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Journal of Virology, December 2009, p. 12325-12335, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01373-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Polymerase Acidic Protein Gene of Influenza A Virus Contributes to Pathogenicity in a Mouse Model{triangledown}

Min-Suk Song,1 Philippe Noriel Q. Pascua,1 Jun Han Lee,1 Yun Hee Baek,1 Ok-Jun Lee,1 Chul-Joong Kim,2 Hyunggee Kim,3 Richard J. Webby,4 Robert G. Webster,4 and Young Ki Choi1*

College of Medicine and Medical Research Institute, Chungbuk National University, 12 Gaeshin-Dong Heungduk-Ku, Cheongju 361-763, Republic of Korea,1 College of Veterinary Medicine, Chungnam National University, 220 Gung-Dong, Yuseoung-Gu, DaeJeon 305-764, Republic of Korea,2 Division of Bioscience and Technology, College of Life and Environmental Science, Korea University, Seoul, Republic of Korea,3 Division of Virology, Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 381054

Received 4 July 2009/ Accepted 18 September 2009

Adaptation of influenza A viruses to a new host species usually involves the mutation of one or more of the eight viral gene segments, and the molecular basis for host range restriction is still poorly understood. To investigate the molecular changes that occur during adaptation of a low-pathogenic avian influenza virus subtype commonly isolated from migratory birds to a mammalian host, we serially passaged the avirulent wild-bird H5N2 strain A/Aquatic bird/Korea/W81/05 (W81) in the lungs of mice. The resulting mouse-adapted strain (ma81) was highly virulent (50% mouse lethal dose = 2.6 log10 50% tissue culture infective dose) and highly lethal. Nonconserved mutations were observed in six viral genes (those for PB2, PB1, PA, HA, NA, and M). Reverse genetic experiments substituting viral genes and mutations demonstrated that the PA gene was a determinant of the enhanced virulence in mice and that a Thr-to-Iso substitution at position 97 of PA played a key role. In growth kinetics studies, ma81 showed enhanced replication in mammalian but not avian cell lines; the PA97I mutation in strain W81 increased its replicative fitness in mice but not in chickens. The high virulence associated with the PA97I mutation in mice corresponded to considerably enhanced polymerase activity in mammalian cells. Furthermore, this characteristic mutation is not conserved among avian influenza viruses but is prevalent among mouse-adapted strains, indicating a host-dependent mutation. To our knowledge, this is the first study that the isoleucine residue at position 97 in PA plays a key role in enhanced virulence in mice and is implicated in the adaptation of avian influenza viruses to mammalian hosts.

* Corresponding author. Mailing address: College of Medicine and Medical Research Institute, Chungbuk National University, 12 Gaeshin-Dong, Heungduk-Ku, Cheongju 361-763, Republic of Korea. Phone: 82-43-261-3384. Fax: 82-43-272-1603. E-mail: choiki55{at}chungbuk.ac.kr

{triangledown} Published ahead of print on 30 September 2009.

Journal of Virology, December 2009, p. 12325-12335, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01373-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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