A single-amino-acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice.
In this study, we explored the molecular basis determining the virulence of H5N1 avian influenza viruses in mammalian hosts by comparing two viruses, A/Duck/Guangxi/12/03 (DK/12) and A/Duck/Guangxi/27/03 (DK/27), which are genetically similar but differ in their pathogenicities in mice. To assess the genetic basis for this difference in virulence, we used reverse genetics to generate a series of reassortants and mutants of these two viruses. We found that a single-amino-acid substitution of serine for proline at position 42 (P42S) in the NS1 protein dramatically increased the virulence of the DK/12 virus in mice, whereas the substitution of proline for serine at the same position (S42P) completely attenuated the DK/27 virus. We further demonstrated that the amino acid S42 of NS1 is critical for the H5N1 influenza virus to antagonize host cell interferon induction and for the NS1 protein to prevent the double-stranded RNA-mediated activation of the NF-kappaB pathway and the IRF-3 pathway. Our results indicate that the NS1 protein is critical for the pathogenicity of H5N1 influenza viruses in mammalian hosts and that the amino acid S42 of NS1 plays a key role in undermining the antiviral immune response of the host cell.
Jiao
Peirong
P
Harbin Veterinary Research Institute, CAAS, 427 Maduan Street, Harbin 150001, People's Republic of China.
Tian
Guobin
G
Li
Yanbing
Y
Deng
Guohua
G
Jiang
Yongping
Y
Liu
Chang
C
Liu
Weilong
W
Bu
Zhigao
Z
Kawaoka
Yoshihiro
Y
Chen
Hualan
H
D019943:Amino Acid Substitution; D000818:Animals; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D007372:Interferons / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000821:virology*; D016865:Reassortant Viruses / Q000235:genetics / Q000472:pathogenicity; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D014774:Virulence
C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins; D007372:Interferons