tetano
Editor, Senior Moderator
J Virol. 2018 Mar 21. pii: JVI.00149-18. doi: 10.1128/JVI.00149-18. [Epub ahead of print]
[h=1]A Naturally Occurring Deletion in the Effector Domain of H5N1 Swine Influenza Virus Nonstructural Protein 1 Regulates Viral Fitness and Host Innate Immunity.[/h] Wang J[SUP]1[/SUP], Zeng Y[SUP]1[/SUP], Xu S[SUP]1[/SUP], Yang J[SUP]1[/SUP], Wang W[SUP]1[/SUP], Zhong B[SUP]2[/SUP], Ge J[SUP]3[/SUP], Yin L[SUP]4[/SUP], Bu Z[SUP]3[/SUP], Shu HB[SUP]2,[/SUP][SUP]4[/SUP], Chen H[SUP]3[/SUP], Lei CQ[SUP]5[/SUP], Zhu Q[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Nonstructural protein 1 (NS1) of influenza A virus regulates innate immune responses via various mechanisms. We previously showed that a naturally occurring deletion (the EALQR motif) in the NS1 effector domain of an H5N1 swine-origin avian influenza virus impairs the inhibition of type I interferon (IFN) in chicken fibroblasts and attenuates virulence in chickens. Here, we found that the virus bearing this deletion in its NS1 effector domain showed diminished inhibition of IFN-related cytokine expression and attenuated virulence in mice. We further show that deletion of the EALQR motif disrupts NS1 dimerization, impairing double-stranded RNA (dsRNA) sequestration and competitive binding with RIG-I. In addition, the EALQR-deleted NS1 could not bind to TRIM25, unlike full-length NS1, and was less able to block TRIM25 oligomerization and self-ubiquitination, further impairing the inhibition of TRIM25-mediated RIG-I ubiquitination compared with full-length NS1. Our data demonstrate that the EALQR deletion prevents NS1 from blocking RIG-I-mediated IFN induction via a novel mechanism to attenuate the viral replication and virulence in mammalian cells and animals.IMPORTANCE H5 highly pathogenic avian influenza viruses have infected more than 800 individuals with an overall 53% case fatality rate across 16 countries. Among viral proteins, nonstructural protein 1 (NS1) of influenza virus is considered a key determinant for type I interferon (IFN) antagonism, pathogenicity, and host range. However, that how NS1 precisely modulates virus-host interaction facilitating virus survival is not fully understood. Here, we report that a naturally occurring deletion (the EALQR motif) in the NS1 effector domain of an H5N1 swine-origin avian influenza virus disrupted the NS1 dimerization, which diminished the blockade of IFN induction via the RIG-I signaling pathway, thereby impairing virus replication and virulence in the host. Our study demonstrates the EALQR motif of NS1 regulates virus fitness to attain a virus-host compromise state in animals, and identifies this critical motif as a potential target for the future development of small molecular drugs and attenuated vaccines.
PMID: 29563291 DOI: 10.1128/JVI.00149-18
[h=1]A Naturally Occurring Deletion in the Effector Domain of H5N1 Swine Influenza Virus Nonstructural Protein 1 Regulates Viral Fitness and Host Innate Immunity.[/h] Wang J[SUP]1[/SUP], Zeng Y[SUP]1[/SUP], Xu S[SUP]1[/SUP], Yang J[SUP]1[/SUP], Wang W[SUP]1[/SUP], Zhong B[SUP]2[/SUP], Ge J[SUP]3[/SUP], Yin L[SUP]4[/SUP], Bu Z[SUP]3[/SUP], Shu HB[SUP]2,[/SUP][SUP]4[/SUP], Chen H[SUP]3[/SUP], Lei CQ[SUP]5[/SUP], Zhu Q[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Nonstructural protein 1 (NS1) of influenza A virus regulates innate immune responses via various mechanisms. We previously showed that a naturally occurring deletion (the EALQR motif) in the NS1 effector domain of an H5N1 swine-origin avian influenza virus impairs the inhibition of type I interferon (IFN) in chicken fibroblasts and attenuates virulence in chickens. Here, we found that the virus bearing this deletion in its NS1 effector domain showed diminished inhibition of IFN-related cytokine expression and attenuated virulence in mice. We further show that deletion of the EALQR motif disrupts NS1 dimerization, impairing double-stranded RNA (dsRNA) sequestration and competitive binding with RIG-I. In addition, the EALQR-deleted NS1 could not bind to TRIM25, unlike full-length NS1, and was less able to block TRIM25 oligomerization and self-ubiquitination, further impairing the inhibition of TRIM25-mediated RIG-I ubiquitination compared with full-length NS1. Our data demonstrate that the EALQR deletion prevents NS1 from blocking RIG-I-mediated IFN induction via a novel mechanism to attenuate the viral replication and virulence in mammalian cells and animals.IMPORTANCE H5 highly pathogenic avian influenza viruses have infected more than 800 individuals with an overall 53% case fatality rate across 16 countries. Among viral proteins, nonstructural protein 1 (NS1) of influenza virus is considered a key determinant for type I interferon (IFN) antagonism, pathogenicity, and host range. However, that how NS1 precisely modulates virus-host interaction facilitating virus survival is not fully understood. Here, we report that a naturally occurring deletion (the EALQR motif) in the NS1 effector domain of an H5N1 swine-origin avian influenza virus disrupted the NS1 dimerization, which diminished the blockade of IFN induction via the RIG-I signaling pathway, thereby impairing virus replication and virulence in the host. Our study demonstrates the EALQR motif of NS1 regulates virus fitness to attain a virus-host compromise state in animals, and identifies this critical motif as a potential target for the future development of small molecular drugs and attenuated vaccines.
PMID: 29563291 DOI: 10.1128/JVI.00149-18