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Neurovirulence of avian influenza virus is dependent on the interaction of viral NP protein with host factor FMRP in the murine brain

Zhang, Xuxiao; Pu, Juan; Sun, Yipeng; Bi, Yuhai; Jiang, Zhimin; Xu, Guanlong; Zhang, Hongyu; Cao, Jing; Chang, Kin-Chow; Liu, Jinhua; Sun, Honglei

Neurovirulence of avian influenza virus is dependent on the interaction of viral NP protein with host factor FMRP in the murine brain Thumbnail


Authors

Xuxiao Zhang

Juan Pu

Yipeng Sun

Yuhai Bi

Zhimin Jiang

Guanlong Xu

Hongyu Zhang

Jing Cao

KIN-CHOW CHANG KIN-CHOW.CHANG@NOTTINGHAM.AC.UK
Professor of Veterinary Molecular Medicine

Jinhua Liu

Honglei Sun



Abstract

Avian influenza viruses (AIVs) are zoonotic viruses that exhibit a range infectivity and severity in the human host. Severe human cases of AIVs infection are often accompanied by neurological symptoms, however, the factors involved in the infection of the central nervous system (CNS) are not well known. In this study, we discovered that avian-like sialic acid (SA)-α2, 3 Gal receptor is highly presented in mammalian (human and mouse) brains. In the generation of a mouse-adapted neurotropic H9N2 AIV (SD16-MA virus) in BALB/c mice, we identified key adaptive mutations in its hemagglutinin (HA) and polymerase basic protein 2 (PB2) genes that conferred viral replication ability in mice brain. The SD16-MA virus showed binding affinity for avian-like SA-α2, 3 Gal receptor, enhanced viral RNP polymerase activity, increased viral protein production and transport that culminated in elevated progeny virus production and severe pathogenicity. We further established that host Fragile X Mental Retardation Protein (FMRP), a highly expressed protein in the brain that physically associated with viral nucleocapsid protein (NP) to facilitate RNP assembly and export, was an essential host factor for the neuronal replication of neurotropic AIVs (H9N2, H5N1 and H10N7 viruses). Our study identified a mechanistic process for AIVs to acquire neurovirulence in mice.

Citation

Zhang, X., Pu, J., Sun, Y., Bi, Y., Jiang, Z., Xu, G., …Sun, H. (2021). Neurovirulence of avian influenza virus is dependent on the interaction of viral NP protein with host factor FMRP in the murine brain. Journal of Virology, 95(7), https://doi.org/10.1128/JVI.01272-20

Journal Article Type Article
Acceptance Date Dec 16, 2020
Online Publication Date Jan 6, 2021
Publication Date 2021-03
Deposit Date Dec 17, 2020
Publicly Available Date Jul 7, 2021
Journal Journal of Virology
Print ISSN 0022-538X
Electronic ISSN 1098-5514
Publisher American Society for Microbiology
Peer Reviewed Peer Reviewed
Volume 95
Issue 7
DOI https://doi.org/10.1128/JVI.01272-20
Public URL https://nottingham-repository.worktribe.com/output/5154904
Publisher URL https://journals.asm.org/doi/10.1128/JVI.01272-20

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