Influenza virus is the causative agent of the seasonal and occasional pandemic flu.The current H1N1 influenza pandemic,announced by the WHO in June 2009,is highly contagious and responsible for global economic losses ...Influenza virus is the causative agent of the seasonal and occasional pandemic flu.The current H1N1 influenza pandemic,announced by the WHO in June 2009,is highly contagious and responsible for global economic losses and fatalities.Although the H1N1 gene segments have three origins in terms of host species,the virus has been named swine-origin influenza virus(S-OIV)due to a predominant swine origin.2009 S-OIV has been shown to highly resemble the 1918 pandemic virus in many aspects.Hemagglutinin is responsible for the host range and receptor binding of the virus and is therefore a primary indicator for the potential of infection.Primary sequence analysis of the 2009 S-OIV hemagglutinin(HA)reveals its closest relationship to that of the 1918 pandemic influenza virus,however,analysis at the structural level is necessary to critically assess the functional significance.In this report,we report the crystal structure of soluble hemagglutinin H1(09H1)at 2.9Å,illustrating that the 09H1 is very similar to the 1918 pandemic HA(18H1)in overall structure and the structural modules,including the five defined antiboby(Ab)-binding epitopes.Our results provide an explanation as to why sera from the survivors of the 1918 pandemics can neutralize the 2009 S-OIV,and people born around the 1918 are resistant to the current pandemic,yet younger generations are more susceptible to the 2009 pandemic.展开更多
H9N2 avian influenza viruses(AIVs)circulate globally in poultry and have become the dominant AIV subtype in China in recent years.Previously,we demonstrated that the H9N2 virus(A/chicken/Eastern China/SDKD1/2015)natur...H9N2 avian influenza viruses(AIVs)circulate globally in poultry and have become the dominant AIV subtype in China in recent years.Previously,we demonstrated that the H9N2 virus(A/chicken/Eastern China/SDKD1/2015)naturally harbors a mammalian-adaptive molecular factor(627K)in the PB2 protein and is weakly pathogenic in mice.Here,we focused on new markers for virulence in mammals.A mouse-adapted H9N2 virus was serially passaged in mice by infecting their lungs.As expected,infected mice showed clinical symptoms and died at passage six.A comparison between the wild-type and mouse-adapted virus sequences identified amino acid substitutions in the hemagglutinin(HA)protein.H9N2 viruses with the T187P t M227L double mutation exhibited an increased affinity to human-type(SAα2,6Gal)receptors and significantly enhanced viral attachment to mouse lung tissues,which contributed to enhancing viral replication and virulence in mice.Additionally,HA with the T187P t M227L mutation enabled H9N2 viral transmission in guinea pigs via direct contact.AIV pathogenicity in mice is a polygenic trait.Our results demonstrated that these HA mutations might be combined with PB2-627K to significantly increase H9N2 virulence in mice,and this enhanced virulence was achieved in other H9N2 AIVs by generating the same combination of mutations.In summary,our study identified novel key elements in the HA protein that are required for H9N2 pathogenicity in mice and provided valuable insights into pandemic preparedness against emerging H_(9)N_(2)strains.展开更多
基金This work is supported by the intramural grant of the Chinese Academy of Sciences(Grant No.KSCX2-YW-R-158)the National Basic Research Program(973 Program)(Grant Nos.2010CB534004 and 2005CB523001)+1 种基金G.F.G.is a distinguished young investigator of the NSFC(Grant No.30525010)Dr.Christopher Vavricka is,partly,supported by the Fellowship for Young International Scientists of the Chinese Academy of Sciences(Grant No.2009Y2BS2).
文摘Influenza virus is the causative agent of the seasonal and occasional pandemic flu.The current H1N1 influenza pandemic,announced by the WHO in June 2009,is highly contagious and responsible for global economic losses and fatalities.Although the H1N1 gene segments have three origins in terms of host species,the virus has been named swine-origin influenza virus(S-OIV)due to a predominant swine origin.2009 S-OIV has been shown to highly resemble the 1918 pandemic virus in many aspects.Hemagglutinin is responsible for the host range and receptor binding of the virus and is therefore a primary indicator for the potential of infection.Primary sequence analysis of the 2009 S-OIV hemagglutinin(HA)reveals its closest relationship to that of the 1918 pandemic influenza virus,however,analysis at the structural level is necessary to critically assess the functional significance.In this report,we report the crystal structure of soluble hemagglutinin H1(09H1)at 2.9Å,illustrating that the 09H1 is very similar to the 1918 pandemic HA(18H1)in overall structure and the structural modules,including the five defined antiboby(Ab)-binding epitopes.Our results provide an explanation as to why sera from the survivors of the 1918 pandemics can neutralize the 2009 S-OIV,and people born around the 1918 are resistant to the current pandemic,yet younger generations are more susceptible to the 2009 pandemic.
基金supported by the National Key Research and Development Project of China:2021YFD1800202by the National Natural Science Foundation of China:31772755,32072892,32072832+1 种基金by the Earmarked Fund for China Agriculture Reasearch System:CARS-40by the Priorty Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘H9N2 avian influenza viruses(AIVs)circulate globally in poultry and have become the dominant AIV subtype in China in recent years.Previously,we demonstrated that the H9N2 virus(A/chicken/Eastern China/SDKD1/2015)naturally harbors a mammalian-adaptive molecular factor(627K)in the PB2 protein and is weakly pathogenic in mice.Here,we focused on new markers for virulence in mammals.A mouse-adapted H9N2 virus was serially passaged in mice by infecting their lungs.As expected,infected mice showed clinical symptoms and died at passage six.A comparison between the wild-type and mouse-adapted virus sequences identified amino acid substitutions in the hemagglutinin(HA)protein.H9N2 viruses with the T187P t M227L double mutation exhibited an increased affinity to human-type(SAα2,6Gal)receptors and significantly enhanced viral attachment to mouse lung tissues,which contributed to enhancing viral replication and virulence in mice.Additionally,HA with the T187P t M227L mutation enabled H9N2 viral transmission in guinea pigs via direct contact.AIV pathogenicity in mice is a polygenic trait.Our results demonstrated that these HA mutations might be combined with PB2-627K to significantly increase H9N2 virulence in mice,and this enhanced virulence was achieved in other H9N2 AIVs by generating the same combination of mutations.In summary,our study identified novel key elements in the HA protein that are required for H9N2 pathogenicity in mice and provided valuable insights into pandemic preparedness against emerging H_(9)N_(2)strains.
