Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection
Huanle Luo, … , Patricia V. Aguilar, Tian Wang
Huanle Luo, … , Patricia V. Aguilar, Tian Wang
Published September 24, 2018
Citation Information: J Clin Invest. 2018;128(11):4980-4991. https://doi.org/10.1172/JCI99902.
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Research Article Inflammation Virology

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 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.

Authors

Huanle Luo, Evandro R. Winkelmann, Shuang Zhu, Wenjuan Ru, Elizabeth Mays, Jesus A. Silvas, Lauren L. Vollmer, Junling Gao, Bi-Hung Peng, Nathen E. Bopp, Courtney Cromer, Chao Shan, Guorui Xie, Guangyu Li, Robert Tesh, Vsevolod L. Popov, Pei-Yong Shi, Shao-Cong Sun, Ping Wu, Robyn S. Klein, Shao-Jun Tang, Wenbo Zhang, Patricia V. Aguilar, Tian Wang

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Figure 6

Peli1 expression and its role in human cells during WNV infection.

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Peli1 expression and its role in human cells during WNV infection. (A) I...
(A) Immunodetection of Peli1 (green), WNV antigen (WNV Ag) (red), and NeuN (purple), in postmortem hippocampal tissues from 1 control and 2 WNV-infected patients. Nuclei were counterstained with DAPI (blue). Scale bar: 8 μm. Insets are images of sections stained with isotype control antibodies or serum (original magnification, ×63). (B and C) RNA levels of Peli1 in SH-SY5–derived neurons and human microglia on days 1 and 4 p.i. were determined by qPCR. Data are presented as the mean ± SEM and are representative of 2 similar experiments (n = 3–4). ##P < 0.01 compared with the noninfected group (unpaired, 2-tailed Student’s t test). (D–H) SHSY-5Y–derived neurons (D) and human microglial cells (E–H) were treated with control or Peli1 siRNA (Peli1 KD), infected with WNV 385-99 at 48 hours, and harvested at the indicated time points. (D and E) Viral load was measured on day 4 by qPCR. (F–H) IL-6, CCL-2, and CCL-5 production in microglial cells was measured on day 4 by Bio-Plex assay. Data are presented as the mean ± SEM and are representative of 2 similar experiments (n = 4). (D–H) *P < 0.05 and **P < 0.01 compared with the control group (unpaired, 2-tailed Student’s t test).