{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:29:12Z","timestamp":1788449352863,"version":"build-2803163510"},"reference-count":102,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institute of Health","doi-asserted-by":"publisher","award":["R01AI093450"],"award-info":[{"award-number":["R01AI093450"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute of Health","doi-asserted-by":"publisher","award":["DE-NA0003525"],"award-info":[{"award-number":["DE-NA0003525"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Louisville","award":["R01AI093450"],"award-info":[{"award-number":["R01AI093450"]}]},{"name":"University of Louisville","award":["DE-NA0003525"],"award-info":[{"award-number":["DE-NA0003525"]}]},{"name":"National Technology and Engineering Solutions of Sandia LLC","award":["R01AI093450"],"award-info":[{"award-number":["R01AI093450"]}]},{"name":"National Technology and Engineering Solutions of Sandia LLC","award":["DE-NA0003525"],"award-info":[{"award-number":["DE-NA0003525"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV) share many genetic and biological features including subtle differences between pathogenic and apathogenic strains. Despite remarkable genetic similarity, the viscerotropic WE strain of LCMV causes a fatal LASV fever-like hepatitis in non-human primates (NHPs) while the mouse-adapted Armstrong (ARM) strain of LCMV is deeply attenuated in NHPs and can vaccinate against LCMV-WE challenge. Here, we demonstrate that internalization of WE is more sensitive to the depletion of membrane cholesterol than ARM infection while ARM infection is more reliant on endosomal acidification. LCMV-ARM induces robust NF-\u03baB and interferon response factor (IRF) activation while LCMV-WE seems to avoid early innate sensing and failed to induce strong NF-\u03baB and IRF responses in dual-reporter monocyte and epithelial cells. Toll-like receptor 2 (TLR-2) signaling appears to play a critical role in NF-\u03baB activation and the silencing of TLR-2 shuts down IL-6 production in ARM but not in WE-infected cells. Pathogenic LCMV-WE infection is poorly recognized in early endosomes and failed to induce TLR-2\/Mal-dependent pro-inflammatory cytokines. Following infection, Interleukin-1 receptor-associated kinase 1 (IRAK-1) expression is diminished in LCMV-ARM- but not LCMV-WE-infected cells, which indicates it is likely involved in the LCMV-ARM NF-\u03baB activation. By confocal microscopy, ARM and WE strains have similar intracellular trafficking although LCMV-ARM infection appears to coincide with greater co-localization of early endosome marker EEA1 with TLR-2. Both strains co-localize with Rab-7, a late endosome marker, but the interaction with LCMV-WE seems to be more prolonged. These findings suggest that LCMV-ARM\u2019s intracellular trafficking pathway may facilitate interaction with innate immune sensors, which promotes the induction of effective innate and adaptive immune responses.<\/jats:p>","DOI":"10.3390\/v16040635","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T04:10:15Z","timestamp":1713499815000},"page":"635","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pathogenic and Apathogenic Strains of Lymphocytic Choriomeningitis Virus Have Distinct Entry and Innate Immune Activation Pathways"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3630-0588","authenticated-orcid":false,"given":"Dylan M.","family":"Johnson","sequence":"first","affiliation":[{"name":"Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, Louisville, KY 94202, USA"},{"name":"Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 94202, USA"},{"name":"Galveston National Laboratory, Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77550, USA"},{"name":"Sandia National Laboratories, Department of Biotechnology & Bioengineering, Livermore, CA 94550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nittaya","family":"Khakhum","sequence":"additional","affiliation":[{"name":"Galveston National Laboratory, Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 94202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikole L.","family":"Warner","sequence":"additional","affiliation":[{"name":"Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, Louisville, KY 94202, USA"},{"name":"Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 94202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny D.","family":"Jokinen","sequence":"additional","affiliation":[{"name":"Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, Louisville, KY 94202, USA"},{"name":"Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 94202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason E.","family":"Comer","sequence":"additional","affiliation":[{"name":"Galveston National Laboratory, Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6523-5116","authenticated-orcid":false,"given":"Igor S.","family":"Lukashevich","sequence":"additional","affiliation":[{"name":"Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, Louisville, KY 94202, USA"},{"name":"Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 94202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.spen.2012.02.002","article-title":"Lymphocytic Choriomeningitis Virus: An Underrecognized Cause of Neurologic Disease in the Fetus, Child, and Adult","volume":"Volume 19","author":"Bonthius","year":"2012","journal-title":"Seminars in Pediatric Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"160","DOI":"10.4149\/av_2013_02_160","article-title":"Lymphocytic Choriomeningitis Virus: Invisible but Not Innocent","volume":"57","year":"2013","journal-title":"Acta Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"001891","DOI":"10.1099\/jgv.0.001891","article-title":"ICTV Virus Taxonomy Profile: Arenaviridae 2023","volume":"104","author":"Radoshitzky","year":"2023","journal-title":"J. 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