-title":"A Comparison of Viral Fitness and Virulence between Emergent Adenovirus 14p1 and Prototype Adenovirus 14p Strains","volume":"54","author":"Anderson","year":"2012","journal-title":"J. Clin. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1128\/JVI.01790-15","article-title":"Low-Level Expression of the E1B 20-Kilodalton Protein by Adenovirus 14p1 Enhances Viral Immunopathogenesis","volume":"90","author":"Radke","year":"2016","journal-title":"J. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4802","DOI":"10.1093\/nar\/gkt172","article-title":"The Adenovirus VA RNA-Derived MiRNAs Are Not Essential for Lytic Virus Growth in Tissue Culture Cells","volume":"41","author":"Kamel","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.virol.2013.08.024","article-title":"Persistently Adenovirus-Infected Lymphoid Cells Express MicroRNAs Derived from the Viral VAI and Especially VAII RNA","volume":"447","author":"Furuse","year":"2013","journal-title":"Virology"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Assadian, F., Kamel, W., Laurell, G., Svensson, C., Punga, T., and Akusj\u00e4rvi, G. (2017). Expression Profile of Epstein-Barr Virus and Human Adenovirus Small RNAs in Tonsillar B and T Lymphocytes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177275"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1261\/rna.061291.117","article-title":"An Ago2-Associated Capped Transcriptional Start Site Small RNA Suppresses Adenovirus DNA Replication","volume":"23","author":"Kamel","year":"2017","journal-title":"RNA"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/5\/898\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:01:07Z","timestamp":1760137267000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/5\/898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,26]]},"references-count":54,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["v14050898"],"URL":"https:\/\/doi.org\/10.3390\/v14050898","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2022,4,26]]}}}