The 2009 swine-origin influenza virus (S-OIV,H1N1 subtype) has developed into a new pandemic influenza as announced by the World Health Organization.In order to uncover clues about the determinants for virulence and p...The 2009 swine-origin influenza virus (S-OIV,H1N1 subtype) has developed into a new pandemic influenza as announced by the World Health Organization.In order to uncover clues about the determinants for virulence and pathogenicity of the virus,we characterized the functional modules of the surface glycoprotein hemagglutinin (HA),the most important protein in molecular epidemiology and pathogenesis of influenza viruses.We analyzed receptor binding sites,basic patch,neutralization antibody epitopes and T cell epitopes in the HA protein of the current S-OIV according to the corresponding functional and structural modules previously characterized in other H1 HA molecules or HA molecules of other subtypes.We compared their differences and similarities systematically.Based on the amino acids defined as the functional and structural modules,the HA protein of 2009 S-OIV should specifically bind to the human 2,6-receptor.The D225G/E mutation in HA,which is found in some isolates,may confer dual binding specificity to the 2,3and 2,6-receptor based on previously reported work.This HA variant contains two basic patches,one of which results in increased basicity,suggesting enhanced membrane fusion function.The 2009 S-OIV HA also has an extra glycosylation site at position 276.Four of the five antibody neutralization epitopes identified in A/RP/8/34(H1N1) were exposed,but the other was hidden by a glycosylation site.The previously identified cytotoxic T cell epitopes in various HA molecules were summarized and their corresponding sequences in 2009 S-OIV HA were defined.These results are critical for understanding the pathogenicity of the virus and host immune response against the virus.展开更多
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
In 2009,a novel swine-origin H1N1 influenza virus emerged in Mexico and quickly spread to other countries,including China.This 2009 pandemic H1N1 can cause human respiratory disease,but its pathogenesis remains poorly...In 2009,a novel swine-origin H1N1 influenza virus emerged in Mexico and quickly spread to other countries,including China.This 2009 pandemic H1N1 can cause human respiratory disease,but its pathogenesis remains poorly understood.Here,we studied the infection and pathogenesis of a new 2009 pandemic strain,A/Wenshan/01/2009 H1N1,in China in human airway epithelial cell lines compared with contemporary seasonal H1N1 influenza virus.Our results showed that viral infection by the A/Wenshan H1N1 induced significant apoptotic cell death in both the human nasopharyngeal carcinoma cell line CNE-2Z and the human lung adenocarcinoma cell line A549.The A/Wenshan H1N1 virus enters both of these cell types more efficiently than the seasonal influenza virus.Viral entry in both cell lines was shown to be mediated by clathrin-and dynamin-dependent endocytosis.Therefore,we discovered that the 2009 pandemic H1N1 strain,A/Wenshan/01/2009,can induce apoptotic cell death in epithelial cells of the human respiratory tract,suggesting a molecular pathogenesis for the 2009 pandemic H1N1.展开更多
Since the 2009 pandemic H1N1 swine-origin influenza A virus (09 S-OIV) has reminded the world about the global threat of the ever changing influenza virus,many questions regarding the detailed re-assortment of influen...Since the 2009 pandemic H1N1 swine-origin influenza A virus (09 S-OIV) has reminded the world about the global threat of the ever changing influenza virus,many questions regarding the detailed re-assortment of influenza viruses yet remain unanswered.Influenza A virus is the causative agent of the pandemic flu and contains 2 major antigenic glycoproteins on its surface:(i) hemagglutinin (HA);and (ii) neuraminidase (NA).The structures of the 09 S-OIV HA and NA proteins (09H1 and 09N1) have recently been resolved in our laboratory and provide some clues as to why the 09 S-OIV re-assortment virus is highly infectious with severe consequences in humans.For example,the 09H1 is highly similar to the HA of the 1918 influenza A pandemic virus in overall structure and especially in regards to its 5 defined antibody binding epitopes.For 09N1,its most distinctive feature is the lack of a 150-loop active site cavity,which was previously predicted to be present in all N1 NAs,and we hypothesize that the 150-loop may play a important role in the substrate specificity (α2,3 or α2,6 linked sialic acid receptors) and enzymatic mechanism of influenza NA.Combination of the HA and NA with special characteristics for the 09 S-OIV might contribute to its high increased transmissibility in humans.展开更多
基金supported by the National Basic Research Program of China (Grant No. 2010CB534004)an intramural grant from the Chinese Academy of Sciences (Grant No. KSCX2-YW-R-158)
文摘The 2009 swine-origin influenza virus (S-OIV,H1N1 subtype) has developed into a new pandemic influenza as announced by the World Health Organization.In order to uncover clues about the determinants for virulence and pathogenicity of the virus,we characterized the functional modules of the surface glycoprotein hemagglutinin (HA),the most important protein in molecular epidemiology and pathogenesis of influenza viruses.We analyzed receptor binding sites,basic patch,neutralization antibody epitopes and T cell epitopes in the HA protein of the current S-OIV according to the corresponding functional and structural modules previously characterized in other H1 HA molecules or HA molecules of other subtypes.We compared their differences and similarities systematically.Based on the amino acids defined as the functional and structural modules,the HA protein of 2009 S-OIV should specifically bind to the human 2,6-receptor.The D225G/E mutation in HA,which is found in some isolates,may confer dual binding specificity to the 2,3and 2,6-receptor based on previously reported work.This HA variant contains two basic patches,one of which results in increased basicity,suggesting enhanced membrane fusion function.The 2009 S-OIV HA also has an extra glycosylation site at position 276.Four of the five antibody neutralization epitopes identified in A/RP/8/34(H1N1) were exposed,but the other was hidden by a glycosylation site.The previously identified cytotoxic T cell epitopes in various HA molecules were summarized and their corresponding sequences in 2009 S-OIV HA were defined.These results are critical for understanding the pathogenicity of the virus and host immune response against the virus.
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 Ministry of Science and Technology(2009CB522105)the Ministry of Health(2009ZX10004-308)of Chinasupport of the Science and Technology Commission of Shanghai Municipality(07pj14096).
文摘In 2009,a novel swine-origin H1N1 influenza virus emerged in Mexico and quickly spread to other countries,including China.This 2009 pandemic H1N1 can cause human respiratory disease,but its pathogenesis remains poorly understood.Here,we studied the infection and pathogenesis of a new 2009 pandemic strain,A/Wenshan/01/2009 H1N1,in China in human airway epithelial cell lines compared with contemporary seasonal H1N1 influenza virus.Our results showed that viral infection by the A/Wenshan H1N1 induced significant apoptotic cell death in both the human nasopharyngeal carcinoma cell line CNE-2Z and the human lung adenocarcinoma cell line A549.The A/Wenshan H1N1 virus enters both of these cell types more efficiently than the seasonal influenza virus.Viral entry in both cell lines was shown to be mediated by clathrin-and dynamin-dependent endocytosis.Therefore,we discovered that the 2009 pandemic H1N1 strain,A/Wenshan/01/2009,can induce apoptotic cell death in epithelial cells of the human respiratory tract,suggesting a molecular pathogenesis for the 2009 pandemic H1N1.
基金supported by Chinese Academy of Sciences Research Fellowship for Young International Scientists (2010Y2SB12)the National Natural Science Foundation of China for International Young Scientists (31050110126) to Vavricka CJthe National Natural Science Foundation of China (81021003) to Gao GF
文摘Since the 2009 pandemic H1N1 swine-origin influenza A virus (09 S-OIV) has reminded the world about the global threat of the ever changing influenza virus,many questions regarding the detailed re-assortment of influenza viruses yet remain unanswered.Influenza A virus is the causative agent of the pandemic flu and contains 2 major antigenic glycoproteins on its surface:(i) hemagglutinin (HA);and (ii) neuraminidase (NA).The structures of the 09 S-OIV HA and NA proteins (09H1 and 09N1) have recently been resolved in our laboratory and provide some clues as to why the 09 S-OIV re-assortment virus is highly infectious with severe consequences in humans.For example,the 09H1 is highly similar to the HA of the 1918 influenza A pandemic virus in overall structure and especially in regards to its 5 defined antibody binding epitopes.For 09N1,its most distinctive feature is the lack of a 150-loop active site cavity,which was previously predicted to be present in all N1 NAs,and we hypothesize that the 150-loop may play a important role in the substrate specificity (α2,3 or α2,6 linked sialic acid receptors) and enzymatic mechanism of influenza NA.Combination of the HA and NA with special characteristics for the 09 S-OIV might contribute to its high increased transmissibility in humans.
