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Axl, a TAM family receptor tyrosine kinase, has been demonstrated to be a receptor mediating enveloped virus infection. Here we show that Axl functions as a suppressor of antiviral response during RSV infection. Knockdown of Axl expression in human cells resulted in cell resistance to RSV infection, although the treatment did not significantly affect RSV binding or cell entry. Mice deficient in Axl showed resistance to RSV infection, including reduction in viral load and in pulmonary injury. Although T lymphocyte and macrophage infiltration was reduced, more IFN-\u03b3\u2013producing cells were present in BAL fluid in Axl \u00a0\u2212\/\u2212 mice. Fewer alternatively activated alveolar macrophages were found in the lungs of Axl\u2212\/\u2212 mice. Axl \u00a0\u2212\/\u2212 mouse embryonic fibroblasts and siRNA-treated human cells had more robust IFN-\u03b2 and IFN-stimulated gene induction of antiviral genes. Furthermore, reexpression of Axl using adenovirus-mediated Axl delivery repressed IFN-stimulated gene induction in Axl-null mouse embryonic fibroblasts by RSV infection. The results suggest that Axl, independent of being a virus entry receptor of RSV infection, negatively regulates IFN signaling to modulate host antiviral response against RSV infection.<\/jats:p>","DOI":"10.1165\/rcmb.2021-0362oc","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T13:50:09Z","timestamp":1652363409000},"page":"227-240","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":14,"title":["Axl Mediates Resistance to Respiratory Syncytial Virus Infection Independent of Cell Attachment"],"prefix":"10.1093","volume":"67","author":[{"given":"Dan","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University"},{"name":"Jiangsu Key Laboratory of Molecular Medicine"},{"name":"Yancheng Medical Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanhui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Molecular Medicine"},{"name":"Institute of Medical Virology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University"},{"name":"Jiangsu Key Laboratory of Molecular Medicine"},{"name":"Institute of Medical Virology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxin","family":"You","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Molecular Medicine"},{"name":"Institute of Medical Virology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University"},{"name":"Jiangsu Key Laboratory of Molecular Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohai","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University"},{"name":"State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, Guangxi, China; 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