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

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