title: Characterization of uncultivable bat influenza virus using a replicative synthetic virus.
abstract: Bats harbor many viruses, which are periodically transmitted to humans resulting in outbreaks of disease (e.g., Ebola, SARS-CoV). Recently, influenza virus-like sequences were identified in bats; however, the viruses could not be cultured. This discovery aroused great interest in understanding the evolutionary history and pandemic potential of bat-influenza. Using synthetic genomics, we were unable to rescue the wild type bat virus, but could rescue a modified bat-influenza virus that had the HA and NA coding regions replaced with those of A/PR/8/1934 (H1N1). This modified bat-influenza virus replicated efficiently in vitro and in mice, resulting in severe disease. Additional studies using a bat-influenza virus that had the HA and NA of A/swine/Texas/4199-2/1998 (H3N2) showed that the PR8 HA and NA contributed to the pathogenicity in mice. Unlike other influenza viruses, engineering truncations hypothesized to reduce interferon antagonism into the NS1 protein didn't attenuate bat-influenza. In contrast, substitution of a putative virulence mutation from the bat-influenza PB2 significantly attenuated the virus in mice and introduction of a putative virulence mutation increased its pathogenicity. Mini-genome replication studies and virus reassortment experiments demonstrated that bat-influenza has very limited genetic and protein compatibility with Type A or Type B influenza viruses, yet it readily reassorts with another divergent bat-influenza virus, suggesting that the bat-influenza lineage may represent a new Genus/Species within the Orthomyxoviridae family. Collectively, our data indicate that the bat-influenza viruses recently identified are authentic viruses that pose little, if any, pandemic threat to humans; however, they provide new insights into the evolution and basic biology of influenza viruses.
authors.affiliation: Virology, J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.
authors.forename: Jingjiao
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.
authors.forename: Qinfang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Bawa
authors.affiliation: Virology, J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Virology, J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: Reed S
authors.initials: RS
authors.lastname: Shabman
authors.affiliation: Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Duff
authors.affiliation: Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.
authors.forename: Jinhwa
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.
authors.forename: Yuekun
authors.initials: Y
authors.lastname: Lang
authors.affiliation: Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.
authors.forename: Nan
authors.initials: N
authors.lastname: Cao
authors.affiliation: Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.
authors.forename: Abdou
authors.initials: A
authors.lastname: Nagy
authors.affiliation: Virology, J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: Xudong
authors.initials: X
authors.lastname: Lin
authors.affiliation: Virology, J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Stockwell
authors.affiliation: Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.
authors.forename: Juergen A
authors.initials: JA
authors.lastname: Richt
authors.affiliation: Virology, J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Wentworth
authors.affiliation: Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ma
mesh_terms: D000818:Animals; D002460:Cell Line; D002685:Chiroptera / Q000821:virology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics*; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics*; D051379:Mice; D009976:Orthomyxoviridae Infections; D013552:Swine; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics*
chemical_list: D014764:Viral Proteins