tetano
Editor, Senior Moderator
J Virol. 2013 Feb 13. [Epub ahead of print]
Synergistic effect of the PDZ and the p85β-binding domains of the NS1 protein in virulence of an avian H5N1 influenza A virus.
Fan S, Macken CA, Li C, Ozawa M, Goto H, Iswahyudi, Nidom CA, Chen H, Neumann G, Kawaoka Y.
Source
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison; Madison, WI.
Abstract
The influenza A virus NS1 protein affects virulence through several mechanisms including the host's innate immune response and various signaling pathways. Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype continue to evolve through reassortment and mutations. Our recent phylogenetic analysis identified a group of HPAI H5N1 viruses with two characteristic mutations in NS1: the avian virus-type PDZ domain-binding motif ESEV (which affects virulence) was replaced with ESKV, and NS1-138F (which is highly conserved among all influenza A viruses and may affect the activation of the PI3K/Akt signaling pathway) was replaced with NS1-138Y. Here, we show that an HPAI H5N1 virus (A/duck/Hunan/69/2004) encoding NS1-ESKV and NS1-138Y was confined to the respiratory tract of infected mice, whereas a mutant encoding NS1-ESEV and NS1-138F caused systemic infection and killed mice more efficiently. Mutation of either one of these sites had small effects on virulence. In addition, we found that the amino acid at NS1-138 affected not only the induction of the PI3K/Akt pathway, but also the interaction of NS1 with cellular PDZ domain proteins. Similarly, the mutation in the PDZ domain-binding motif of NS1 altered its binding to cellular PDZ domain proteins and affected Akt phosphorylation. These findings suggest a functional interplay between the mutations at NS1-138 and NS1-229 that results in a synergistic effect on influenza virulence.
PMID:
23408626
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23408626
Synergistic effect of the PDZ and the p85β-binding domains of the NS1 protein in virulence of an avian H5N1 influenza A virus.
Fan S, Macken CA, Li C, Ozawa M, Goto H, Iswahyudi, Nidom CA, Chen H, Neumann G, Kawaoka Y.
Source
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison; Madison, WI.
Abstract
The influenza A virus NS1 protein affects virulence through several mechanisms including the host's innate immune response and various signaling pathways. Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype continue to evolve through reassortment and mutations. Our recent phylogenetic analysis identified a group of HPAI H5N1 viruses with two characteristic mutations in NS1: the avian virus-type PDZ domain-binding motif ESEV (which affects virulence) was replaced with ESKV, and NS1-138F (which is highly conserved among all influenza A viruses and may affect the activation of the PI3K/Akt signaling pathway) was replaced with NS1-138Y. Here, we show that an HPAI H5N1 virus (A/duck/Hunan/69/2004) encoding NS1-ESKV and NS1-138Y was confined to the respiratory tract of infected mice, whereas a mutant encoding NS1-ESEV and NS1-138F caused systemic infection and killed mice more efficiently. Mutation of either one of these sites had small effects on virulence. In addition, we found that the amino acid at NS1-138 affected not only the induction of the PI3K/Akt pathway, but also the interaction of NS1 with cellular PDZ domain proteins. Similarly, the mutation in the PDZ domain-binding motif of NS1 altered its binding to cellular PDZ domain proteins and affected Akt phosphorylation. These findings suggest a functional interplay between the mutations at NS1-138 and NS1-229 that results in a synergistic effect on influenza virulence.
PMID:
23408626
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23408626