TY - JOUR AU - Luo, Huanle AU - Winkelmann, Evandro R. AU - Zhu, Shuang AU - Ru, Wenjuan AU - Mays, Elizabeth AU - Silvas, Jesus A. AU - Vollmer, Lauren L. AU - Gao, Junling AU - Peng, Bi-Hung AU - Bopp, Nathen E. AU - Cromer, Courtney AU - Shan, Chao AU - Xie, Guorui AU - Li, Guangyu AU - Tesh, Robert AU - Popov, Vsevolod L. AU - Shi, Pei-Yong AU - Sun, Shao-Cong AU - Wu, Ping AU - Klein, Robyn S. AU - Tang, Shao-Jun AU - Zhang, Wenbo AU - Aguilar, Patricia V. AU - Wang, Tian T1 - Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection PY - 2018/11/01/ AB - The E3 ubiquitin ligase Pellino 1 (Peli1) is a microglia-specific mediator of autoimmune encephalomyelitis. Its role in neurotropic flavivirus infection is largely unknown. Here, we report that mice deficient in Peli1 (Peli1–/–) were more resistant to lethal West Nile virus (WNV) infection and exhibited reduced viral loads in tissues and attenuated brain inflammation. Peli1 mediates chemokine and proinflammatory cytokine production in microglia and promotes T cell and macrophage infiltration into the CNS. Unexpectedly, Peli1 was required for WNV entry and replication in mouse macrophages and mouse and human neurons and microglia. It was also highly expressed on WNV-infected neurons and adjacent inflammatory cells from postmortem patients who died of acute WNV encephalitis. WNV passaged in Peli1–/– macrophages or neurons induced a lower viral load and impaired activation in WT microglia and thereby reduced lethality in mice. Smaducin-6, which blocks interactions between Peli1 and IRAK1, RIP1, and IKKε, did not inhibit WNV-triggered microglia activation. Collectively, our findings suggest a nonimmune regulatory role for Peli1 in promoting microglia activation during WNV infection and identify a potentially novel host factor for flavivirus cell entry and replication. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI99902 VL - 128 IS - 11 UR - https://doi.org/10.1172/JCI99902 SP - 4980 EP - 4991 PB - The American Society for Clinical Investigation ER -