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This study highlights the crucial roles of host factors, specifically mitogen\u2010activated protein kinase 2 (\n                    <jats:italic>mk2<\/jats:italic>\n                    ) and mitogen\u2010activated protein kinase 3 (\n                    <jats:italic>mk3<\/jats:italic>\n                    ), both of which are stress\u2010stimulated serine\/threonine kinases. The roles of\n                    <jats:italic>mk2<\/jats:italic>\n                    and\n                    <jats:italic>mk3<\/jats:italic>\n                    were investigated by generating single (\n                    <jats:italic>mk2b<\/jats:italic>\n                    \u2212\/\u2212 and\n                    <jats:italic>mk3<\/jats:italic>\n                    \u2212\/\u2212) and double knockouts (\n                    <jats:italic>mk2b<\/jats:italic>\n                    \u2212\/\u2212\n                    <jats:italic>mk3<\/jats:italic>\n                    \u2212\/\u2212) in a zebrafish model using the CRISPR\u2010Cas9 technique, followed by chikungunya virus (CHIKV) infection. All knockout lines exhibited significantly higher CHIKV titers and severe phenotypes compared to the WT control, with\n                    <jats:italic>mk3<\/jats:italic>\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    showing the greatest susceptibility. After CHIKV infection, expression levels of TNF\u2010\u03b1 changed across all knockout models. Notably,\n                    <jats:italic>mk2b<\/jats:italic>\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    and\n                    <jats:italic>mk2b<\/jats:italic>\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    <jats:italic>mk3<\/jats:italic>\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    double knockout larvae exhibited reduced TNF\u2010\u03b1 expression, suggesting that higher levels of TNF\u2010\u03b1 may be associated with viral clearance via the p38\u2010MK2\u2010TNF\u2010\u03b1 signaling axis. In contrast,\n                    <jats:italic>mk3<\/jats:italic>\n                    \u2212\/\u2212 zebrafish exhibited increased vulnerability to CHIKV through alternative, yet unidentified, pathways. Furthermore, an increase in viral titer corresponded with an enhanced host immune response, as indicated by significantly higher expression levels of\n                    <jats:italic>ifn\u02781<\/jats:italic>\n                    and\n                    <jats:italic>rsad2<\/jats:italic>\n                    in all knockout groups. In conclusion, this study confirms that the\n                    <jats:italic>mk2b<\/jats:italic>\n                    and\n                    <jats:italic>mk3<\/jats:italic>\n                    host proteins are essential in controlling CHIKV infection at the organism level. These findings might have implications towards designing strategies for future antiviral therapeutics. Furthermore, the knockout model of\n                    <jats:italic>mk2b<\/jats:italic>\n                    and\n                    <jats:italic>mk3<\/jats:italic>\n                    in zebrafish could serve as a valuable tool for studying their roles in other viral infections.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501236rr","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T18:23:40Z","timestamp":1761071020000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CRISPR\u2010Induced Mutations of\n                    <i>mk2b<\/i>\n                    and\n                    <i>mk3<\/i>\n                    Host Proteins Enhance Chikungunya Virus Susceptibility and Modulate Host Immune Responses in Zebrafish"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5429-9587","authenticated-orcid":false,"given":"Supriya Suman","family":"Keshry","sequence":"first","affiliation":[{"name":"BRIC\u2010 Institute of Life Sciences  Bhubaneswar India"},{"name":"School of Biotechnology Kalinga Institute of Industrial Technology (KIIT) University  Bhubaneswar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4784-567X","authenticated-orcid":false,"given":"Usharani","family":"Nayak","sequence":"additional","affiliation":[{"name":"BRIC\u2010 Institute of Life Sciences  Bhubaneswar India"},{"name":"Regional Centre for Biotechnology  Faridabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0187-571X","authenticated-orcid":false,"given":"Prabhudutta","family":"Mamidi","sequence":"additional","affiliation":[{"name":"All India Institute of Medical Sciences  Bhubaneswar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6957-3245","authenticated-orcid":false,"given":"Suryasikha","family":"Mohanty","sequence":"additional","affiliation":[{"name":"BRIC\u2010 Institute of Life Sciences  Bhubaneswar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8946-841X","authenticated-orcid":false,"given":"Udvas","family":"Ghorai","sequence":"additional","affiliation":[{"name":"BRIC\u2010 Institute of Life Sciences  Bhubaneswar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4815-8221","authenticated-orcid":false,"given":"Rajeeb. 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