Tweet
H7N9, Another internal gene mutation suggests mammalian adaptation
@ironorehopper --->@HaertlG --->@WestonSMare --->@WHO
''There're words about a new viral isolate from human without E627K...''
11:13am · 20 Apr 13 · TweetDeck
=-=
@HaertlG --> @ironorehopper -->@WestonSMare -->@WHO
''Checked. it is true. but it has another mutation which has same effect as 627. so virus properties same.''
@ 1:19pm · 20 Apr 13 · web
-
Some PubMed entries for D701N in PB2 of flu A viruses of animal origin:
J Virol. 2010 Oct;84(20):10606-18. doi: 10.1128/JVI.01187-10. Epub 2010 Aug 11.
PB2 and hemagglutinin mutations are major determinants of host range and virulence in mouse-adapted influenza A virus.
Ping J, Dankar SK, Forbes NE, Keleta L, Zhou Y, Tyler S, Brown EG.
Source
Department of Biochemistry, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
Abstract
Serial mouse lung passage of a human influenza A virus, A/Hong Kong/1/68 (H3N2) (HK-wt), produced a mouse-adapted variant, MA, with nine mutations that was >10(3.8)-fold more virulent. In this study, we demonstrate that MA mutations of the PB2 (D701N) and hemagglutinin (HA) (G218W in HA1 and T156N in HA2) genes were the most adaptive genetic determinants for increased growth and virulence in the mouse model. Recombinant viruses expressing each of the mutated MA genome segments on the HK-wt backbone showed significantly increased disease severity, whereas only the mouse-adapted PB2 gene increased virulence, as determined by the 50% lethal dose ([LD(50)] >10(1.4)-fold). The converse comparisons of recombinant MA viruses expressing each of the HK-wt genome segments showed the greatest decrease in virulence due to the HA gene (10(2)-fold), with lesser decreases due to the M1, NS1, NA, and PB1 genes (10(0.3)- to 10(0.8)-fold), and undetectable effects on the LD(50) for the PB2 and NP genes. The HK PB2 gene did, however, attenuate MA infection, as measured by weight loss and time to death. Replication of adaptive mutations in vivo and in vitro showed both viral gene backbone and host range effects. Minigenome transcription assays showed that PB1 and PB2 mutations increased polymerase activity and that the PB2 D701N mutation was comparable in effect to the mammalian adaptive PB2 E627K mutation. Our results demonstrate that host range and virulence are controlled by multiple genes, with major roles for mutations in PB2 and HA.
PMID: 20702632 [PubMed - indexed for MEDLINE] PMCID: PMC2950562
J Virol. 2010 Apr;84(8):3752-8. doi: 10.1128/JVI.02634-09. Epub 2010 Feb 3.
Introduction of virulence markers in PB2 of pandemic swine-origin influenza virus does not result in enhanced virulence or transmission.
Herfst S, Chutinimitkul S, Ye J, de Wit E, Munster VJ, Schrauwen EJ, Bestebroer TM, Jonges M, Meijer A, Koopmans M, Rimmelzwaan GF, Osterhaus AD, Perez DR, Fouchier RA.
Source
Department of Virology, Erasmus Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, Netherlands.
Abstract
In the first 6 months of the H1N1 swine-origin influenza virus (S-OIV) pandemic, the vast majority of infections were relatively mild. It has been postulated that mutations in the viral genome could result in more virulent viruses, leading to a more severe pandemic. Mutations E627K and D701N in the PB2 protein have previously been identified as determinants of avian and pandemic influenza virus virulence in mammals. These mutations were absent in S-OIVs detected early in the 2009 pandemic. Here, using reverse genetics, mutations E627K, D701N, and E677G were introduced into the prototype S-OIV A/Netherlands/602/2009, and their effects on virus replication, virulence, and transmission were investigated. Mutations E627K and D701N caused increased reporter gene expression driven by the S-OIV polymerase complex. None of the three mutations affected virus replication in vitro. The mutations had no major impact on virus replication in the respiratory tracts of mice and ferrets or on pathogenesis. All three mutant viruses were transmitted via aerosols or respiratory droplets in ferrets. Thus, the impact of key known virulence markers in PB2 in the context of current S-OIVs was surprisingly small. This study does not exclude the possibility of emergence of S-OIVs with other virulence-associated mutations in the future. We conclude that surveillance studies aimed at detecting S-OIVs with increased virulence or transmission should not rely solely on virulence markers identified in the past but should include detailed characterization of virus phenotypes, guided by genetic signatures of viruses detected in severe cases of disease in humans.
PMID: 20130063 [PubMed - indexed for MEDLINE] PMCID: PMC2849492
MBio. 2012 Jul 31;3(4):e00166-12. doi: 10.1128/mBio.00166-12. Print 2012.
Emergence of fatal avian influenza in New England harbor seals.
Anthony SJ, St Leger JA, Pugliares K, Ip HS, Chan JM, Carpenter ZW, Navarrete-Macias I, Sanchez-Leon M, Saliki JT, Pedersen J, Karesh W, Daszak P, Rabadan R, Rowles T, Lipkin WI.
Source
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA. sja2127@columbia.edu
Abstract
From September to December 2011, 162 New England harbor seals died in an outbreak of pneumonia. Sequence analysis of postmortem samples revealed the presence of an avian H3N8 influenza A virus, similar to a virus circulating in North American waterfowl since at least 2002 but with mutations that indicate recent adaption to mammalian hosts. These include a D701N mutation in the viral PB2 protein, previously reported in highly pathogenic H5N1 avian influenza viruses infecting people. Lectin staining and agglutination assays indicated the presence of the avian-preferred SAα-2,3 and mammalian SAα-2,6 receptors in seal respiratory tract, and the ability of the virus to agglutinate erythrocytes bearing either the SAα-2,3 or the SAα-2,6 receptor. The emergence of this A/harbor seal/Massachusetts/1/2011 virus may herald the appearance of an H3N8 influenza clade with potential for persistence and cross-species transmission. IMPORTANCE: The emergence of new strains of influenza virus is always of great public concern, especially when the infection of a new mammalian host has the potential to result in a widespread outbreak of disease. Here we report the emergence of an avian influenza virus (H3N8) in New England harbor seals which caused an outbreak of pneumonia and contributed to a U.S. federally recognized unusual mortality event (UME). This outbreak is particularly significant, not only because of the disease it caused in seals but also because the virus has naturally acquired mutations that are known to increase transmissibility and virulence in mammals. Monitoring the spillover and adaptation of avian viruses in mammalian species is critically important if we are to understand the factors that lead to both epizootic and zoonotic emergence.
PMID: 22851656 [PubMed - indexed for MEDLINE] PMCID: PMC3419516
-
------
''There're words about a new viral isolate from human without E627K...''
11:13am · 20 Apr 13 · TweetDeck
=-=
@HaertlG --> @ironorehopper -->@WestonSMare -->@WHO
''Checked. it is true. but it has another mutation which has same effect as 627. so virus properties same.''
@ 1:19pm · 20 Apr 13 · web
-
Some PubMed entries for D701N in PB2 of flu A viruses of animal origin:
J Virol. 2010 Oct;84(20):10606-18. doi: 10.1128/JVI.01187-10. Epub 2010 Aug 11.
PB2 and hemagglutinin mutations are major determinants of host range and virulence in mouse-adapted influenza A virus.
Ping J, Dankar SK, Forbes NE, Keleta L, Zhou Y, Tyler S, Brown EG.
Source
Department of Biochemistry, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
Abstract
Serial mouse lung passage of a human influenza A virus, A/Hong Kong/1/68 (H3N2) (HK-wt), produced a mouse-adapted variant, MA, with nine mutations that was >10(3.8)-fold more virulent. In this study, we demonstrate that MA mutations of the PB2 (D701N) and hemagglutinin (HA) (G218W in HA1 and T156N in HA2) genes were the most adaptive genetic determinants for increased growth and virulence in the mouse model. Recombinant viruses expressing each of the mutated MA genome segments on the HK-wt backbone showed significantly increased disease severity, whereas only the mouse-adapted PB2 gene increased virulence, as determined by the 50% lethal dose ([LD(50)] >10(1.4)-fold). The converse comparisons of recombinant MA viruses expressing each of the HK-wt genome segments showed the greatest decrease in virulence due to the HA gene (10(2)-fold), with lesser decreases due to the M1, NS1, NA, and PB1 genes (10(0.3)- to 10(0.8)-fold), and undetectable effects on the LD(50) for the PB2 and NP genes. The HK PB2 gene did, however, attenuate MA infection, as measured by weight loss and time to death. Replication of adaptive mutations in vivo and in vitro showed both viral gene backbone and host range effects. Minigenome transcription assays showed that PB1 and PB2 mutations increased polymerase activity and that the PB2 D701N mutation was comparable in effect to the mammalian adaptive PB2 E627K mutation. Our results demonstrate that host range and virulence are controlled by multiple genes, with major roles for mutations in PB2 and HA.
PMID: 20702632 [PubMed - indexed for MEDLINE] PMCID: PMC2950562
J Virol. 2010 Apr;84(8):3752-8. doi: 10.1128/JVI.02634-09. Epub 2010 Feb 3.
Introduction of virulence markers in PB2 of pandemic swine-origin influenza virus does not result in enhanced virulence or transmission.
Herfst S, Chutinimitkul S, Ye J, de Wit E, Munster VJ, Schrauwen EJ, Bestebroer TM, Jonges M, Meijer A, Koopmans M, Rimmelzwaan GF, Osterhaus AD, Perez DR, Fouchier RA.
Source
Department of Virology, Erasmus Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, Netherlands.
Abstract
In the first 6 months of the H1N1 swine-origin influenza virus (S-OIV) pandemic, the vast majority of infections were relatively mild. It has been postulated that mutations in the viral genome could result in more virulent viruses, leading to a more severe pandemic. Mutations E627K and D701N in the PB2 protein have previously been identified as determinants of avian and pandemic influenza virus virulence in mammals. These mutations were absent in S-OIVs detected early in the 2009 pandemic. Here, using reverse genetics, mutations E627K, D701N, and E677G were introduced into the prototype S-OIV A/Netherlands/602/2009, and their effects on virus replication, virulence, and transmission were investigated. Mutations E627K and D701N caused increased reporter gene expression driven by the S-OIV polymerase complex. None of the three mutations affected virus replication in vitro. The mutations had no major impact on virus replication in the respiratory tracts of mice and ferrets or on pathogenesis. All three mutant viruses were transmitted via aerosols or respiratory droplets in ferrets. Thus, the impact of key known virulence markers in PB2 in the context of current S-OIVs was surprisingly small. This study does not exclude the possibility of emergence of S-OIVs with other virulence-associated mutations in the future. We conclude that surveillance studies aimed at detecting S-OIVs with increased virulence or transmission should not rely solely on virulence markers identified in the past but should include detailed characterization of virus phenotypes, guided by genetic signatures of viruses detected in severe cases of disease in humans.
PMID: 20130063 [PubMed - indexed for MEDLINE] PMCID: PMC2849492
MBio. 2012 Jul 31;3(4):e00166-12. doi: 10.1128/mBio.00166-12. Print 2012.
Emergence of fatal avian influenza in New England harbor seals.
Anthony SJ, St Leger JA, Pugliares K, Ip HS, Chan JM, Carpenter ZW, Navarrete-Macias I, Sanchez-Leon M, Saliki JT, Pedersen J, Karesh W, Daszak P, Rabadan R, Rowles T, Lipkin WI.
Source
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA. sja2127@columbia.edu
Abstract
From September to December 2011, 162 New England harbor seals died in an outbreak of pneumonia. Sequence analysis of postmortem samples revealed the presence of an avian H3N8 influenza A virus, similar to a virus circulating in North American waterfowl since at least 2002 but with mutations that indicate recent adaption to mammalian hosts. These include a D701N mutation in the viral PB2 protein, previously reported in highly pathogenic H5N1 avian influenza viruses infecting people. Lectin staining and agglutination assays indicated the presence of the avian-preferred SAα-2,3 and mammalian SAα-2,6 receptors in seal respiratory tract, and the ability of the virus to agglutinate erythrocytes bearing either the SAα-2,3 or the SAα-2,6 receptor. The emergence of this A/harbor seal/Massachusetts/1/2011 virus may herald the appearance of an H3N8 influenza clade with potential for persistence and cross-species transmission. IMPORTANCE: The emergence of new strains of influenza virus is always of great public concern, especially when the infection of a new mammalian host has the potential to result in a widespread outbreak of disease. Here we report the emergence of an avian influenza virus (H3N8) in New England harbor seals which caused an outbreak of pneumonia and contributed to a U.S. federally recognized unusual mortality event (UME). This outbreak is particularly significant, not only because of the disease it caused in seals but also because the virus has naturally acquired mutations that are known to increase transmissibility and virulence in mammals. Monitoring the spillover and adaptation of avian viruses in mammalian species is critically important if we are to understand the factors that lead to both epizootic and zoonotic emergence.
PMID: 22851656 [PubMed - indexed for MEDLINE] PMCID: PMC3419516
-
------
Comment