The lipopeptide Pam3CSK4 inhibits Rift Valley fever virus infection and protects from encephalitis

Rift Valley fever virus (RVFV) is an encephalitic bunyavirus that can infect neurons in the brain. There are no approved therapeutics that can protect from RVFV encephalitis. Innate immunity, the first line of defense against infection, canonically antagonizes viruses through interferon signaling. We found that interferons did not efficiently protect primary cortical neurons from RVFV, unlike other cell types. To identify alternative neuronal antiviral pathways, we screened innate immune ligands and discovered that the TLR2 ligand Pam3CSK4 inhibited RVFV infection, and other bunyaviruses. Mechanistically, we found that Pam3CSK4 blocks viral fusion, independent of TLR2. In a mouse model of RVFV encephalitis, Pam3CSK4 treatment protected animals from infection and mortality. Overall, Pam3CSK4 is a bunyavirus fusion inhibitor active in primary neurons and the brain, representing a new approach toward the development of treatments for encephalitic bunyavirus infections.裂谷热病毒（Rift Valley fever virus, RVFV）是一种嗜神经性布尼亚病毒，可感染大脑神经元。目前尚无获批的治疗药物可用于预防RVFV脑炎。先天免疫作为抗感染的第一道防线，传统上通过干扰素信号通路拮抗病毒。我们的研究发现，与其他细胞类型不同，干扰素无法有效保护原代皮层神经元免受RVFV感染。为鉴定替代性神经元抗病毒通路，我们筛选了先天免疫配体，发现Toll样受体2（TLR2）配体Pam3CSK4可抑制RVFV及其他布尼亚病毒的感染。机制研究表明，Pam3CSK4可不依赖TLR2阻断病毒融合过程。在RVFV脑炎小鼠模型中，Pam3CSK4治疗可保护动物免受感染并降低死亡率。综上，Pam3CSK4是一种可在原代神经元及大脑中发挥活性的布尼亚病毒融合抑制剂，为嗜神经性布尼亚病毒感染的治疗药物开发提供了全新思路。