A Single-Amino-Acid Substitution in the NS1 Protein Changes the Pathogenicity of H5N1 Avian Influenza Viruses in Mice

[sharon sanders]

A Single-Amino-Acid Substitution in the NS1 Protein Changes the Pathogenicity of H5N1 Avian Influenza Viruses in Mice<sup>

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Peirong Jiao,¹ Guobin Tian,¹ Yanbing Li,¹ Guohua Deng,¹ Yongping Jiang,¹ Chang Liu,¹ Weilong Liu,¹ Zhigao Bu,¹ Yoshihiro Kawaoka,²^,3^,4 and Hualan Chen¹^* Animal Influenza Laboratory of the Ministry of Agriculture and National Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 427 Maduan Street, Harbin 150001, People's Republic of China,¹ Division of Virology, Department of Microbiology and Immunology,² International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan,³ Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706⁴
Received 6 August 2007/ Accepted 6 November 2007
<!-- ABS --> In this study, we explored the molecular basis determining thevirulence of H5N1 avian influenza viruses in mammalian hostsby 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 pathogenicitiesin mice. To assess the genetic basis for this difference invirulence, we used reverse genetics to generate a series ofreassortants and mutants of these two viruses. We found thata single-amino-acid substitution of serine for proline at position42 (P42S) in the NS1 protein dramatically increased the virulenceof the DK/12 virus in mice, whereas the substitution of prolinefor serine at the same position (S42P) completely attenuatedthe DK/27 virus. We further demonstrated that the amino acidS42 of NS1 is critical for the H5N1 influenza virus to antagonizehost cell interferon induction and for the NS1 protein to preventthe double-stranded RNA-mediated activation of the NF-

B pathwayand the IRF-3 pathway. Our results indicate that the NS1 proteinis critical for the pathogenicity of H5N1 influenza virusesin mammalian hosts and that the amino acid S42 of NS1 playsa key role in undermining the antiviral immune response of thehost cell.

http://jvi.asm.org/cgi/content/abstract/82/3/1146