{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T12:46:14Z","timestamp":1782477974989,"version":"3.54.5"},"reference-count":81,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T00:00:00Z","timestamp":1682726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Commission"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>West Nile virus (WNV) is amplified in an enzootic cycle involving birds as amplifying hosts. Because they do not develop high levels of viremia, humans and horses are considered to be dead-end hosts. Mosquitoes, especially from the Culex genus, are vectors responsible for transmission between hosts. Consequently, understanding WNV epidemiology and infection requires comparative and integrated analyses in bird, mammalian, and insect hosts. So far, markers of WNV virulence have mainly been determined in mammalian model organisms (essentially mice), while data in avian models are still missing. WNV Israel 1998 (IS98) is a highly virulent strain that is closely genetically related to the strain introduced into North America in 1999, NY99 (genomic sequence homology &gt; 99%). The latter probably entered the continent at New York City, generating the most impactful WNV outbreak ever documented in wild birds, horses, and humans. In contrast, the WNV Italy 2008 strain (IT08) induced only limited mortality in birds and mammals in Europe during the summer of 2008. To test whether genetic polymorphism between IS98 and IT08 could account for differences in disease spread and burden, we generated chimeric viruses between IS98 and IT08, focusing on the 3\u2032 end of the genome (NS4A, NS4B, NS5, and 3\u2032UTR regions) where most of the non-synonymous mutations were detected. In vitro and in vivo comparative analyses of parental and chimeric viruses demonstrated a role for NS4A\/NS4B\/5\u2032NS5 in the decreased virulence of IT08 in SPF chickens, possibly due to the NS4B-E249D mutation. Additionally, significant differences between the highly virulent strain IS98 and the other three viruses were observed in mice, implying the existence of additional molecular determinants of virulence in mammals, such as the amino acid changes NS5-V258A, NS5-N280K, NS5-A372V, and NS5-R422K. As previously shown, our work also suggests that genetic determinants of WNV virulence can be host-dependent.<\/jats:p>","DOI":"10.3390\/v15051094","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T12:02:31Z","timestamp":1682942551000},"page":"1094","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Evaluation of NS4A, NS4B, NS5 and 3\u2032UTR Genetic Determinants of WNV Lineage 1 Virulence in Birds and Mammals"],"prefix":"10.3390","volume":"15","author":[{"given":"Lise","family":"Fiacre","sequence":"first","affiliation":[{"name":"Animal Health Laboratory, L\u2019alimentation et L\u2019environnement (INRAE), Institut National de Recherche pour L\u2019agriculture, \u00c9cole V\u00e9t\u00e9rinaire d\u2019Alfort (ENVA), Agence Nationale de S\u00e9curit\u00e9 Sanitaire de L\u2019alimentation, de L\u2019environnement et du Travail (ANSES), UMR Virology, 94700 Maisons-Alfort, France"},{"name":"Centre de Coop\u00e9ration Internationale en Recherche Agronomique pour le D\u00e9veloppement (CIRAD), UMR ASTRE, 97170 Petit-Bourg, France"},{"name":"ASTRE, CIRAD, INRAe, University of Montpellier, 34000 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steeve","family":"Lowenski","sequence":"additional","affiliation":[{"name":"Animal Health Laboratory, L\u2019alimentation et L\u2019environnement (INRAE), Institut National de Recherche pour L\u2019agriculture, \u00c9cole V\u00e9t\u00e9rinaire d\u2019Alfort (ENVA), Agence Nationale de S\u00e9curit\u00e9 Sanitaire de L\u2019alimentation, de L\u2019environnement et du Travail (ANSES), UMR Virology, 94700 Maisons-Alfort, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Bahuon","sequence":"additional","affiliation":[{"name":"Animal Health Laboratory, L\u2019alimentation et L\u2019environnement (INRAE), Institut National de Recherche pour 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L\u2019environnement et du Travail (ANSES), UMR Virology, 94700 Maisons-Alfort, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6733-8503","authenticated-orcid":false,"given":"St\u00e9phan","family":"Zientara","sequence":"additional","affiliation":[{"name":"Animal Health Laboratory, L\u2019alimentation et L\u2019environnement (INRAE), Institut National de Recherche pour L\u2019agriculture, \u00c9cole V\u00e9t\u00e9rinaire d\u2019Alfort (ENVA), Agence Nationale de S\u00e9curit\u00e9 Sanitaire de L\u2019alimentation, de L\u2019environnement et du Travail (ANSES), UMR Virology, 94700 Maisons-Alfort, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2125-9743","authenticated-orcid":false,"given":"Miguel-\u00c1ngel","family":"Jim\u00e9nez-Clavero","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Sanidad Animal (CISA-INIA), CSIC, Carretera Algete-El Casar 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8535-2133","authenticated-orcid":false,"given":"Sylvie","family":"Lecollinet","sequence":"additional","affiliation":[{"name":"Animal Health Laboratory, L\u2019alimentation et L\u2019environnement (INRAE), Institut National de Recherche pour L\u2019agriculture, \u00c9cole V\u00e9t\u00e9rinaire d\u2019Alfort (ENVA), Agence Nationale de S\u00e9curit\u00e9 Sanitaire de L\u2019alimentation, de L\u2019environnement et du Travail (ANSES), UMR Virology, 94700 Maisons-Alfort, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"471","DOI":"10.4269\/ajtmh.1940.s1-20.471","article-title":"A neurotropic virus isolated from the blood of a native of uganda","volume":"s1-20","author":"Smithburn","year":"1940","journal-title":"Am. 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