{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T01:13:35Z","timestamp":1773105215673,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFF0724501"],"award-info":[{"award-number":["2023YFF0724501"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Veterinary Sciences"],"abstract":"<jats:p>Japanese encephalitis virus (JEV) is an important flavivirus that causes zoonotic and arboviral diseases. Infection with JEV not only induces acute central nervous system (CNS) infectious diseases but also leads to reproductive disorders. Currently, research on the pathogenic mechanism of JEV has mainly focused on CNS inflammation caused by infection, while studies on the pathogenic mechanism of JEV targeting the reproductive system are relatively scarce. This study used TM3 cells as a model to investigate the regulatory role of the CD4 molecule in JEV infection, the STAT1 signaling pathway, and inflammatory factors. Firstly, we found that CD4 knockdown significantly inhibited JEV replication in TM3 cells. Further virus adsorption and internalization experiments confirmed that CD4 knockdown specifically impaired the early stages of JEV invasion into cells. Additionally, CD4 knockdown also drastically attenuated JEV infection-induced STAT1 phosphorylation (p-STAT1) and the production of downstream inflammatory factors. To distinguish whether CD4 affects p-STAT1 through an indirect effect of reduced viral load or its direct involvement in signal transduction, we performed experiments using RO8191, a specific agonist of the STAT1 signaling pathway. The results showed that RO8191 treatment increased the expression levels of p-STAT1 protein and inflammatory factor mRNA in both normal cells and CD4 knockdown cells, but the recovery amplitude in the CD4 knockdown group was significantly lower. In contrast, CD4 complementation significantly elevated the expression levels of p-STAT1 protein and inflammatory factor mRNA. In conclusion, this study demonstrates that the CD4 molecule positively regulates JEV proliferation in TM3 cells, while also modulating STAT1\u2014a key factor in the STAT signaling pathway\u2014and downstream inflammatory cytokines. Notably, this regulatory effect operates independently of viral replication. These findings provide a theoretical foundation for further elucidation of JEV pathogenic mechanisms and offer a scientific basis for the prevention and control of JEV.<\/jats:p>","DOI":"10.3390\/vetsci13030254","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T13:27:18Z","timestamp":1773062838000},"page":"254","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD4 Molecule Plays an Important Role in the Inflammatory Response Induced by Japanese Encephalitis Virus Infection"],"prefix":"10.3390","volume":"13","author":[{"given":"Xinran","family":"Li","sequence":"first","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanyuan","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinlei","family":"Liu","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Dai","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Gu","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruiqin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahui","family":"Li","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haodong","family":"Chen","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-4167","authenticated-orcid":false,"given":"Rui","family":"Wu","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"},{"name":"Sichuan Science-Observation Experiment Station of Veterinary Drugs and Veterinary Diagnostic Technology, Ministry of Agriculture, Chengdu 611330, China"},{"name":"National Animal Experiments Teaching Demonstration Center, Sichuan Agricultural University, Chengdu 611330, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1146\/annurev.ento.54.110807.090510","article-title":"Ecology and Geographical Expansion of Japanese Encephalitis Virus","volume":"54","author":"Ritchie","year":"2009","journal-title":"Annu. 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