{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T07:00:21Z","timestamp":1791961221207,"version":"4.3.4"},"reference-count":49,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2015,2,17]],"date-time":"2015-02-17T00:00:00Z","timestamp":1424131200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2015,2,27]],"date-time":"2015-02-27T00:00:00Z","timestamp":1424995200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2015,2,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Many viruses express noncoding RNAs (ncRNAs). The gammaherpesviruses (\u03b3HVs), including Epstein-Barr virus, Kaposi\u2019s sarcoma-associated herpesvirus, and murine \u03b3HV68, each contain multiple ncRNA genes, including microRNAs (miRNAs). While these ncRNAs can regulate multiple host and viral processes\n            <jats:italic>in vitro<\/jats:italic>\n            , the genetic contribution of these RNAs to infection and pathogenesis remains largely unknown. To study the functional contribution of these RNAs to \u03b3HV infection, we have used \u03b3HV68, a small-animal model of \u03b3HV pathogenesis. \u03b3HV68 encodes eight small hybrid ncRNAs that contain both tRNA-like elements and functional miRNAs. These genes are transcribed by RNA polymerase III and are referred to as the \u03b3HV68 TMERs (tRNA-miRNA-encoded RNAs). To determine the total concerted genetic contribution of these ncRNAs to \u03b3HV acute infection and pathogenesis, we generated and characterized a recombinant \u03b3HV68 strain devoid of all eight TMERs. TMER-deficient \u03b3HV68 has wild-type levels of lytic replication\n            <jats:italic>in vitro<\/jats:italic>\n            and normal establishment of latency in B cells early following acute infection\n            <jats:italic>in vivo<\/jats:italic>\n            . In contrast, during acute infection of immunodeficient mice, TMER-deficient \u03b3HV68 has reduced virulence in a model of viral pneumonia, despite having an enhanced frequency of virus-infected cells. Strikingly, expression of a single viral tRNA-like molecule, in the absence of all other virus-encoded TMERs and miRNAs, reverses both attenuation in virulence and enhanced frequency of infected cells. These data show that \u03b3HV ncRNAs play critical roles in acute infection and virulence in immunocompromised hosts and identify these RNAs as a new potential target to modulate \u03b3HV-induced infection and pathogenesis.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            The gammaherpesviruses (\u03b3HVs) are a subfamily of viruses associated with chronic inflammatory diseases and cancer, particularly in immunocompromised individuals. These viruses uniformly encode multiple types of noncoding RNAs (ncRNAs) that are not translated into proteins. It remains unclear how virus-expressed ncRNAs influence the course and outcome of infection\n            <jats:italic>in vivo<\/jats:italic>\n            . Here, we generated a mouse \u03b3HV that lacks the expression of multiple ncRNAs. Notably, this mutant virus is critically impaired in the ability to cause disease in immunocompromised hosts yet shows a paradoxical increase in infected cells early during infection in these hosts. While the original mouse virus encodes multiple ncRNAs, the expression of a single domain of one ncRNA can partially reverse the defects of the mutant virus. These studies demonstrate that \u03b3HV ncRNAs can directly contribute to virus-induced disease\n            <jats:italic>in vivo<\/jats:italic>\n            and that these RNAs may be multifunctional, allowing the opportunity to specifically interfere with different functional domains of these RNAs.\n          <\/jats:p>","DOI":"10.1128\/mbio.01670-14","type":"journal-article","created":{"date-parts":[[2015,2,18]],"date-time":"2015-02-18T07:20:41Z","timestamp":1424244041000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":46,"title":["Gammaherpesvirus Small Noncoding RNAs Are Bifunctional Elements That Regulate Infection and Contribute to Virulence\n            <i>In Vivo<\/i>"],"prefix":"10.1128","volume":"6","author":[{"given":"Kevin W.","family":"Diebel","sequence":"first","affiliation":[{"name":"Department of Immunology &amp; Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"Oko","sequence":"additional","affiliation":[{"name":"Department of Immunology &amp; Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva M.","family":"Medina","sequence":"additional","affiliation":[{"name":"Department of Immunology &amp; Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian F.","family":"Niemeyer","sequence":"additional","affiliation":[{"name":"Department of Immunology &amp; Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody J.","family":"Warren","sequence":"additional","affiliation":[{"name":"Department of Immunology &amp; Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Claypool","sequence":"additional","affiliation":[{"name":"Department of Immunology &amp; Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Tibbetts","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics &amp; Microbiology, University of Florida College of Medicine, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlyne D.","family":"Cool","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA"},{"name":"Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric 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