{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:50:19Z","timestamp":1792018219195,"version":"4.4.0"},"reference-count":47,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"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":["J Virol"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Serious permanent neurological or psychiatric dysfunction may result from virus infections in the central nervous system (CNS). Olfactory sensory neurons are in direct contact with the external environment, making them susceptible to infection by viruses that can enter the brain via the olfactory nerve. The rarity of full brain viral infections raises the important question of whether unique immune defense mechanisms protect the brain. Here we show that both RNA (vesicular stomatitis virus [VSV]) and DNA (cytomegalovirus [CMV]) virus inoculations of the nasal mucosa leading to olfactory bulb (OB) infection activate long-distance signaling that upregulates antiviral interferon (IFN)-stimulated gene (ISG) expression in uninfected remote regions of the brain. This signaling mechanism is dependent on IFN-\u03b1\/\u03b2 receptors deep within the brain, leading to the activation of a distant antiviral state that prevents infection of the caudal brain. In normal mice, VSV replication is limited to the OB, and these animals typically survive the infection. In contrast, mice lacking the IFN-\u03b1\/\u03b2 receptor succumbed to the infection, with VSV spreading throughout the brain. Chemical destruction of the olfactory sensory neurons blocked both virus trafficking into the OB and the IFN response in the caudal brain, indicating a direct signaling within the brain after intranasal infection. Most signaling within the brain occurs across the 20-nm synaptic cleft. The unique long-distance IFN signaling described here occurs across many millimeters within the brain and is critical for survival and normal brain function.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    The olfactory mucosa can serve as a conduit for a number of viruses to enter the brain. Yet infections in the CNS rarely occur. The mechanism responsible for protecting the brain from viruses that successfully invade the OB, the first site of infection subsequent to infection of the nasal mucosa, remains elusive. Here we demonstrate that the protection is mediated by a long-distance interferon signaling, particularly IFN-\u03b2 released by infected neurons in the OB. Strikingly, in the absence of neurotropic virus infection, ISGs are induced in the posterior regions of the brain, activating an antiviral state and preventing further virus invasion.\n                  <\/jats:p>","DOI":"10.1128\/jvi.03509-13","type":"journal-article","created":{"date-parts":[[2014,1,15]],"date-time":"2014-01-15T23:09:04Z","timestamp":1389827344000},"page":"3695-3704","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":59,"title":["Long-Distance Interferon Signaling within the Brain Blocks Virus Spread"],"prefix":"10.1128","volume":"88","author":[{"given":"Anthony N.","family":"van den Pol","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Robek","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"Viral infections of the nervous system","author":"Johnson RT","year":"1998","unstructured":"JohnsonRT. 1998. Viral infections of the nervous system. Lippincott-Raven, Philadelphia, PA."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1089\/088282403322396208"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1994.1576"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3109\/13550280009030756"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00189527"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(91)90145-2"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.27.1.67"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1105143108"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1080\/13550280590922793"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/342387"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1053\/tvjl.1998.0303"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02111-12"},{"key":"e_1_3_2_14_2","first-page":"47","volume-title":"Infections of the fetus and newborn infant","author":"Hanshaw JB","year":"1975","unstructured":"HanshawJBScheinerAPMoxleyAWGaevLAbelV. 1975. CNS sequelae of congenital cytomegalovirus infection, p 47\u201354. In KrugmanSGershoenAA (ed), Infections of the fetus and newborn infant. A. R. Liss, New York, NY."},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(05)80859-5"},{"key":"e_1_3_2_16_2","volume-title":"Biology and infection","author":"Ho M","year":"1991","unstructured":"HoM. 1991. Cytomegalovirus. Biology and infection. Plenum, New York, NY."},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02161-09"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.17.8842-8854.2002"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01592-06"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00818709"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1080\/13550280701460565"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0800596"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002712"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.2000.0736"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.3.1309-1327.2002"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-24-10948.1999"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9861(20001127)427:4<559::AID-CNE5>3.0.CO;2-4"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8009221"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22305"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.20606"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01097-13"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1995.1197"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.9.5333-5338.2003"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602460103"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4002013"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2647"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.66.1.15"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.4161\/viru.2.4.16138"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1995.tb00090.x"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00272-10"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1100552108"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000017"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2010.0060"},{"key":"e_1_3_2_44_2","first-page":"2629","volume-title":"Fields virology","author":"Mocarski ES","year":"2001","unstructured":"MocarskiESCourcelleCT. 2001. Cytomegaloviruses and their replication, p 2629\u20132674. In KnipeDMHowleyPMGriffinDELambRAMartinMARoizmanBStrausSE (ed), Fields virology, 4th ed. Lippincott Williams & Wilkins, New York, NY.","edition":"4"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01206454"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.11-04-00979.1991"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1136281"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01106-12"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.03509-13","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.03509-13","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T10:46:34Z","timestamp":1646477194000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.03509-13"}},"subtitle":[],"editor":[{"given":"S.","family":"Perlman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2014,4]]},"references-count":47,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2014,4]]}},"alternative-id":["10.1128\/JVI.03509-13"],"URL":"https:\/\/doi.org\/10.1128\/jvi.03509-13","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.718240637.793491789","asserted-by":"object"}]},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4]]},"assertion":[{"value":"2013-12-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-01-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-03-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}