The A487 residue in the E protein of duck Tembusu virus significantly enhances viral replication and increases its neurovirulence in Kunming mice

作者：Yu He, Jiaqi Guo, Xiaoli Wang, Zhen Wu, Tao Wang, Mingshu Wang, Renyong Jia, Dekang Zhu, Mafeng Liu, Xinxin Zhao, Qiao Yang, Ying Wu, Shaqiu Zhang, Juan Huang, Xumin Ou, Di Sun, Anchun Cheng, Shun Chen · 发表于：Journal of Virology · 年份：2025 · DOI：10.1128/jvi.00308-25 · 被引用次数：5 · 研究领域：Mosquito-borne diseases and control、Viral Infections and Vectors、Vector-borne infectious diseases

ABSTRACT Tembusu virus (TMUV), an emerging avian orthoflavivirus, causes severe egg-drop syndrome and encephalitis in ducks. Although ducks are the natural host, mice serve as a valuable model for studying neuropathogenesis, as TMUV-infected mice recapitulate key neurological symptoms observed in ducks, such as paralysis and encephalitis. In the previous study, we observed that the TMUV strain CQW1 exhibited unexpectedly low neurovirulence in mice compared with earlier strains, highlighting potential genetic determinants of pathogenicity that may influence viral evolution and disease outcomes in natural hosts. In this study, we investigated the murine neurovirulence of TMUV strains from two major phylogenetic clusters (2.1 and 2.2). The Cluster 2.2 strain CHN-YC demonstrated markedly higher neurovirulence in Kunming mice than Cluster 2.1 strains (CQW1 and SCS01), with robust viral replication in the brain, pronounced histopathological damage, and elevated proinflammatory cytokine levels. Comparative genomic analysis identified seven amino acid substitutions in the E-NS1 region, with variations unique to Cluster 2.1 strains or specific to CQW1. By introducing these substitutions into CQW1 via reverse genetics, we restored high murine neurovirulence and identified the E protein substitution V487A as critical for this phenotype. Mechanistically, E-V487A enhances viral assembly, which boosts replication efficiency in vitro and in vivo . This substitution is located in the E prote...