Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell Rep. 2024 Oct 22;43(10):114809. doi: 10.1016/j.celrep.2024.114809. Epub 2024 Oct 5.
The very-low-density lipoprotein receptor (VLDLR) has been reported as an entry receptor for Semliki Forest (SFV) and Eastern equine encephalitis (EEEV) alphaviruses in cell cultures. However, the role of VLDLR in alphavirus pathogenesis and the extent to which other alphaviruses can engage VLDLR remains unclear. Here, using a surface protein-targeted CRISPR-Cas9 screen, we identify VLDLR as a receptor for Western equine encephalitis virus (WEEV) and demonstrate that it promotes the infection of multiple viruses in the WEE antigenic complex. In vivo studies show that the pathogenicity of WEEV, EEEV, and SFV, but not the distantly related Venezuelan equine encephalitis virus, is markedly diminished in VLDLR-deficient mice and that mice treated with a soluble VLDLR-Fc decoy molecule are protected against disease. Overall, these results expand our understanding of the role of VLDLR in alphavirus pathogenesis and provide a potential path for developing countermeasures against alphaviruses from different antigenic complexes.
极低密度脂蛋白受体 (VLDLR) 已被报道为细胞培养中 Semliki Forest (SFV) 和东部马脑炎 (EEEV) 甲病毒的进入受体。然而，VLDLR 在甲病毒发病机制中的作用以及其他甲病毒能够结合 VLDLR 的程度尚不清楚。在这里，我们使用表面蛋白靶向的 CRISPR-Cas9 筛选，鉴定出 VLDLR 是 Western equine encephalitis virus (WEEV) 的受体，并证明它促进了 WEE 抗原复合物中多种病毒的感染。体内研究表明，WEEV、EEEV 和 SFV 的致病性，但与远亲委内瑞拉马脑炎病毒不同，在 VLDLR 缺陷型小鼠中明显降低，并且用可溶性 VLDLR-Fc 诱饵分子处理的小鼠对疾病有保护作用。总的来说，这些结果扩展了我们对 VLDLR 在甲病毒发病机制中的作用的理解，并为开发针对不同抗原复合物的甲病毒的对策提供了一个潜在途径。
