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J Virol. 2018 Mar 21. pii: JVI.00149-18. doi: 10.1128/JVI.00149-18. [Epub ahead of print]
A Naturally Occurring Deletion in the Effector Domain of H5N1 Swine Influenza Virus Nonstructural Protein 1 Regulates Viral Fitness and Host Innate Immunity.
Wang J1, Zeng Y1, Xu S1, Yang J1, Wang W1, Zhong B2, Ge J3, Yin L4, Bu Z3, Shu HB2,4, Chen H3, Lei CQ5, Zhu Q6.
Author information
Abstract
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
A Naturally Occurring Deletion in the Effector Domain of H5N1 Swine Influenza Virus Nonstructural Protein 1 Regulates Viral Fitness and Host Innate Immunity.
Wang J1, Zeng Y1, Xu S1, Yang J1, Wang W1, Zhong B2, Ge J3, Yin L4, Bu Z3, Shu HB2,4, Chen H3, Lei CQ5, Zhu Q6.
Author information
Abstract
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