@article{02a6e6a490c145c08b899d73cb2ab4c0,
title = "Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection",
abstract = "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 IKKκ, 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.",
author = "Huanle Luo and Evandro Winkelmann and Shuang Zhu and Wenjuan Ru and Elizabeth Mays and Silvas, {Jesus A.} and Vollmer, {Lauren L.} and Junling Gao and Bihung Peng and Bopp, {Nathen E.} and Courtney Cromer and Chao Shan and Guorui Xie and Guangyu Li and Robert Tesh and Popov, {Vsevolod L.} and Shi, {Pei Yong} and Sun, {Shao Cong} and Ping Wu and Klein, {Robyn S.} and Shao-Jun Tang and Wenbo Zhang and Aguilar, {Patricia V.} and Tian Wang",
note = "Funding Information: This work was supported in part by the Institute for Human Infections and Immunity at UTMB (to TW), NIH grants R01 AI099123 and R01 AI27744 (to TW), R01NS079166, R01NS095747, and R01DA036165 (to SJT), U19 AI083019 and R01 NS052632 (to RSK), and R01 EY022694 and R01 EY026629 (to WZ). JAS was supported by NIH grant F31 AI124662-01. PVA and VLP were partially supported by NIH grant R24 AI120942. We thank the Texas A&M Institute for Genomic Medicine for the Peli1–/–mice; A. Cardona from the University of Texas San Antonio; and Par-tha Sarkar from UTMB for BV2 cells and SHSY-5Y cells; Beth Levy for human postmortem hippocampal tissues; Lan Pang for technique support; and Linsey Yeager for assistance with manuscript preparation. Publisher Copyright: {\textcopyright} 2018 American Society for Clinical Investigation. All rights reserved.",
year = "2018",
month = nov,
day = "1",
doi = "10.1172/JCI99902",
language = "English (US)",
volume = "128",
pages = "4980--4991",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",
}