{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T07:44:18Z","timestamp":1776843858214,"version":"3.51.2"},"reference-count":57,"publisher":"American Society for Microbiology","issue":"14","license":[{"start":{"date-parts":[[2014,7,15]],"date-time":"2014-07-15T00:00:00Z","timestamp":1405382400000},"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":[[2014,7,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Successful adaptive immunity to virus infection often depends on the initial innate response. Previously, we demonstrated that Jun\u00edn virus, the etiological agent responsible for Argentine hemorrhagic fever (AHF), activates an early innate immune response via an interaction between the viral glycoprotein and Toll-like receptor 2 (TLR2). Here we show that TLR2\/6 but not TLR1\/2 heterodimers sense Jun\u00edn virus glycoprotein and induce a cytokine response, which in turn upregulates the expression of the RNA helicases RIG-I and MDA5. NF-\u03baB and Erk1\/2 were important in the cytokine response, since both proteins were phosphorylated as a result of the interaction of virus with TLR2, and treatment with an Erk1\/2-specific inhibitor blocked cytokine production. We show that the Jun\u00edn virus glycoprotein activates cytokine production in a human macrophage cell line as well. Moreover, we show that TLR2-mediated immune response plays a role in viral clearance because wild-type mice cleared Candid 1 (JUNV C1), the vaccine strain of Jun\u00edn virus, more rapidly than did TLR2 knockout mice. This clearance correlated with the generation of Jun\u00edn virus-specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. However, infected wild-type and TLR2 knockout mice developed TLR2-independent blocking antibody responses with similar kinetics. We also show that microglia and astrocytes but not neurons are susceptible to infection with JUNV C1. Although JUNV C1 infection of the brain also triggered a TLR2-dependent cytokine response, virus levels were equivalent in wild-type and TLR2 knockout mice.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    Jun\u00edn virus is transmitted by rodents native to Argentina and is associated with both systemic disease and, in some patients, neurological symptoms. Humans become infected when they inhale aerosolized Jun\u00edn virus. AHF has a 15 to 30% mortality rate, and patients who clear the infection develop a strong antibody response to Jun\u00edn virus. Here we investigated what factors determine the immune response to Jun\u00edn virus. We show that a strong initial innate immune response to JUNV C1 determines how quickly mice can clear systemic infection and that this depended on the cellular immune response. In contrast, induction of an innate immune response in the brain had no effect on virus infection levels. These findings may explain how the initial immune response to Jun\u00edn virus infection could determine different outcomes in humans.\n                  <\/jats:p>","DOI":"10.1128\/jvi.00050-14","type":"journal-article","created":{"date-parts":[[2014,4,24]],"date-time":"2014-04-24T00:23:34Z","timestamp":1398299014000},"page":"7703-7714","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":38,"title":["Toll-Like Receptor 2-Mediated Innate Immune Responses against Jun\u00edn Virus in Mice Lead to Antiviral Adaptive Immune Responses during Systemic Infection and Do Not Affect Viral Replication in the Brain"],"prefix":"10.1128","volume":"88","author":[{"given":"Christian D.","family":"Cuevas","sequence":"first","affiliation":[{"name":"Department of Microbiology, Institute for Immunology, and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan R.","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute for Immunology, and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"1791","volume-title":"Fields virology","author":"Buchmeier MJ","year":"2007","unstructured":"BuchmeierMJde la TorreJCPetersCJ. 2007. Arenaviridae: the viruses and their replication, p 1791\u20131828. In KnipeDMHowleyPMGriffinDELambRAMartinMARoizmanBStrausSE (ed), Fields virology, 5th ed. Lippincott Williams & Wilkins, Philadelphia, PA.","edition":"5"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2011.02.009"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/166.5.1203"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/v4102317"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/143.1.1"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(84)90299-X"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.1890270218"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11262-005-5843-2"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-3542(87)90017-9"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1159\/000149662"},{"key":"e_1_3_2_12_2","first-page":"58","article-title":"Junin virus replication in peripheral blood mononuclear cells of patients with Argentine haemorrhagic fever","volume":"34","author":"Ambrosio M","year":"1990","unstructured":"AmbrosioMVallejosASaavedraCMaizteguiJI. 1990. Junin virus replication in peripheral blood mononuclear cells of patients with Argentine haemorrhagic fever. Acta Virol. 34:58\u201363.","journal-title":"Acta Virol."},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001659"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/149.3.428"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1089\/jir.1985.5.383"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.55.1.255"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1999.60.85"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05304-11"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2003.10.003"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3024.2010.01247.x"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/13.7.933"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.1.10"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11262-010-0450-2"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01389-10"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1997.8934"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01321114"},{"key":"e_1_3_2_27_2","first-page":"567","article-title":"Clinical and epidemiological patterns of Argentine haemorrhagic fever","volume":"52","author":"Maiztegui JI","year":"1975","unstructured":"MaizteguiJI. 1975. Clinical and epidemiological patterns of Argentine haemorrhagic fever. Bull. World Health Organ. 52:567\u2013575.","journal-title":"Bull. World Health Organ."},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-78-7-1605"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.14.4.965-974.1974"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2008.08.059"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2011.07.007"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00671-08"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0207128"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2010.06.011"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2006.04.005"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2011.01.011"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir665"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000926"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01362-09"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00187-12"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00882-07"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001137"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.2174\/138920291407131220153526"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(08)60197-2"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80469-0"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80470-7"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.11.6081"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.68.11.7358-7366.1994"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1133"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903752"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.4.1851"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni978"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2007.11.018"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/32588"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04267"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802317"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1135299"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636516"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00050-14","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00050-14","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T10:37:34Z","timestamp":1646476654000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.00050-14"}},"subtitle":[],"editor":[{"given":"M. S.","family":"Diamond","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2014,7,15]]},"references-count":57,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2014,7,15]]}},"alternative-id":["10.1128\/JVI.00050-14"],"URL":"https:\/\/doi.org\/10.1128\/jvi.00050-14","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.718361091.793494680","asserted-by":"object"}]},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,7,15]]},"assertion":[{"value":"2014-01-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-04-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-06-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}