SnapShot: Evolution of Human Influenza A Viruses Isabel Wendel, Mikhail Matrosovich, Hans Dieter Klenk Institut für Virologie, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany
A INFLUENZA PANDEMICS 1918
1957
Spanish Influenza (>40 Million deaths)
Asian Influenza (1 Million deaths)
1968
1977
Hong Kong Influenza (1 Million deaths)
2009 Swine origin Influenza (>200,000 deaths)
Russian Influenza
H1N1/2009 H3N2 H2N2 H1N1
H1N1
1918
1957
1968
2009
H1N1 pandemic
H2N2 pandemic
H3N2 pandemic
H1N1 pandemic
? H1N2 triple reassortant
H1N1 Eurasian avian-like swine
(PB2, PB1, PA, HA, NP, NS)
H?N?
H?N?
H1N1 seasonal
(PB2, PA, NP, M, NS)
H2N2 avian
H2N2 seasonal
(PB1, HA NA)
(PB2, PA, NP, NA, M ,NS)
B INFLUENZA A VIRUS Structure
RNA segments
Virion
Proteins
1
PB2
2
PB1
3
PA
4
HA
5
NP
6
NA
7
M1, M2
8
NS1, NS2
H3N? avian
(PB1, HA)
H3N2 seasonal (PB1, NA)
(NA, M)
H1N1 avian
(PB2, PA)
H1N1 classical swine
H1N1 avian
(HA, NP, M, NS)
C RECEPTOR SPECIFICITY IS A MAJOR HOST RANGE DETERMINANT Receptor in birds
Receptor in pigs and humans
1 2 3 4 5 6 7 8
PB2
PB1
PB1
RNP PA
vRNA
416 Cell Host & Microbe 17, March 11, 2015 ©2015 Elsevier Inc.
Key amino acid substitutions in the receptor-binding site of pandemic viruses
DOI http://dx.doi.org/10.1016/j.chom.2015.02.001
See online version for legends and references
SnapShot: Evolution of Human Influenza A Viruses Isabel Wendel, Mikhail Matrosovich, Hans Dieter Klenk Institut für Virologie, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany Influenza A viruses are important pathogens with a wide host range. The available evidence indicates that they originate from a large virus pool indigenous to wild aquatic birds (Webster et al., 1992; Olsen et al., 2006). Since the host barriers are not an insurmountable obstacle for the avian viruses, they can be transmitted to other species, including man. Most of the transmissions are transient. On rare occasions, however, the viruses may undergo human adaptation. Such a virus may then give rise to a pandemic, as has been the case in 1918, 1957, 1968, and 2009 (Figure A adapted from Klenk et al., 2011 and Sorrel et al., 2011). Interspecies transmission and adaptation to a new host is facilitated by the high genetic flexibility of influenza A viruses. Their genome consists of eight RNA segments, each one encoding 1–3 structural and non-structural proteins (Figure B). They include the hemagglutinin (HA) and the neuraminidase (NA) comprising 18 (H1–H18) and 10 (N1–N10) subtypes, respectively, as well as the polymerase complex and the non-structural NS1 protein. HA is the major envelope glycoprotein that initiates infection by binding to sialic acid-containing cell receptors (Figure C) and by inducing membrane fusion. The viral polymerase that is composed of the subunits PB1, PB2, and PA mediates transcription and replication of the viral genome. NS1 is an interferon antagonist. In addition to the gene products shown in Figure B, several non-essential proteins have been described (Shaw and Palese, 2013). The segmentation of the viral genome allows exchange of gene segments between different viruses upon co-infection (gene reassortment), and due to the infidelity of polymerase, there is a high mutation rate. Influenza virus replication depends on the biosynthetic machinery of the cell and is under the control of the defense mechanisms developed by the host against infection (Shaw and Palese, 2013). Host specificity is therefore a result of the interaction of numerous host factors with all viral proteins, among which, however, the polymerase complex, HA, and NS1 appear to play particularly prominent roles. These proteins harbor several important adaptive mutations including mutations changing specificity of HA for sialyl-a2,3-galactose receptors in birds to sialyl-a2,6-galactose receptors in humans (Taubenberger and Kash, 2010; Klenk et al., 2011) (Figure C). Some of these adaptive mutations mediate airborne transmissibility, an essential trait of a pandemic virus (Sorrell et al., 2011). Intermediate hosts play an important role in the adaptation process. Circulation of avian viruses in pigs and possibly in domestic gallinaceous birds may facilitate acquisition of adaptive mutations and thus promote transmission to humans. In addition, the pig may serve as a mixing vessel in which both avian and mammalian viruses reassort to give rise to a new mammalian virus (Scholtissek, 1995). By these mechanisms, viruses with new surface glycoproteins and therefore a distinct change in antigenicity may be generated. If a new virus with such an antigenic shift occurs in man, it may cause a pandemic. Epidemic viruses are derived from pandemic viruses by antigenic drift—gradual, minor antigenic changes caused by point mutations in HA and NA. A new pandemic virus usually drives the contemporary seasonal virus down to extinction, as happened in 1957, 1968, and 2009, but sometimes pandemic and seasonal viruses continue to co-circulate over extended periods of time, as is the case since 1977. It has been estimated that there have been at least 14 pandemics in the last 500 years (Taubenberger and Kash, 2010), of which, however, only the five most recent are well documented (Figure A). The Spanish influenza (H1N1) was the most devastating one, taking the lives of about 50 million people worldwide. Contrary to its name, it presumably emerged in the United States in the spring of 1918 and within a year swept around the globe in three waves. The virus has been reconstituted from archival patient samples (Tumpey et al., 2005), but its ancestors are unknown. It has been proposed that the virus either arose by reassortment of an avian and a mammalian virus or that it was derived from an avian virus by gradual adaptation to the human host without reassortment. After 1918 the H1N1 virus caused seasonal epidemics until 1957, when the H2N2 virus of the Asian pandemic emerged in Southern China. This virus was derived from the seasonal H1N1 virus that had acquired HA, NA, and PB1 gene segments from an avian H2N2 virus by reassortment (Kilbourne, 2006). With ~1 million deaths, the H2N2 pandemic virus was significantly less pathogenic than the 1918 virus. The H2N2 virus circulated in the human population until 1968, when the H3N2 virus of the Hong Kong pandemic emerged. The H3N2 virus was again the result of gene reassortment between the previous H2N2 virus and avian viruses providing the HA and PB1 genes (Kilbourne, 2006). In terms of mortality, the Hong Kong pandemic resembled the previous one. In 1977 an H1N1 virus closely resembling isolates in the 1950s re-emerged from an unknown source at the Russian-Chinese border (Kilbourne, 2006). This virus co-circulated until 2009 with the H3N2 virus. The H1N1 virus of the 2009 pandemic was derived from a swine virus containing the NA and M genes of the Eurasian avian-like H1N1 virus lineage that emerged around 1980 in pigs and the other gene segment of a “triple reassortant” swine virus (Neumann et al., 2009). The “triple reassortant” emerged in the late 1990s in North American pigs and contained PB2 and PA of an avian virus, PB1 and NA of human H3N2 virus, and the other four genes of “classical” swine virus related to the 1918 H1N1 pandemic virus. Seasonal H1N1 viruses derived from the 2009 pandemic virus are now co-circulating with H3N2 viruses. References Kilbourne, E.D. (2006). Emerg. Infect. Dis. 12, 9–14. Klenk, H.D., Garten, W., and Matrosovich, M. (2011). BioEssays 33, 180–188. Neumann, G., Noda, T., and Kawaoka, Y. (2009). Nature 459, 931–939. Olsen, B., Munster, V.J., Wallensten, A., Waldenström, J., Osterhaus, A.D., and Fouchier, R.A. (2006). Science 312, 384–388. Scholtissek, C. (1995). Virus Genes 11, 209–215. Shaw, M.L., and Palese, P. (2013). Orthomyxoviruses. In Fields Virology, D.M. Knipe and P.M. Howley, eds. (Philadelphia: Lippincott Williams & Wilkins), pp. 1151–1185. Sorrell, E.M., Schrauwen, E.J., Linster, M., De Graaf, M., Herfst, S., and Fouchier, R.A. (2011). Curr Opin Virol 1, 635–642. Taubenberger, J.K., and Kash, J.C. (2010). Cell Host Microbe 7, 440–451. Tumpey, T.M., Basler, C.F., Aguilar, P.V., Zeng, H., Solórzano, A., Swayne, D.E., Cox, N.J., Katz, J.M., Taubenberger, J.K., Palese, P., and García-Sastre, A. (2005). Science 310, 77–80. Webster, R.G., Bean, W.J., Gorman, O.T., Chambers, T.M., and Kawaoka, Y. (1992). Microbiol. Rev. 56, 152–179.
416.e1 Cell Host & Microbe 17, March 11, 2015 ©2015 Elsevier Inc. DOI http://dx.doi.org/10.1016/j.chom.2015.02.001
A INFLUENZA PANDEMICS 1918
1957
Spanish Influenza (>40 Million deaths)
Asian Influenza (1 Million deaths)
1968
1977
Hong Kong Influenza (1 Million deaths)
2009 Swine origin Influenza (>200,000 deaths)
Russian Influenza
H1N1/2009 H3N2 H2N2 H1N1
H1N1
1918
1957
1968
2009
H1N1 pandemic
H2N2 pandemic
H3N2 pandemic
H1N1 pandemic
? H1N2 triple reassortant
H1N1 Eurasian avian-like swine
(PB2, PB1, PA, HA, NP, NS)
H?N?
H?N?
H1N1 seasonal
(PB2, PA, NP, M, NS)
H2N2 avian
H2N2 seasonal
(PB1, HA NA)
(PB2, PA, NP, NA, M ,NS)
B INFLUENZA A VIRUS Structure
RNA segments
Virion
Proteins
1
PB2
2
PB1
3
PA
4
HA
5
NP
6
NA
7
M1, M2
8
NS1, NS2
H3N? avian
(PB1, HA)
H3N2 seasonal (PB1, NA)
(NA, M)
H1N1 avian
(PB2, PA)
H1N1 classical swine
H1N1 avian
(HA, NP, M, NS)
C RECEPTOR SPECIFICITY IS A MAJOR HOST RANGE DETERMINANT Receptor in birds
Receptor in pigs and humans
1 2 3 4 5 6 7 8
PB2
PB1
PB1
RNP PA
vRNA
416 Cell Host & Microbe 17, March 11, 2015 ©2015 Elsevier Inc.
Key amino acid substitutions in the receptor-binding site of pandemic viruses
DOI http://dx.doi.org/10.1016/j.chom.2015.02.001
See online version for legends and references
SnapShot: Evolution of Human Influenza A Viruses Isabel Wendel, Mikhail Matrosovich, Hans Dieter Klenk Institut für Virologie, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany Influenza A viruses are important pathogens with a wide host range. The available evidence indicates that they originate from a large virus pool indigenous to wild aquatic birds (Webster et al., 1992; Olsen et al., 2006). Since the host barriers are not an insurmountable obstacle for the avian viruses, they can be transmitted to other species, including man. Most of the transmissions are transient. On rare occasions, however, the viruses may undergo human adaptation. Such a virus may then give rise to a pandemic, as has been the case in 1918, 1957, 1968, and 2009 (Figure A adapted from Klenk et al., 2011 and Sorrel et al., 2011). Interspecies transmission and adaptation to a new host is facilitated by the high genetic flexibility of influenza A viruses. Their genome consists of eight RNA segments, each one encoding 1–3 structural and non-structural proteins (Figure B). They include the hemagglutinin (HA) and the neuraminidase (NA) comprising 18 (H1–H18) and 10 (N1–N10) subtypes, respectively, as well as the polymerase complex and the non-structural NS1 protein. HA is the major envelope glycoprotein that initiates infection by binding to sialic acid-containing cell receptors (Figure C) and by inducing membrane fusion. The viral polymerase that is composed of the subunits PB1, PB2, and PA mediates transcription and replication of the viral genome. NS1 is an interferon antagonist. In addition to the gene products shown in Figure B, several non-essential proteins have been described (Shaw and Palese, 2013). The segmentation of the viral genome allows exchange of gene segments between different viruses upon co-infection (gene reassortment), and due to the infidelity of polymerase, there is a high mutation rate. Influenza virus replication depends on the biosynthetic machinery of the cell and is under the control of the defense mechanisms developed by the host against infection (Shaw and Palese, 2013). Host specificity is therefore a result of the interaction of numerous host factors with all viral proteins, among which, however, the polymerase complex, HA, and NS1 appear to play particularly prominent roles. These proteins harbor several important adaptive mutations including mutations changing specificity of HA for sialyl-a2,3-galactose receptors in birds to sialyl-a2,6-galactose receptors in humans (Taubenberger and Kash, 2010; Klenk et al., 2011) (Figure C). Some of these adaptive mutations mediate airborne transmissibility, an essential trait of a pandemic virus (Sorrell et al., 2011). Intermediate hosts play an important role in the adaptation process. Circulation of avian viruses in pigs and possibly in domestic gallinaceous birds may facilitate acquisition of adaptive mutations and thus promote transmission to humans. In addition, the pig may serve as a mixing vessel in which both avian and mammalian viruses reassort to give rise to a new mammalian virus (Scholtissek, 1995). By these mechanisms, viruses with new surface glycoproteins and therefore a distinct change in antigenicity may be generated. If a new virus with such an antigenic shift occurs in man, it may cause a pandemic. Epidemic viruses are derived from pandemic viruses by antigenic drift—gradual, minor antigenic changes caused by point mutations in HA and NA. A new pandemic virus usually drives the contemporary seasonal virus down to extinction, as happened in 1957, 1968, and 2009, but sometimes pandemic and seasonal viruses continue to co-circulate over extended periods of time, as is the case since 1977. It has been estimated that there have been at least 14 pandemics in the last 500 years (Taubenberger and Kash, 2010), of which, however, only the five most recent are well documented (Figure A). The Spanish influenza (H1N1) was the most devastating one, taking the lives of about 50 million people worldwide. Contrary to its name, it presumably emerged in the United States in the spring of 1918 and within a year swept around the globe in three waves. The virus has been reconstituted from archival patient samples (Tumpey et al., 2005), but its ancestors are unknown. It has been proposed that the virus either arose by reassortment of an avian and a mammalian virus or that it was derived from an avian virus by gradual adaptation to the human host without reassortment. After 1918 the H1N1 virus caused seasonal epidemics until 1957, when the H2N2 virus of the Asian pandemic emerged in Southern China. This virus was derived from the seasonal H1N1 virus that had acquired HA, NA, and PB1 gene segments from an avian H2N2 virus by reassortment (Kilbourne, 2006). With ~1 million deaths, the H2N2 pandemic virus was significantly less pathogenic than the 1918 virus. The H2N2 virus circulated in the human population until 1968, when the H3N2 virus of the Hong Kong pandemic emerged. The H3N2 virus was again the result of gene reassortment between the previous H2N2 virus and avian viruses providing the HA and PB1 genes (Kilbourne, 2006). In terms of mortality, the Hong Kong pandemic resembled the previous one. In 1977 an H1N1 virus closely resembling isolates in the 1950s re-emerged from an unknown source at the Russian-Chinese border (Kilbourne, 2006). This virus co-circulated until 2009 with the H3N2 virus. The H1N1 virus of the 2009 pandemic was derived from a swine virus containing the NA and M genes of the Eurasian avian-like H1N1 virus lineage that emerged around 1980 in pigs and the other gene segment of a “triple reassortant” swine virus (Neumann et al., 2009). The “triple reassortant” emerged in the late 1990s in North American pigs and contained PB2 and PA of an avian virus, PB1 and NA of human H3N2 virus, and the other four genes of “classical” swine virus related to the 1918 H1N1 pandemic virus. Seasonal H1N1 viruses derived from the 2009 pandemic virus are now co-circulating with H3N2 viruses. References Kilbourne, E.D. (2006). Emerg. Infect. Dis. 12, 9–14. Klenk, H.D., Garten, W., and Matrosovich, M. (2011). BioEssays 33, 180–188. Neumann, G., Noda, T., and Kawaoka, Y. (2009). Nature 459, 931–939. Olsen, B., Munster, V.J., Wallensten, A., Waldenström, J., Osterhaus, A.D., and Fouchier, R.A. (2006). Science 312, 384–388. Scholtissek, C. (1995). Virus Genes 11, 209–215. Shaw, M.L., and Palese, P. (2013). Orthomyxoviruses. In Fields Virology, D.M. Knipe and P.M. Howley, eds. (Philadelphia: Lippincott Williams & Wilkins), pp. 1151–1185. Sorrell, E.M., Schrauwen, E.J., Linster, M., De Graaf, M., Herfst, S., and Fouchier, R.A. (2011). Curr Opin Virol 1, 635–642. Taubenberger, J.K., and Kash, J.C. (2010). Cell Host Microbe 7, 440–451. Tumpey, T.M., Basler, C.F., Aguilar, P.V., Zeng, H., Solórzano, A., Swayne, D.E., Cox, N.J., Katz, J.M., Taubenberger, J.K., Palese, P., and García-Sastre, A. (2005). Science 310, 77–80. Webster, R.G., Bean, W.J., Gorman, O.T., Chambers, T.M., and Kawaoka, Y. (1992). Microbiol. Rev. 56, 152–179.
416.e1 Cell Host & Microbe 17, March 11, 2015 ©2015 Elsevier Inc. DOI http://dx.doi.org/10.1016/j.chom.2015.02.001
