RESUMEN
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.
RESUMEN
The influenza A virus of the H7N9 subtype (FLUAV H7N9) emerged in Eastern China provinces in 2013 causing illness in both poultry and humans. Most reported FLUAV H7N9 human cases were related to those associated with the live poultry market chain. From 2013 to 2017, there were five epidemic waves of human infections, and from the end of 2016, the number of human cases increased sharply. To control FLUAV H7N9 in the market chain, the so-called '1110' policy at live poultry markets and a national vaccination programme were implemented. The relative efficacy of these two measures on the number of poultry and human infections has not been quantified and compared. To explore their efficacy, a cross-sectional study was conducted in six provinces of China, and the vaccination and surveillance data of H7N9 were analysed. Our survey data showed that poultry vendors were not widely aware of and did not accept the '1110' policy. For subjective and objective factors, some measures of the '1110' policy were not implemented in live bird markets (LBMs). However, the national vaccination programme achieved good immune effects and sharply decreased poultry FLUAV H7N9 infections. The detection rates of FLUAV H7N9 in LBMs and farms gradually decreased since the vaccination programme was implemented. Our analysis also indicated that human infections were closely related to poultry virus carriage rates; therefore, controlling FLUAV H7N9 circulation in poultry was an effective measure to control FLUAV H7N9 infections in humans. Although LBMs play a significant role in human infections, the management measures may not be implemented efficiently; hence, we need to conduct more investigations before developing related policies.