Giuseppe
Emeritus
J Virol. 2009 Sep 30. [Epub ahead of print]
The Polymerase Acidic Protein Gene of Influenza A Virus Contributes to Pathogenicity in a Mouse Model.
Song MS, Pascua PN, Lee JH, Baek YH, Lee OJ, Kim CJ, Kim H, Webby RJ, Webster RG, Choi YK. - College of Medicine and Medical Research Institute, Chungbuk National University, 12 Gaeshin-Dong Heungduk-Ku, Cheongju 361-763, Republic of Korea; College of Veterinary Medicine, Chungnam National University, 220 Gung-Dong, Yuseoung-Gu, DaeJeon 305-764, Republic of Korea; Division of Bioscience and Technology, College of Life and Environmental Science, Korea University, Seoul, Republic of Korea; Division of Virology, Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA.
Adaptation of influenza A viruses to a new host species usually involves mutation of one or more of the eight viral gene segments and the molecular basis for host-range restriction are 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 isolate A/Aquatic bird/Korea/W81/05 (W81) in the lungs of mice. The resulting mouse-adapted strain (ma81) was highly virulent (MLD50= 2.6 log10 TCID50) and highly lethal. Non-conserved mutations were observed in six viral genes (PB2, PB1, PA, HA, NA, and M). Reverse genetics 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 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. Further, 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 for enhanced virulence in mice and implicated in the adaptation of avian influenza viruses to mammalian hosts.
PMID: 19793828 [PubMed - as supplied by publisher]
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The Polymerase Acidic Protein Gene of Influenza A Virus Contributes to Pathogenicity in a Mouse Model.
Song MS, Pascua PN, Lee JH, Baek YH, Lee OJ, Kim CJ, Kim H, Webby RJ, Webster RG, Choi YK. - College of Medicine and Medical Research Institute, Chungbuk National University, 12 Gaeshin-Dong Heungduk-Ku, Cheongju 361-763, Republic of Korea; College of Veterinary Medicine, Chungnam National University, 220 Gung-Dong, Yuseoung-Gu, DaeJeon 305-764, Republic of Korea; Division of Bioscience and Technology, College of Life and Environmental Science, Korea University, Seoul, Republic of Korea; Division of Virology, Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA.
Adaptation of influenza A viruses to a new host species usually involves mutation of one or more of the eight viral gene segments and the molecular basis for host-range restriction are 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 isolate A/Aquatic bird/Korea/W81/05 (W81) in the lungs of mice. The resulting mouse-adapted strain (ma81) was highly virulent (MLD50= 2.6 log10 TCID50) and highly lethal. Non-conserved mutations were observed in six viral genes (PB2, PB1, PA, HA, NA, and M). Reverse genetics 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 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. Further, 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 for enhanced virulence in mice and implicated in the adaptation of avian influenza viruses to mammalian hosts.
PMID: 19793828 [PubMed - as supplied by publisher]
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