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
Decades have passed since the first discovery of H10-subtype avian influenza virus(AIV) in chickens in 1949,and it has been detected in many species including mammals such as minks,pigs,seals and humans.Cases of human...Decades have passed since the first discovery of H10-subtype avian influenza virus(AIV) in chickens in 1949,and it has been detected in many species including mammals such as minks,pigs,seals and humans.Cases of human infections with H10N8viruses identified in China in 2013 have raised widespread attention.Two novel reassortant H10N3 viruses were isolated from chickens in December 2019 in eastern China during routine surveillance for AIVs.The internal genes of these viruses were derived from genotype S(G57) H9N2 and were consistent with H5N6,H7N9 and H10N8,which cause fatal infections in humans.Their viral pathogenicity and transmissibility were further studied in different animal models.The two H10N3 isolates had low pathogenicity in chickens and were transmitted between chickens via direct contact.These viruses were highly pathogenic in mice and could be transmitted between guinea pigs via direct contact and respiratory droplets.More importantly,these viruses can bind to both human-type SAα-2,6-Gal receptors and avian-type SAα-2,3-Gal receptors.Asymptomatic shedding in chickens and good adaptability to mammals of these H10N3 isolates would make it easier to transmit to humans and pose a threat to public health.展开更多
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.
基金supported by the National Key Research and Development Project of China (2016YFD0500202-1,2016YFD0501601)the National Natural Science Foundation of China(31772755)+3 种基金Jiangsu Provincial Natural Science Fund for Excellent Young Scholars (BK20170068)the Earmarked Fund For China Agriculture Research System (CARS-40)the Open Project Program of Jiangsu Key Laboratory of Zoonosis (R1808)the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)。
文摘Decades have passed since the first discovery of H10-subtype avian influenza virus(AIV) in chickens in 1949,and it has been detected in many species including mammals such as minks,pigs,seals and humans.Cases of human infections with H10N8viruses identified in China in 2013 have raised widespread attention.Two novel reassortant H10N3 viruses were isolated from chickens in December 2019 in eastern China during routine surveillance for AIVs.The internal genes of these viruses were derived from genotype S(G57) H9N2 and were consistent with H5N6,H7N9 and H10N8,which cause fatal infections in humans.Their viral pathogenicity and transmissibility were further studied in different animal models.The two H10N3 isolates had low pathogenicity in chickens and were transmitted between chickens via direct contact.These viruses were highly pathogenic in mice and could be transmitted between guinea pigs via direct contact and respiratory droplets.More importantly,these viruses can bind to both human-type SAα-2,6-Gal receptors and avian-type SAα-2,3-Gal receptors.Asymptomatic shedding in chickens and good adaptability to mammals of these H10N3 isolates would make it easier to transmit to humans and pose a threat to public health.
