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, Bihung Peng, Nathen E. Bopp, Courtney Cromer, Chao Shan, Guorui Xie, Guangyu Li, Robert Tesh, Vsevolod Popov, Pei-Yong Shi, Shao Cong Sun, Ping Wu, Robyn S. Klein & 4 others Shao-Jun Tang, Wenbo Zhang, Patricia Aguilar, Tian Wang

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4980-4991
Number of pages12
JournalThe Journal of clinical investigation
Volume128
Issue number11
DOIs
StatePublished - Nov 1 2018

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West Nile virus
Virus Diseases
Virus Replication
Microglia
Macrophages
Encephalitis
Viral Load
Neurons
Flavivirus Infections
Encephalomyelitis
Flavivirus
Virus Internalization
Ubiquitin-Protein Ligases
Chemokines
Cytokines
T-Lymphocytes

Keywords

  • Inflammation
  • Innate immunity
  • Neurological disorders
  • Virology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection. / Luo, Huanle; Winkelmann, Evandro R.; Zhu, Shuang; Ru, Wenjuan; Mays, Elizabeth; Silvas, Jesus A.; Vollmer, Lauren L.; Gao, Junling; Peng, Bihung; Bopp, Nathen E.; Cromer, Courtney; Shan, Chao; Xie, Guorui; Li, Guangyu; Tesh, Robert; Popov, Vsevolod; Shi, Pei-Yong; Sun, Shao Cong; Wu, Ping; Klein, Robyn S.; Tang, Shao-Jun; Zhang, Wenbo; Aguilar, Patricia; Wang, Tian.

In: The Journal of clinical investigation, Vol. 128, No. 11, 01.11.2018, p. 4980-4991.

Research output: Contribution to journalArticle

Luo, H, Winkelmann, ER, Zhu, S, Ru, W, Mays, E, Silvas, JA, Vollmer, LL, Gao, J, Peng, B, Bopp, NE, Cromer, C, Shan, C, Xie, G, Li, G, Tesh, R, Popov, V, Shi, P-Y, Sun, SC, Wu, P, Klein, RS, Tang, S-J, Zhang, W, Aguilar, P & Wang, T 2018, 'Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection', The Journal of clinical investigation, vol. 128, no. 11, pp. 4980-4991. https://doi.org/10.1172/JCI99902
Luo, Huanle ; Winkelmann, Evandro R. ; Zhu, Shuang ; Ru, Wenjuan ; Mays, Elizabeth ; Silvas, Jesus A. ; Vollmer, Lauren L. ; Gao, Junling ; Peng, Bihung ; Bopp, Nathen E. ; Cromer, Courtney ; Shan, Chao ; Xie, Guorui ; Li, Guangyu ; Tesh, Robert ; Popov, Vsevolod ; Shi, Pei-Yong ; Sun, Shao Cong ; Wu, Ping ; Klein, Robyn S. ; Tang, Shao-Jun ; Zhang, Wenbo ; Aguilar, Patricia ; Wang, Tian. / Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection. In: The Journal of clinical investigation. 2018 ; Vol. 128, No. 11. pp. 4980-4991.
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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, Bihung

AU - Bopp, Nathen E.

AU - Cromer, Courtney

AU - Shan, Chao

AU - Xie, Guorui

AU - Li, Guangyu

AU - Tesh, Robert

AU - Popov, Vsevolod

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

AU - Wang, Tian

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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.

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