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J Virol. 2014 Oct 1. pii: JVI.01736-14. [Epub ahead of print]
A Combination of HA and PA Mutations Enhances Virulence in a Mouse-adapted H6N6 Influenza A Virus.
Tan L1, Su S2, Smith DK3, He S1, Zheng Y1, Shao Z1, Ma J1, Zhu H3, Zhang G2.
Author information
Abstract
H6N6 viruses are commonly isolated from domestic ducks and avian-to-swine transmissions of H6N6 viruses have been detected in China. Whether subsequent adaptation of H6N6 viruses in mammals would increase their pathogenicity towards humans is not known. To address this, we generated a mouse-adapted swine influenza H6N6 virus (GDK6-MA) which exhibited greater virulence than the wild-type virus (GDK6). Amino acid substitutions in PB2 (E627K), PA (I38M) and HA (L111F, H156N and S263R) occurred in GDK6-MA. HA H156N resulted in enlarged plaque sizes on MDCK cells and enhanced early stage viral replication in mammalian cells. PA I38M raised polymerase activity in vitro but did not change virus replication in either mammalian cells or mice. These single substitutions had only limited effects on virulence, however, a combination of HA H156N, S263R and PA I38M in the GDK6 backbone led to a significantly more virulent variant. This suggests these substitutions can compensate for the lack of PB2-627K and modulate virulence, revealing a new determinant of pathogenicity for H6N6 viruses in mice, which might also pose a threat to human health.
IMPORTANCE:
Avian H6N6 influenza viruses are enzootic in domestic ducks and have been detected in swine in China. Infections of mammals by H6N6 viruses raise the possibility of viral adaptation and increasing pathogenicity in the new hosts. To examine the molecular mechanisms of adaptation, a mouse-adapted avian-origin swine influenza H6N6 virus (GDK6-MA), which had higher virulence than its parental virus, was generated. Specific mutations were found in PB2 (E627K), PA (I38M) and HA (L111F, H156N, S263R) and were assessed for their virulence in mice. The combination of HA H156N, S263R and PA I38M compensated for the lack of PB2-627K and showed increased pathogenicity in mice, revealing a novel mechanism that can affect the virulence of influenza viruses. H6N6 viruses should be monitored for more virulent forms in the field that could threaten human health.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
25275121
[PubMed - as supplied by publisher]
A Combination of HA and PA Mutations Enhances Virulence in a Mouse-adapted H6N6 Influenza A Virus.
Tan L1, Su S2, Smith DK3, He S1, Zheng Y1, Shao Z1, Ma J1, Zhu H3, Zhang G2.
Author information
Abstract
H6N6 viruses are commonly isolated from domestic ducks and avian-to-swine transmissions of H6N6 viruses have been detected in China. Whether subsequent adaptation of H6N6 viruses in mammals would increase their pathogenicity towards humans is not known. To address this, we generated a mouse-adapted swine influenza H6N6 virus (GDK6-MA) which exhibited greater virulence than the wild-type virus (GDK6). Amino acid substitutions in PB2 (E627K), PA (I38M) and HA (L111F, H156N and S263R) occurred in GDK6-MA. HA H156N resulted in enlarged plaque sizes on MDCK cells and enhanced early stage viral replication in mammalian cells. PA I38M raised polymerase activity in vitro but did not change virus replication in either mammalian cells or mice. These single substitutions had only limited effects on virulence, however, a combination of HA H156N, S263R and PA I38M in the GDK6 backbone led to a significantly more virulent variant. This suggests these substitutions can compensate for the lack of PB2-627K and modulate virulence, revealing a new determinant of pathogenicity for H6N6 viruses in mice, which might also pose a threat to human health.
IMPORTANCE:
Avian H6N6 influenza viruses are enzootic in domestic ducks and have been detected in swine in China. Infections of mammals by H6N6 viruses raise the possibility of viral adaptation and increasing pathogenicity in the new hosts. To examine the molecular mechanisms of adaptation, a mouse-adapted avian-origin swine influenza H6N6 virus (GDK6-MA), which had higher virulence than its parental virus, was generated. Specific mutations were found in PB2 (E627K), PA (I38M) and HA (L111F, H156N, S263R) and were assessed for their virulence in mice. The combination of HA H156N, S263R and PA I38M compensated for the lack of PB2-627K and showed increased pathogenicity in mice, revealing a novel mechanism that can affect the virulence of influenza viruses. H6N6 viruses should be monitored for more virulent forms in the field that could threaten human health.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
25275121
[PubMed - as supplied by publisher]
