{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:06:33Z","timestamp":1792613193113,"version":"4.5.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T00:00:00Z","timestamp":1645574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AG069226"],"award-info":[{"award-number":["R21AG069226"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>The ongoing pandemic of coronavirus disease 2019 (COVID-19), which results from the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a significant global public health threat, with molecular mechanisms underlying its pathogenesis largely unknown. In the context of viral infections, small non-coding RNAs (sncRNAs) are known to play important roles in regulating the host responses, viral replication, and host-virus interaction. Compared with other subfamilies of sncRNAs, including microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), tRNA-derived RNA fragments (tRFs) are relatively new and emerge as a significant regulator of host-virus interactions. Using T4 PNK\u2010RNA\u2010seq, a modified next-generation sequencing (NGS), we found that sncRNA profiles in human nasopharyngeal swabs (NPS) samples are significantly impacted by SARS-CoV-2. Among impacted sncRNAs, tRFs are the most significantly affected and most of them are derived from the 5\u2032-end of tRNAs (tRF5). Such a change was also observed in SARS-CoV-2-infected airway epithelial cells. In addition to host-derived ncRNAs, we also identified several small virus-derived ncRNAs (svRNAs), among which a svRNA derived from CoV2 genomic site 346 to 382 (sv-CoV2-346) has the highest expression. The induction of both tRFs and sv-CoV2-346 has not been reported previously, as the lack of the 3\u2032-OH ends of these sncRNAs prevents them to be detected by routine NGS. In summary, our studies demonstrated the involvement of tRFs in COVID-19 and revealed new CoV2 svRNAs.<\/jats:p>","DOI":"10.3389\/fmolb.2022.821137","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T09:09:39Z","timestamp":1645607379000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Changes of Small Non-coding RNAs by Severe Acute Respiratory Syndrome Coronavirus 2 Infection"],"prefix":"10.3389","volume":"9","author":[{"given":"Wenzhe","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Jin","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binbin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Awadalkareem","family":"Adam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gengming","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Tunkle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Goru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Imirowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leanne","family":"Henry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inhan","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianli","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyong","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1152\/physrev.00041.2015","article-title":"Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches","volume":"96","author":"Beermann","year":"2016","journal-title":"Physiol. Rev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1007\/s00408-016-9875-2","article-title":"Cells and Culture Systems Used to Model the Small Airway Epithelium","volume":"194","author":"Bhowmick","year":"2016","journal-title":"Lung"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2020","DOI":"10.15252\/embj.201489282","article-title":"Aberrant Methylation of T RNA S Links Cellular Stress to Neuro\u2010developmental Disorders","volume":"33","author":"Blanco","year":"2014","journal-title":"EMBO J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1016\/j.cell.2020.04.026","article-title":"Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19","volume":"181","author":"Blanco-Melo","year":"2020","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e107405","DOI":"10.15252\/embj.2020107405","article-title":"Syncytia Formation by SARS-CoV-2-Infected Cells","volume":"40","author":"Buchrieser","year":"2021","journal-title":"EMBO J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"11644","DOI":"10.1038\/s41598-017-11271-4","article-title":"Fast-track Development of an In Vitro 3D Lung\/immune Cell Model to Study Aspergillus Infections","volume":"7","author":"Chandorkar","year":"2017","journal-title":"Sci. Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"444324","DOI":"10.1101\/2021.05.16.444324","article-title":"Verification of SARS-CoV-2-Encoded Small RNAs and Contribution to Infection-Associated Lung Inflammation","volume":"2005","author":"Cheng","year":"20212021","journal-title":"bioRxiv"},{"key":"B8","doi-asserted-by":"publisher","first-page":"609732","DOI":"10.3389\/fmolb.2020.609732","article-title":"ELAC2, an Enzyme for tRNA Maturation, Plays a Role in the Cleavage of a Mature tRNA to Produce a tRNA-Derived RNA Fragment during Respiratory Syncytial Virus Infection","volume":"7","author":"Choi","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/jbt.20325","article-title":"Small Noncoding RNAs: Biogenesis, Function, and Emerging Significance in Toxicology","volume":"24","author":"Choudhuri","year":"2010","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1186\/1471-2105-14-S14-S2","article-title":"Systematic Classification of Non-coding RNAs by Epigenomic Similarity","author":"Dozmorov","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"B11","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1038\/nsmb.2296","article-title":"The Mechanics of miRNA-Mediated Gene Silencing: a Look under the Hood of miRISC","volume":"19","author":"Fabian","year":"2012","journal-title":"Nat. Struct. Mol. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.febslet.2008.12.043","article-title":"Stress Induces tRNA Cleavage by Angiogenin in Mammalian Cells","volume":"583","author":"Fu","year":"2009","journal-title":"FEBS Lett."},{"key":"B13","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/s41421-021-00289-8","article-title":"A Virus-Derived microRNA-like Small RNA Serves as a Serum Biomarker to Prioritize the COVID-19 Patients at High Risk of Developing Severe Disease","volume":"7","author":"Fu","year":"2021","journal-title":"Cell Discov"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e101695","DOI":"10.15252\/embj.2019101695","article-title":"Phospho-RNA-seq: a Modified Small RNA-Seq Method that Reveals Circulating mRNA and lncRNA Fragments as Potential Biomarkers in Human Plasma","volume":"38","author":"Giraldez","year":"2019","journal-title":"EMBO J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.virol.2011.01.002","article-title":"Virus-encoded microRNAs","volume":"411","author":"Grundhoff","year":"2011","journal-title":"Virology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.ymeth.2007.09.009","article-title":"Identification of microRNAs and Other Small Regulatory RNAs Using cDNA Library Sequencing","volume":"44","author":"Hafner","year":"2008","journal-title":"Methods"},{"key":"B17","doi-asserted-by":"publisher","first-page":"967946","DOI":"10.1155\/2014\/967946","article-title":"A Computational Approach for Predicting Role of Human MicroRNAs in MERS-CoV Genome","volume":"2014","author":"Hasan","year":"2014","journal-title":"Adv. Bioinformatics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.tiv.2017.11.005","article-title":"Human Lung Epithelial Cell Cultures for Analysis of Inhaled Toxicants: Lessons Learned and Future Directions","volume":"47","author":"Hiemstra","year":"2018","journal-title":"Toxicol. Vitro"},{"key":"B19","doi-asserted-by":"publisher","first-page":"3429","DOI":"10.1093\/nar\/gkg599","article-title":"Vienna RNA Secondary Structure Server","volume":"31","author":"Hofacker","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"E3816","DOI":"10.1073\/pnas.1510077112","article-title":"Sex Hormone-dependent tRNA Halves Enhance Cell Proliferation in Breast and Prostate Cancers","volume":"112","author":"Honda","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B21","doi-asserted-by":"publisher","first-page":"8859996","DOI":"10.1155\/2021\/8859996","article-title":"Potential Prognostic Biomarkers of Lung Adenocarcinoma Based on Bioinformatic Analysis","volume":"2021","author":"Hou","year":"2021","journal-title":"Biomed. Res. Int."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2210","DOI":"10.1093\/nar\/gkr848","article-title":"West Nile Virus Encodes a microRNA-like Small RNA in the 3' Untranslated Region Which Up-Regulates GATA4 mRNA and Facilitates Virus Replication in Mosquito Cells","volume":"40","author":"Hussain","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"18201","DOI":"10.1073\/pnas.1407361111","article-title":"G-quadruplex Structures Contribute to the Neuroprotective Effects of Angiogenin-Induced tRNA Fragments","volume":"111","author":"Ivanov","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B24","doi-asserted-by":"publisher","first-page":"D493","DOI":"10.1093\/nar\/gkh103","article-title":"The UCSC Table Browser Data Retrieval Tool","volume":"32","author":"Karolchik","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"765","DOI":"10.3389\/fgene.2020.00765","article-title":"Epigenetic Regulator miRNA Pattern Differences Among SARS-CoV, SARS-CoV-2, and SARS-CoV-2 World-wide Isolates Delineated the Mystery behind the Epic Pathogenicity and Distinct Clinical Characteristics of Pandemic COVID-19","volume":"11","author":"Khan","year":"2020","journal-title":"Front. Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2639","DOI":"10.1101\/gad.1837609","article-title":"A Novel Class of Small RNAs: tRNA-Derived RNA Fragments (tRFs)","volume":"23","author":"Lee","year":"2009","journal-title":"Genes Dev."},{"key":"B27","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/cr.2018.3","article-title":"H5N1 Influenza Virus-specific miRNA-like Small RNA Increases Cytokine Production and Mouse Mortality via Targeting poly(rC)-Binding Protein 2","volume":"28","author":"Li","year":"2018","journal-title":"Cell Res"},{"key":"B28","doi-asserted-by":"publisher","first-page":"16838","DOI":"10.1038\/s41598-018-34899-2","article-title":"A tRNA-Derived RNA Fragment Plays an Important Role in the Mechanism of Arsenite -induced Cellular Responses","volume":"8","author":"Liu","year":"2018","journal-title":"Sci. Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e7837","DOI":"10.1371\/journal.pone.0007837","article-title":"MicroRNome Analysis Unravels the Molecular Basis of SARS Infection in Bronchoalveolar Stem Cells","volume":"4","author":"Mallick","year":"2009","journal-title":"PLoS One"},{"key":"B30","doi-asserted-by":"publisher","first-page":"E5334","DOI":"10.1073\/pnas.1714397115","article-title":"Human Plasma and Serum Extracellular Small RNA Reference Profiles and Their Clinical Utility","volume":"115","author":"Max","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B31","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.chom.2017.01.015","article-title":"SARS-CoV-Encoded Small RNAs Contribute to Infection-Associated Lung Pathology","volume":"21","author":"Morales","year":"2017","journal-title":"Cell Host & Microbe"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3846","DOI":"10.1128\/jvi.79.6.3846-3850.2005","article-title":"Exogenous ACE2 Expression Allows Refractory Cell Lines to Support Severe Acute Respiratory Syndrome Coronavirus Replication","volume":"79","author":"Mossel","year":"2005","journal-title":"J. Virol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"11525","DOI":"10.1073\/pnas.1001984107","article-title":"Influenza A Virus-Generated Small RNAs Regulate the Switch from Transcription to Replication","volume":"107","author":"Perez","year":"2010","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/1479-5876-12-3","article-title":"Methods and Matrices: Approaches to Identifying miRNAs for Nasopharyngeal Carcinoma","volume":"12","author":"Plieskatt","year":"2014","journal-title":"J. Transl Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e112","DOI":"10.1093\/nar\/gks339","article-title":"Automated 3D Structure Composition for Large RNAs","volume":"40","author":"Popenda","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"212","DOI":"10.4103\/1673-5374.265560","article-title":"Pathological Significance of tRNA-Derived Small RNAs in Neurological Disorders","volume":"15","author":"Qin","year":"2020","journal-title":"Neural Regen. Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"588168","DOI":"10.3389\/fcimb.2020.588168","article-title":"Regulation of Host Innate Immunity by Non-coding RNAs during Dengue Virus Infection","volume":"10","author":"Rajput","year":"2020","journal-title":"Front. Cel. Infect. Microbiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e1143076","DOI":"10.1080\/21690731.2016.1143076","article-title":"tRNA Wobble Modifications and Protein Homeostasis","volume":"4","author":"Ranjan","year":"2016","journal-title":"Translation"},{"key":"B39","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1093\/carcin\/bgx026","article-title":"Small Non-coding RNA and Cancer","volume":"38","author":"Romano","year":"2017","journal-title":"Carcinogenesis"},{"key":"B40","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/j.cub.2004.03.008","article-title":"The RNA-Induced Silencing Complex Is a Mg2+-dependent Endonuclease","volume":"14","author":"Schwarz","year":"2004","journal-title":"Curr. Biol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"2003988","DOI":"10.1183\/13993003.03988-2020","article-title":"Influenza Virus Infection Increases ACE2 Expression and Shedding in Human Small Airway Epithelial Cells","volume":"58","author":"Schweitzer","year":"2021","journal-title":"Eur. Respir. J."},{"key":"B42","doi-asserted-by":"publisher","first-page":"7675","DOI":"10.1038\/srep07675","article-title":"Small tRNA-Derived RNAs Are Increased and More Abundant Than microRNAs in Chronic Hepatitis B and C","volume":"5","author":"Selitsky","year":"2015","journal-title":"Sci. Rep."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1007\/s00109-018-1693-y","article-title":"Transfer RNA-Derived Fragments and tRNA Halves: Biogenesis, Biological Functions and Their Roles in Diseases","volume":"96","author":"Shen","year":"2018","journal-title":"J. Mol. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.canlet.2017.10.031","article-title":"Roles of tRNA-Derived Fragments in Human Cancers","volume":"414","author":"Sun","year":"2018","journal-title":"Cancer Lett."},{"key":"B45","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1101\/gad.259077.115","article-title":"Viral Noncoding RNAs: More Surprises","volume":"29","author":"Tycowski","year":"2015","journal-title":"Genes Dev."},{"key":"B46","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1186\/1471-2164-11-288","article-title":"Analysis of microRNA Transcriptome by Deep Sequencing of Small RNA Libraries of Peripheral Blood","volume":"11","author":"Vaz","year":"2010","journal-title":"BMC Genomics"},{"key":"B47","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/mt.2012.237","article-title":"Identification and Functional Characterization of tRNA-Derived RNA Fragments (tRFs) in Respiratory Syncytial Virus Infection","volume":"21","author":"Wang","year":"2013","journal-title":"Mol. Ther."},{"key":"B48","doi-asserted-by":"publisher","first-page":"12789","DOI":"10.1093\/nar\/gku952","article-title":"A Cytoplasmic RNA Virus Generates Functional Viral Small RNAs and Regulates Viral IRES Activity in Mammalian Cells","volume":"42","author":"Weng","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"e01218","DOI":"10.1128\/JVI.01218-20","article-title":"Broad Anti-coronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo","volume":"94","author":"Weston","year":"2020","journal-title":"J. Virol."},{"key":"B50","volume-title":"World Health Organization","author":"World Health","year":"2021"},{"key":"B51","doi-asserted-by":"publisher","first-page":"345","DOI":"10.3390\/v12030345","article-title":"Non-Coding RNAs and Their Role in Respiratory Syncytial Virus (RSV) and Human Metapneumovirus (hMPV) Infections","volume":"12","author":"Wu","year":"2020"},{"key":"B52","doi-asserted-by":"publisher","first-page":"793","DOI":"10.3233\/jad-200917","article-title":"tRNA-Derived Fragments in Alzheimer's Disease: Implications for New Disease Biomarkers and Neuropathological Mechanisms","volume":"79","author":"Wu","year":"2021","journal-title":"Jad"},{"key":"B53","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1164\/rccm.202003-0541oc","article-title":"Expression of the SARS-CoV-2 ACE2 Receptor in the Human Airway Epithelium","volume":"202","author":"Zhang","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1099\/jgv.0.000852","article-title":"Identification of Two Novel Functional tRNA-Derived Fragments Induced in Response to Respiratory Syncytial Virus Infection","volume":"98","author":"Zhou","year":"2017","journal-title":"J. Gen. Virol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.canlet.2018.01.015","article-title":"tRNA-derived Small Non-coding RNAs in Human Disease","volume":"419","author":"Zhu","year":"2018","journal-title":"Cancer Lett."},{"key":"B56","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1056\/nejmoa2001017","article-title":"A Novel Coronavirus from Patients with Pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N. Engl. J. Med."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2022.821137\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T09:09:54Z","timestamp":1645607394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2022.821137\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,23]]},"references-count":56,"alternative-id":["10.3389\/fmolb.2022.821137"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2022.821137","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.12.16.472982","asserted-by":"object"}]},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,23]]},"article-number":"821137"}}