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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 IKK?, 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.

SUBMITTER: Luo H

PROVIDER: S-EPMC6205407 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Luo Huanle H Winkelmann Evandro R ER Zhu Shuang S Ru Wenjuan W Mays Elizabeth E Silvas Jesus A JA Vollmer Lauren L LL Gao Junling J Peng Bi-Hung BH Bopp Nathen E NE Cromer Courtney C Shan Chao C Xie Guorui G Li Guangyu G Tesh Robert R Popov Vsevolod L VL Shi Pei-Yong PY Sun Shao-Cong SC Wu Ping P Klein Robyn S RS Tang Shao-Jun SJ Zhang Wenbo W Aguilar Patricia V PV Wang Tian T

The Journal of clinical investigation 20180924 11

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 int ...[more]

PMID: 30247157

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Project description:West Nile virus (WNV) is the most prevalent mosquito-borne virus in the United States with approximately 2,000 cases each year. There are currently no approved human vaccines and a lack of prophylactic and therapeutic treatments. Understanding host responses to infection may reveal potential intervention targets to reduce virus replication and disease progression. The use of Drosophila melanogaster as a model organism to understand innate immunity and host antiviral responses is well-established. Previous studies revealed that insulin-mediated signaling regulates WNV infection in invertebrates by regulating canonical antiviral pathways. Because insulin signaling is well-conserved across insect and mammalian species, we sought to determine if results using D. melanogaster can be extrapolated for the analysis of orthologous pathways in humans. Here, we identify insulin-mediated endothelin signaling using the D. melanogaster model and evaluate an orthologous pathway in human cells during WNV infection. We demonstrate that endothelin signaling reduces WNV replication through the activation of canonical antiviral signaling. Taken together, our findings show that endothelin-mediated antiviral immunity is broadly conserved across species and reduces replication of viruses that can cause severe human disease. IMPORTANCE Arboviruses, particularly those transmitted by mosquitoes, pose a significant threat to humans and are an increasing concern because of climate change, human activity, and expanding vector-competent populations. West Nile virus is of significant concern as the most frequent mosquito-borne disease transmitted annually within the continental United States. Here, we identify a previously uncharacterized signaling pathway that impacts West Nile virus infection, namely endothelin signaling. Additionally, we demonstrate that we can successfully translate results obtained from D. melanogaster into the more relevant human system. Our results add to the growing field of insulin-mediated antiviral immunity and identify potential biomarkers or intervention targets to better address West Nile virus infection and severe disease.

Dataset Information

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

Publications

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

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