{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:20:36Z","timestamp":1776399636745,"version":"3.51.2"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012844","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000}}],"reference-count":187,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007201","name":"Utah Science Technology and Research","doi-asserted-by":"publisher","award":["USTAR A34637"],"award-info":[{"award-number":["USTAR A34637"]}],"id":[{"id":"10.13039\/100007201","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007201","name":"Utah Science Technology and Research","doi-asserted-by":"publisher","award":["USTAR A36815"],"award-info":[{"award-number":["USTAR A36815"]}],"id":[{"id":"10.13039\/100007201","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007199","name":"Utah Agricultural Experiment Station","doi-asserted-by":"publisher","award":["UAES UTA01345"],"award-info":[{"award-number":["UAES UTA01345"]}],"id":[{"id":"10.13039\/100007199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007199","name":"Utah Agricultural Experiment Station","doi-asserted-by":"publisher","award":["UAES UTA01655"],"award-info":[{"award-number":["UAES UTA01655"]}],"id":[{"id":"10.13039\/100007199","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Japanese encephalitis virus (JEV), a neuroinvasive and neurovirulent orthoflavivirus, can be prevented in humans with the SA<jats:sub>14<\/jats:sub>-14-2 vaccine, a live-attenuated version derived from the wild-type SA<jats:sub>14<\/jats:sub> strain. To determine the viral factors responsible for the differences in pathogenicity between SA<jats:sub>14<\/jats:sub> and SA<jats:sub>14<\/jats:sub>-14-2, we initially established a reverse genetics system that includes a pair of full-length infectious cDNAs for both strains. Using this cDNA pair, we then systematically exchanged genomic regions between SA<jats:sub>14<\/jats:sub> and SA<jats:sub>14<\/jats:sub>-14-2 to generate 20 chimeric viruses and evaluated their replication capability in cell culture and their pathogenic potential in mice. Our findings revealed the following: (<jats:italic>i<\/jats:italic>) The single envelope (E) protein of SA<jats:sub>14<\/jats:sub>-14-2, which contains nine mutations (eight in the ectodomain and one in the stem region), is both necessary and sufficient to render SA<jats:sub>14<\/jats:sub> non-neuroinvasive and non-neurovirulent. (<jats:italic>ii<\/jats:italic>) Conversely, the E protein of SA<jats:sub>14<\/jats:sub> alone is necessary for SA<jats:sub>14<\/jats:sub>-14-2 to become highly neurovirulent, but it is not sufficient to make it highly neuroinvasive. (<jats:italic>iii<\/jats:italic>) The limited neuroinvasiveness of an SA<jats:sub>14<\/jats:sub>-14-2 derivative that contains the E gene of SA<jats:sub>14<\/jats:sub> significantly increases (approaching that of the wild-type strain) when two viral nonstructural proteins are replaced by their counterparts from SA<jats:sub>14<\/jats:sub>: (<jats:italic>a<\/jats:italic>) NS1\/1\u2019, which has four mutations on the external surface of the core \u03b2-ladder domain; and (<jats:italic>b<\/jats:italic>) NS2A, which has two mutations in the N-terminal region, including two non-transmembrane \u03b1-helices. In line with their roles in viral pathogenicity, the E, NS1\/1\u2019, and NS2A genes all contribute to the enhanced spread of the virus in cell culture. Collectively, our data reveal for the first time that the E protein of JEV has a dual function: It is the master regulator of viral neurovirulence and also the primary initiator of viral neuroinvasion. After the initial E-mediated neuroinvasion, the NS1\/1\u2019 and NS2A proteins act as secondary promoters, further amplifying viral neuroinvasiveness.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012844","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T18:45:43Z","timestamp":1736275543000},"page":"e1012844","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Key virulence factors responsible for differences in pathogenicity between clinically proven live-attenuated Japanese encephalitis vaccine SA14-14-2 and its pre-attenuated highly virulent parent SA14"],"prefix":"10.1371","volume":"21","author":[{"given":"Byung-Hak","family":"Song","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang-Im","family":"Yun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph L.","family":"Goldhardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiyoun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3974-3405","authenticated-orcid":true,"given":"Young-Min","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,1,7]]},"reference":[{"issue":"1","key":"ppat.1012844.ref001","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1099\/jgv.0.000672","article-title":"ICTV virus taxonomy profile: Flaviviridae","volume":"98","author":"P Simmonds","year":"2017","journal-title":"J Gen Virol"},{"issue":"10","key":"ppat.1012844.ref002","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.3390\/v14102213","article-title":"The Japanese encephalitis antigenic complex viruses: from structure to immunity","volume":"14","author":"B Khare","year":"2022","journal-title":"Viruses"},{"key":"ppat.1012844.ref003","first-page":"1","article-title":"The Japanese encephalitis serological group of flaviviruses: a brief introduction to the group","volume":"267","author":"JS Mackenzie","year":"2002","journal-title":"Curr Top Microbiol Immunol"},{"issue":"4","key":"ppat.1012844.ref004","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1056\/NEJMra030476","article-title":"Flavivirus encephalitis","volume":"351","author":"T. 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