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

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

  • J Virol. 2021 Jan 6;95(7):e01272-20. doi: 10.1128/JVI.01272-20.
Xuxiao Zhang 1 Juan Pu 1 Yipeng Sun 1 Bi Yuhai 2 3 Zhimin Jiang 1 Guanlong Xu 1 Hongyu Zhang 1 Jing Cao 4 Kin-Chow Chang 5 Jinhua Liu 6 Honglei Sun 6
Affiliations

Affiliations

  • 1 Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
  • 2 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • 3 CAS Center for Influenza Research and Early-Warning (CASCIRE), Chinese Academy of Sciences, Beijing, China.
  • 4 Laboratory of Anatomy of Domestic Animal, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
  • 5 School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, United Kingdom.
  • 6 Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China shlei668@163.com ljh@cau.edu.cn.
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.IMPORTANCE Infection of the CNS is a serious complication of human cases of AIVs Infection. The viral and host factors associated with neurovirulence of AIVs Infection are not well understood. We identified and functionally characterized specific changes in the viral HA and PB2 genes of a mouse-adapted neurotropic avian H9N2 virus responsible for enhanced virus replication in neuronal cells and pathogenicity in mice. Importantly, we showed that host FMRP was a crucial host factor that was necessary for neurotropic AIVs (H9N2, H5N1 and H10N7 viruses) to replicate in neuronal cells. Our findings have provided insights into the pathogenesis of neurovirulence of AIV Infection.

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