H6 Influenza Viruses Pose a Potential Threat to Human Health

Influenza viruses of the H6 subtype have been isolated from wild and domestic aquatic and terrestrial avian species throughout the world since their first detection in a turkey in Massachusetts in 1965. Since 1997, H6 viruses with different neuraminidase (NA) subtypes have been detected frequently in the live poultry markets of southern China. Although sequence information has been gathered over the last few years, the H6 viruses have not been fully biologically characterized. To investigate the potential risk posed by H6 viruses to humans, here we assessed the receptor-binding preference, replication, and transmissibility in mammals of a series of H6 viruses isolated from live poultry markets in southern China from 2008 to 2011. Among the 257 H6 strains tested, 87 viruses recognized the human type receptor. Genome sequence analysis of 38 representative H6 viruses revealed 30 different genotypes, indicating that these viruses are actively circulating and reassorting in nature. Thirty-seven of 38 viruses tested in mice replicated efficiently in the lungs and some caused mild disease; none, however, were lethal. We also tested the direct contact transmission of 10 H6 viruses in guinea pigs and found that 5 viruses did not transmit to the contact animals, 3 viruses transmitted to one of the three contact animals, and

[1]  R. Webster,et al.  Evolution and ecology of influenza A viruses. , 1992, Current topics in microbiology and immunology.

[2]  X. Kan,et al.  Origin and molecular characteristics of a novel 2013 avian influenza A(H6N1) virus causing human infection in Taiwan. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  Guohua Deng,et al.  H7N9 Influenza Viruses Are Transmissible in Ferrets by Respiratory Droplet , 2013, Science.

[4]  Weizhong Yang,et al.  Biological features of novel avian influenza A (H7N9) virus , 2013, Nature.

[5]  Noriko Kishida,et al.  Characterization of H7N9 influenza A viruses isolated from humans , 2013, Nature.

[6]  Y. Kawaoka,et al.  Complex Reassortment of Multiple Subtypes of Avian Influenza Viruses in Domestic Ducks at the Dongting Lake Region of China , 2013, Journal of Virology.

[7]  Guohua Deng,et al.  H5N1 Hybrid Viruses Bearing 2009/H1N1 Virus Genes Transmit in Guinea Pigs by Respiratory Droplet , 2013, Science.

[8]  Nathan W. Stebbins,et al.  Glycan Receptor Binding of the Influenza A Virus H7N9 Hemagglutinin , 2013, Cell.

[9]  Hualan Chen,et al.  Isolation and characterization of H7N9 viruses from live poultry markets — Implication of the source of current H7N9 infection in humans , 2013 .

[10]  Bing Xu,et al.  Characterization of low-pathogenic H6N6 avian influenza viruses in central China , 2012, Archives of Virology.

[11]  Y. Kawaoka,et al.  Key Molecular Factors in Hemagglutinin and PB2 Contribute to Efficient Transmission of the 2009 H1N1 Pandemic Influenza Virus , 2012, Journal of Virology.

[12]  Theo M Bestebroer,et al.  Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets , 2012, Science.

[13]  David K. Smith,et al.  Establishment and Lineage Replacement of H6 Influenza Viruses in Domestic Ducks in Southern China , 2012, Journal of Virology.

[14]  C. Viboud,et al.  Recrudescent wave of pandemic A/H1N1 influenza in Mexico, winter 2011-2012: Age shift and severity , 2012, PLoS currents.

[15]  Lin Ma,et al.  Pandemic (H1N1) 2009 Virus Circulating in Pigs, Guangxi, China , 2012, Emerging infectious diseases.

[16]  Zhi-xun Xie,et al.  Complete Genome Sequence Analysis of an H6N1 Avian Influenza Virus Isolated from Guangxi Pockmark Ducks , 2012, Journal of Virology.

[17]  Zhiqiang Duan,et al.  Molecular evolution of the H6 subtype influenza a viruses from poultry in eastern China from 2002 to 2010 , 2011, Virology Journal.

[18]  H. Poo,et al.  Emergence of Mammalian Species-Infectious and -Pathogenic Avian Influenza H6N5 Virus with No Evidence of Adaptation , 2011, Journal of Virology.

[19]  D. Pérez,et al.  Phylogenetic Analysis of H6 Influenza Viruses Isolated from Rosy-Billed Pochards (Netta peposaca) in Argentina Reveals the Presence of Different HA Gene Clusters , 2011, Journal of Virology.

[20]  X. Wan,et al.  Identification of an H6N6 swine influenza virus in southern China. , 2011, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[21]  M. Wongphatcharachai,et al.  Pandemic (H1N1) 2009 Virus on Commercial Swine Farm, Thailand , 2010, Emerging infectious diseases.

[22]  Ryo Takano,et al.  Influenza A (H5N1) Viruses from Pigs, Indonesia , 2010, Emerging infectious diseases.

[23]  Hualan Chen,et al.  Continued Evolution of H5N1 Influenza Viruses in Wild Birds, Domestic Poultry, and Humans in China from 2004 to 2009 , 2010, Journal of Virology.

[24]  Gavin J. D. Smith,et al.  Establishment of an H6N2 Influenza Virus Lineage in Domestic Ducks in Southern China , 2010, Journal of Virology.

[25]  Andrew P. Dobson,et al.  Spatial and Temporal Association of Outbreaks of H5N1 Influenza Virus Infection in Wild Birds with the 0°C Isotherm , 2010, PLoS pathogens.

[26]  T. Joseph,et al.  Pandemic (H1N1) 2009 Infection in Swine Herds, Manitoba, Canada , 2010, Emerging infectious diseases.

[27]  G. Kayali,et al.  Evidence of Previous Avian Influenza Infection among US Turkey Workers , 2009, Zoonoses and public health.

[28]  J. Oem,et al.  Genetic relatedness of H6 subtype avian influenza viruses isolated from wild birds and domestic ducks in Korea and their pathogenicity in animals. , 2010, The Journal of general virology.

[29]  Zejun Li,et al.  Identification of Amino Acids in HA and PB2 Critical for the Transmission of H5N1 Avian Influenza Viruses in a Mammalian Host , 2009, PLoS pathogens.

[30]  Marion Koopmans,et al.  Pathogenesis and Transmission of Swine-Origin 2009 A(H1N1) Influenza Virus in Ferrets , 2009, Science.

[31]  Ron A M Fouchier,et al.  Antigenic and Genetic Characteristics of Swine-Origin 2009 A(H1N1) Influenza Viruses Circulating in Humans , 2009, Science.

[32]  Rahul Raman,et al.  Transmission and Pathogenesis of Swine-Origin 2009 A(H1N1) Influenza Viruses in Ferrets and Mice , 2009, Science.

[33]  John Steel,et al.  Transmission of Influenza Virus in a Mammalian Host Is Increased by PB2 Amino Acids 627K or 627E/701N , 2009, PLoS pathogens.

[34]  I. Wilson,et al.  Recent avian H5N1 viruses exhibit increased propensity for acquiring human receptor specificity. , 2008, Journal of molecular biology.

[35]  K. Subbarao,et al.  Avian Influenza H6 Viruses Productively Infect and Cause Illness in Mice and Ferrets , 2008, Journal of Virology.

[36]  R. Lamb,et al.  A new influenza virus virulence determinant: The NS1 protein four C-terminal residues modulate pathogenicity , 2008, Proceedings of the National Academy of Sciences.

[37]  Gavin J. D. Smith,et al.  Establishment of Influenza A Virus (H6N1) in Minor Poultry Species in Southern China , 2007, Journal of Virology.

[38]  A. Capuano,et al.  Infection due to 3 avian influenza subtypes in United States veterinarians. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[39]  A. Osterhaus,et al.  Spatial, Temporal, and Species Variation in Prevalence of Influenza A Viruses in Wild Migratory Birds , 2007, PLoS pathogens.

[40]  David E. Swayne,et al.  A Two-Amino Acid Change in the Hemagglutinin of the 1918 Influenza Virus Abolishes Transmission , 2007, Science.

[41]  M. Cheng,et al.  Genetic and Pathogenic Characterization of H6N1 Avian Influenza Viruses Isolated in Taiwan Between 1972 and 2005 , 2006, Avian diseases.

[42]  C. Naeve,et al.  Large-Scale Sequence Analysis of Avian Influenza Isolates , 2006, Science.

[43]  A. Olivier,et al.  Outbreaks of avian influenza H6N2 viruses in chickens arose by a reassortment of H6N8 and H9N2 ostrich viruses , 2006, Virus Genes.

[44]  D. Stallknecht,et al.  Phylogenetic analyses of type A influenza genes in natural reservoir species in North America reveals genetic variation. , 2005, Virus research.

[45]  Hualan Chen,et al.  Evolution of H9N2 influenza viruses from domestic poultry in Mainland China. , 2005, Virology.

[46]  R. Webster,et al.  Molecular Basis of Replication of Duck H5N1 Influenza Viruses in a Mammalian Mouse Model , 2005, Journal of Virology.

[47]  Ian A. Wilson,et al.  A Single Amino Acid Substitution in 1918 Influenza Virus Hemagglutinin Changes Receptor Binding Specificity , 2005, Journal of Virology.

[48]  R. Webster,et al.  Avian influenza viruses in Korean live poultry markets and their pathogenic potential. , 2005, Virology.

[49]  N. Cox,et al.  Genetic analysis of human H2N2 and early H3N2 influenza viruses, 1957-1972: evidence for genetic divergence and multiple reassortment events. , 2004, Virology.

[50]  Y Li,et al.  The evolution of H5N1 influenza viruses in ducks in southern China. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Ching-Ho Wang,et al.  Experimental Selection of Virus Derivatives with Variations in Virulence from a Single Low-Pathogenicity H6N1 Avian Influenza Virus Field Isolate , 2003, Avian diseases.

[52]  R. Webster,et al.  Multiple Genotypes of Nonpathogenic H6N2 Influenza Viruses Isolated from Chickens in California , 2003, Avian diseases.

[53]  P. Woolcock,et al.  Low-Pathogenicity Avian Influenza Virus (H6N2) in Chickens in California, 2000–02 , 2003, Avian diseases.

[54]  A. Abbott Human fatality adds fresh impetus to fight against bird flu , 2003, Nature.

[55]  D. Senne Avian Influenza in the Western Hemisphere Including the Pacific Islands and Australia , 2003, Avian diseases.

[56]  P. Woolcock,et al.  The Occurrence of Avian Influenza A Subtype H6N2 in Commercial Layer Flocks in Southern California (2000–02): Clinicopathologic Findings , 2003, Avian diseases.

[57]  D. Alexander,et al.  Report on Avian Influenza in the Eastern Hemisphere During 1997–2002 , 2003, Avian diseases.

[58]  D. Senne,et al.  Type A Influenza Virus Surveillance in Free-Flying, Nonmigratory Ducks Residing on the Eastern Shore of Maryland , 2003, Avian diseases.

[59]  D. Stallknecht,et al.  Avian Influenza Viruses in Minnesota Ducks During 1998–2000 , 2003, Avian diseases.

[60]  B. Panigrahy,et al.  Avian Influenza Virus Subtypes Inside and Outside the Live Bird Markets, 1993–2000: A Spatial and Temporal Relationship , 2002, Avian diseases.

[61]  Y. Guan,et al.  Molecular Evolution of H6 Influenza Viruses from Poultry in Southeastern China: Prevalence of H6N1 Influenza Viruses Possessing Seven A/Hong Kong/156/97 (H5N1)-Like Genes in Poultry , 2002, Journal of Virology.

[62]  Yoshihiro Kawaoka,et al.  Molecular Basis for High Virulence of Hong Kong H5N1 Influenza A Viruses , 2001, Science.

[63]  Yoshihiro Kawaoka,et al.  Early Alterations of the Receptor-Binding Properties of H1, H2, and H3 Avian Influenza Virus Hemagglutinins after Their Introduction into Mammals , 2000, Journal of Virology.

[64]  R. Webster,et al.  Characterization of the Influenza A Virus Gene Pool in Avian Species in Southern China: Was H6N1 a Derivative or a Precursor of H5N1? , 2000, Journal of Virology.

[65]  M. Peiris,et al.  Human infection with influenza H9N2 , 1999, The Lancet.

[66]  Y. Kawaoka,et al.  The Role of Influenza A Virus Hemagglutinin Residues 226 and 228 in Receptor Specificity and Host Range Restriction , 1998, Journal of Virology.

[67]  S. Teneberg,et al.  Avian influenza A viruses differ from human viruses by recognition of sialyloligosaccharides and gangliosides and by a higher conservation of the HA receptor-binding site. , 1997, Virology.

[68]  Jeffery K. Taubenberger,et al.  Initial Genetic Characterization of the 1918 “Spanish” Influenza Virus , 1997, Science.

[69]  R. Webster,et al.  Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics , 1989, Journal of virology.

[70]  J. Paulson,et al.  Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. , 1983, Virology.

[71]  C. Scholtissek,et al.  On the origin of the human influenza virus subtypes H2N2 and H3N2. , 1978, Virology.

[72]  R. Webster,et al.  Isolation and characterization of influenza A viruses from avian species in Hong Kong. , 1977, Bulletin of the World Health Organization.

[73]  W. G. Laver,et al.  Isolation of a type A influenza virus from an Australian pelagic bird. , 1973, Virology.

[74]  D. P. Anderson,et al.  Avian influenza virus infections. II. Experimental epizootiology of influenza A-turkey-Wisconsin-1966 virus in turkeys. , 1970, Avian diseases.