title: A novel activation mechanism of avian influenza virus H9N2 by furin.
abstract: Avian influenza virus H9N2 is prevalent in waterfowl and has become endemic in poultry in Asia and the Middle East. H9N2 influenza viruses have served as a reservoir of internal genes for other avian influenza viruses that infect humans, and several cases of human infection by H9N2 influenza viruses have indicated its pandemic potential. Fortunately, an extensive surveillance program enables close monitoring of H9N2 influenza viruses worldwide and has generated a large repository of virus sequences and phylogenetic information. Despite the large quantity of sequences in different databases, very little is known about specific virus isolates and their pathogenesis. Here, we characterize a low-pathogenicity avian influenza virus, A/chicken/Israel/810/2001 (H9N2) (Israel810), which is representative of influenza virus strains that have caused severe morbidity and mortality in poultry farms. We show that under certain circumstances the Israel810 hemagglutinin (HA) can be activated by furin, a hallmark of highly pathogenic avian influenza virus. We demonstrate that Israel810 HA can be cleaved in cells with high levels of furin expression and that a mutation that eliminates a glycosylation site in HA(1) allows the Israel810 HA to gain universal cleavage in cell culture. Pseudoparticles generated from Israel810 HA, or the glycosylation mutant, transduce cells efficiently. In contrast, introduction of a polybasic cleavage site into Israel810 HA leads to pseudoviruses that are compromised for transduction. Our data indicate a mechanism for an H9N2 evolutionary pathway that may allow it to gain virulence in a distinct manner from H5 and H7 influenza viruses.
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
authors.forename: Longping V
authors.initials: LV
authors.lastname: Tse
authors.forename: Alice M
authors.initials: AM
authors.lastname: Hamilton
authors.forename: Tamar
authors.initials: T
authors.lastname: Friling
authors.forename: Gary R
authors.initials: GR
authors.lastname: Whittaker
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002645:Chickens; D045683:Furin / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053127:Influenza A Virus, H9N2 Subtype / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D005585:Influenza in Birds / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D007251:Influenza, Human / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D008969:Molecular Sequence Data; D011201:Poultry Diseases / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D011499:Protein Processing, Post-Translational; D016415:Sequence Alignment
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D045683:Furin