{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:25:35Z","timestamp":1790144735495,"version":"4.0.1"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2015,5,6]],"date-time":"2015-05-06T00:00:00Z","timestamp":1430870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Among Herpesviruses, Human Cytomegalovirus (HCMV or HHV-5) represents a major threat during congenital or neonatal infections, which may lead to encephalitis with serious neurological consequences. However, as opposed to other less prevalent pathogens, the mechanisms and genetic susceptibility factors for CMV encephalitis are poorly understood. This lack of information considerably reduces the prognostic and\/or therapeutic possibilities. To easily monitor the effects of genetic defects on brain dissemination following CMV infection we used a recently developed in vivo mouse model based on the neonatal inoculation of a MCMV genetically engineered to express Luciferase. Here, we further validate this protocol for live imaging, and demonstrate increased lethality associated with viral infection and encephalitis in mutant mice lacking Dicer activity. Our data indicate that miRNAs are important players in the control of MCMV pathogenesis and suggest that miRNA-based endothelial functions and integrity are crucial for CMV encephalitis.<\/jats:p>","DOI":"10.3390\/v7052308","type":"journal-article","created":{"date-parts":[[2015,5,6]],"date-time":"2015-05-06T10:58:41Z","timestamp":1430909921000},"page":"2308-2320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Increased Viral Dissemination in the Brain and Lethality in MCMV-Infected, Dicer-Deficient Neonates"],"prefix":"10.3390","volume":"7","author":[{"given":"Eleonore","family":"Ostermann","sequence":"first","affiliation":[{"name":"Immunorhumatologie Mol\u00e9culaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et H\u00e9matologie, Facult\u00e9 de M\u00e9decine, F\u00e9d\u00e9ration de M\u00e9decine Translationnelle de Strasbourg (FMTS), Universit\u00e9 de Strasbourg, Strasbourg. 1, Place de l\u2019H\u00f4pital, 67085 Strasbourg Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Macquin","sequence":"additional","affiliation":[{"name":"Immunorhumatologie Mol\u00e9culaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et H\u00e9matologie, Facult\u00e9 de M\u00e9decine, F\u00e9d\u00e9ration de M\u00e9decine Translationnelle de Strasbourg (FMTS), Universit\u00e9 de Strasbourg, Strasbourg. 1, Place de l\u2019H\u00f4pital, 67085 Strasbourg Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Krezel","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, UMR 7104 CNRS, U 964 INSERM, Universit\u00e9 de Strasbourg, 67081 Strasbourg Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiamak","family":"Bahram","sequence":"additional","affiliation":[{"name":"Immunorhumatologie Mol\u00e9culaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et H\u00e9matologie, Facult\u00e9 de M\u00e9decine, F\u00e9d\u00e9ration de M\u00e9decine Translationnelle de Strasbourg (FMTS), Universit\u00e9 de Strasbourg, Strasbourg. 1, Place de l\u2019H\u00f4pital, 67085 Strasbourg Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-7080","authenticated-orcid":false,"given":"Philippe","family":"Georgel","sequence":"additional","affiliation":[{"name":"Immunorhumatologie Mol\u00e9culaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et H\u00e9matologie, Facult\u00e9 de M\u00e9decine, F\u00e9d\u00e9ration de M\u00e9decine Translationnelle de Strasbourg (FMTS), Universit\u00e9 de Strasbourg, Strasbourg. 1, Place de l\u2019H\u00f4pital, 67085 Strasbourg Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1111\/j.1365-2796.2010.02220.x","article-title":"Modulation of host innate and adaptive immune defenses by cytomegalovirus: Timing is everything","volume":"267","author":"Loewendorf","year":"2010","journal-title":"J. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.coph.2008.07.002","article-title":"Antiviral strategies to combat cytomegalovirus infections in transplant recipients","volume":"8","author":"Lischka","year":"2008","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.18632\/oncotarget.383","article-title":"Is human cytomegalovirus a target in cancer therapy?","volume":"2","author":"Johnsen","year":"2011","journal-title":"Oncotarget"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0165-2427(02)00078-8","article-title":"Immunity in neonates","volume":"87","author":"Morein","year":"2002","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.it.2009.09.002","article-title":"Neonatal immunity: Faulty T-helpers and the shortcomings of dendritic cells","volume":"30","author":"Zaghouani","year":"2009","journal-title":"Trends Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1016\/j.jcpa.2007.04.008","article-title":"Immune responsiveness in the neonatal period","volume":"137","author":"Morein","year":"2007","journal-title":"J. Comp. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1128\/CMR.00023-08","article-title":"Neuropathogenesis of congenital cytomegalovirus infection: Disease mechanisms and prospects for intervention","volume":"22","author":"Cheeran","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/j.1741-4520.2009.00222.x","article-title":"Effects of cytomegalovirus infection on embryogenesis and brain development","volume":"49","author":"Tsutsui","year":"2009","journal-title":"Congenit. Anom."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4889","DOI":"10.1172\/JCI59259","article-title":"Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency","volume":"121","author":"Lorenzo","year":"2011","journal-title":"J. Clin. Invest."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1002\/eji.200939414","article-title":"IL-12 and type I IFN response of neonatal myeloid DC to human CMV infection","volume":"39","author":"Renneson","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1097\/ACI.0b013e3282f151d2","article-title":"Genetic susceptibility to herpes simplex virus 1 encephalitis in mice and humans","volume":"7","author":"Zhang","year":"2007","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1007\/s00335-005-0164-2","article-title":"Analysis of the MCMV resistome by ENU mutagenesis","volume":"17","author":"Crozat","year":"2006","journal-title":"Mamm. Genome"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3516","DOI":"10.1073\/pnas.0400525101","article-title":"Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection","volume":"101","author":"Tabeta","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.immuni.2004.06.007","article-title":"TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function","volume":"21","author":"Krug","year":"2004","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1093\/bfgp\/4.3.203","article-title":"Genetic analysis of innate resistance to mouse cytomegalovirus (MCMV)","volume":"4","author":"Beutler","year":"2005","journal-title":"Brief Funct. Genomic. Proteomic."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/1743-422X-8-70","article-title":"Murine model for congenital CMV infection and hearing impairment","volume":"8","author":"Juanjuan","year":"2011","journal-title":"Virol. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1084\/jem.20071489","article-title":"Altered development of the brain after focal herpesvirus infection of the central nervous system","volume":"205","author":"Koontz","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.4049\/jimmunol.181.3.2111","article-title":"CD8+ T lymphocytes control murine cytomegalovirus replication in the central nervous system of newborn animals","volume":"181","author":"Bantug","year":"2008","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ostermann, E., Macquin, C., Bahram, S., and Georgel, P. (2013). Use of in vivo imaging to monitor the progression of experimental mouse cytomegalovirus infection in neonates. J. Vis. Exp.","DOI":"10.3791\/50409-v"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/j.1749-6632.2011.06335.x","article-title":"Animal welfare and the 3Rs in European biomedical research","volume":"1245","author":"Wells","year":"2011","journal-title":"Ann. NY Acad. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/imr.12053","article-title":"RNA-based mechanisms regulating host-virus interactions","volume":"253","author":"Zhou","year":"2013","journal-title":"Immunol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1126\/science.1096781","article-title":"Identification of virus-encoded microRNAs","volume":"304","author":"Pfeffer","year":"2004","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nmeth746","article-title":"Identification of microRNAs of the herpesvirus family","volume":"2","author":"Pfeffer","year":"2005","journal-title":"Nat. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s11262-009-0347-0","article-title":"Cytomegalovirus microRNAs","volume":"38","author":"Dolken","year":"2009","journal-title":"Virus Genes"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nrm3838","article-title":"Regulation of microRNA biogenesis","volume":"15","author":"Ha","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e43744","DOI":"10.1371\/journal.pone.0043744","article-title":"Deregulation of type I IFN-dependent genes correlates with increased susceptibility to cytomegalovirus acute infection of dicer mutant mice","volume":"7","author":"Ostermann","year":"2012","journal-title":"PLOS ONE"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.immuni.2007.05.014","article-title":"Hypersusceptibility to vesicular stomatitis virus infection in Dicer1-deficient mice is due to impaired miR24 and miR93 expression","volume":"27","author":"Otsuka","year":"2007","journal-title":"Immunity"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e16211","DOI":"10.1371\/journal.pone.0016211","article-title":"Murine cytomegalovirus infection of neural stem cells alters neurogenesis in the developing brain","volume":"6","author":"Mutnal","year":"2011","journal-title":"PLOS ONE"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1126\/science.1139522","article-title":"TLR3 deficiency in patients with herpes simplex encephalitis","volume":"317","author":"Zhang","year":"2007","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1126\/science.1128346","article-title":"Herpes simplex virus encephalitis in human UNC-93B deficiency","volume":"314","author":"Casrouge","year":"2006","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1099\/vir.0.029827-0","article-title":"Single cell detection of latent cytomegalovirus reactivation in host tissue","volume":"92","author":"Marquardt","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12172","DOI":"10.1128\/JVI.01214-08","article-title":"Passive immunization reduces murine cytomegalovirus-induced brain pathology in newborn mice","volume":"82","author":"Cekinovic","year":"2008","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.coi.2013.10.015","article-title":"Dicer\u2019s role as an antiviral: Still an enigma","volume":"26","author":"MacKay","year":"2014","journal-title":"Curr. Opin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/ni.1916","article-title":"The human cytomegalovirus microRNA miR-UL112 acts synergistically with a cellular microRNA to escape immune elimination","volume":"11","author":"Nachmani","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4151","DOI":"10.1128\/JVI.05303-11","article-title":"Enhanced susceptibility of Ago1\/3 double-null mice to influenza A virus infection","volume":"86","author":"Oguin","year":"2012","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e1002366","DOI":"10.1371\/journal.ppat.1002366","article-title":"Shedding light on the elusive role of endothelial cells in cytomegalovirus dissemination","volume":"7","author":"Sacher","year":"2011","journal-title":"PLOS Pathog."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.gde.2009.04.002","article-title":"AngiomiRs\u2014Key regulators of angiogenesis","volume":"19","author":"Wang","year":"2009","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12135","DOI":"10.1073\/pnas.0505479102","article-title":"Characterization of Dicer-deficient murine embryonic stem cells","volume":"102","author":"Murchison","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1084\/jem.182.4.1045","article-title":"Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration","volume":"182","author":"Orange","year":"1995","journal-title":"J. Exp. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9492","DOI":"10.1128\/JVI.79.15.9492-9502.2005","article-title":"Frequent coinfection of cells explains functional in vivo complementation between cytomegalovirus variants in the multiply infected host","volume":"79","author":"Podlech","year":"2005","journal-title":"J. Virol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/7\/5\/2308\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:45:53Z","timestamp":1760215553000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/7\/5\/2308"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,5,6]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2015,5]]}},"alternative-id":["v7052308"],"URL":"https:\/\/doi.org\/10.3390\/v7052308","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,5,6]]}}}