Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection
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
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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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 4

Peli1 mediates neuroinflammation in the CNS after WNV infection.

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Peli1 mediates neuroinflammation in the CNS after WNV infection. (A) RN...
(A) RNA levels of Peli1 in the brains of WT mice following WNV infection were determined by qPCR assay. Data are presented as the mean ± SEM of samples pooled from 2 to 3 independent experiments (n = 8). ##P < 0.01 compared with the noninfected group (unpaired, 2-tailed Student’s t test). (B–G) RNA levels of cytokines and chemokines in the brain at the indicated time points were determined by qPCR assay. Data are presented as the mean ± SEM of 6 to 10 samples pooled from 2 independent experiments. (H–J) Brain leukocyte infiltration following WNV infection. (H) The number of brain leukocytes is presented as the mean ± SEM of 9 to 10 mice from 2 independent experiments, including naive microglial cells (NMGs), activated microglial cells (AMGs), macrophages (Mθs), and CD4+ and CD8+ T cells on day 9 p.i. (analyzed by flow cytometry). (I) Representative flow plot. (B–H) *P < 0.05 and **P < 0.01 compared with the WT group (unpaired, 2-tailed Student’s t test). (J) Survival of WT and Peli1–/– mice after i.c. injection with WNV 385-99 (n = 9 per group). *P < 0.05 compared with the WT group (log-rank test).