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Article: D225G mutation in hemagglutinin of pandemic influenza H1N1 (2009) virus enhances virulence in mice
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TitleD225G mutation in hemagglutinin of pandemic influenza H1N1 (2009) virus enhances virulence in mice
 
AuthorsZheng, B1 1 1
Chan, KH1
Zhang, AJX1
Zhou, J1 1
Chan, CCS1
Poon, VKM1
Zhang, K1
Leung, VHC1
Jin, DY1
Woo, PCY1 1 1
Chan, JFW1
To, KKW1 1
Chen, H1 1 1
Yuen, KY1 1 1
 
KeywordsAdaptation
D222G
D225G
H1N1
Hemagglutinin
Influenza
Pandemic
Sialic acid
 
Issue Date2010
 
PublisherSociety for Experimental Biology and Medicine. The Journal's web site is located at http://www.ebmonline.org/
 
CitationExperimental Biology And Medicine, 2010, v. 235 n. 8, p. 981-988 [How to Cite?]
DOI: http://dx.doi.org/10.1258/ebm.2010.010071
 
AbstractAlthough the majority of infections by the pandemic influenza H1N1 (2009) virus is mild, a higher mortality occurs in young adults with no risk factors for complications. Some of these severe cases were infected by the virus with an aspartate to glycine substitution at 225 position (D225G, H3 numbering) in the hemagglutinin (HA). Previous studies with the highly virulent 1918 pandemic H1N1 virus suggested that such substitution was associated with a dual binding specificity of the virus for both α2,3- and α2,6-linked sialic acid receptors on host cells. Thus, the D225G mutant may cause more severe disease with its increased predilection for the lower respiratory tract, where the α2,3 sialic acid receptor is more prevalent, but this hypothesis has not been investigated. We obtained a mutant virus after four sequential passages in lungs of BALB/c mice with a wild-type pandemic influenza A H1N1 (2009) virus. One plaque purified mutant virus had a single non-synonymous D225G mutation in the HA gene. This mutant was more lethal to chick embryo and produced a viral load of about two log higher than that of the wild-type parental virus during the first 24 h. A pathogenicity test showed that the 50% lethal dose in mice (LD50) was reduced from over 2 × 10 6 plaque-forming units (PFU) with the parental virus to just 150 PFU with the mutant virus. The survival of mice challenged with the mutant virus was significantly decreased when compared with the parental virus (P < 0.0001). Significantly higher viral titers and elevated proinflammatory cytokines in lung homogenates of mice infected with the mutant virus were found, which were compatible with severe histopathological changes of pneumonitis. The only consistent mutation in the genomes of viral clones obtained from dying mice was D225G substitution. Copyright © 2010 by the Society for Experimental Biology and Medicine.
 
ISSN1535-3702
2012 Impact Factor: 2.803
2012 SCImago Journal Rankings: 0.932
 
DOIhttp://dx.doi.org/10.1258/ebm.2010.010071
 
ISI Accession Number IDWOS:000280586600011
Funding AgencyGrant Number
Providence Foundation Limited
HKSAR Research Grant Council
Food and Health Bureau of the HKSAR
Shaw Foundation
Funding Information:

This work is partly supported by the Providence Foundation Limited in memory of the late Dr Lui Hac Minh, the HKSAR Research Grant Council, Research Fund for the Control of Infectious Diseases of the Food and Health Bureau of the HKSAR and The Shaw Foundation.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorZheng, B
 
dc.contributor.authorChan, KH
 
dc.contributor.authorZhang, AJX
 
dc.contributor.authorZhou, J
 
dc.contributor.authorChan, CCS
 
dc.contributor.authorPoon, VKM
 
dc.contributor.authorZhang, K
 
dc.contributor.authorLeung, VHC
 
dc.contributor.authorJin, DY
 
dc.contributor.authorWoo, PCY
 
dc.contributor.authorChan, JFW
 
dc.contributor.authorTo, KKW
 
dc.contributor.authorChen, H
 
dc.contributor.authorYuen, KY
 
dc.date.accessioned2010-10-31T11:13:23Z
 
dc.date.available2010-10-31T11:13:23Z
 
dc.date.issued2010
 
dc.description.abstractAlthough the majority of infections by the pandemic influenza H1N1 (2009) virus is mild, a higher mortality occurs in young adults with no risk factors for complications. Some of these severe cases were infected by the virus with an aspartate to glycine substitution at 225 position (D225G, H3 numbering) in the hemagglutinin (HA). Previous studies with the highly virulent 1918 pandemic H1N1 virus suggested that such substitution was associated with a dual binding specificity of the virus for both α2,3- and α2,6-linked sialic acid receptors on host cells. Thus, the D225G mutant may cause more severe disease with its increased predilection for the lower respiratory tract, where the α2,3 sialic acid receptor is more prevalent, but this hypothesis has not been investigated. We obtained a mutant virus after four sequential passages in lungs of BALB/c mice with a wild-type pandemic influenza A H1N1 (2009) virus. One plaque purified mutant virus had a single non-synonymous D225G mutation in the HA gene. This mutant was more lethal to chick embryo and produced a viral load of about two log higher than that of the wild-type parental virus during the first 24 h. A pathogenicity test showed that the 50% lethal dose in mice (LD50) was reduced from over 2 × 10 6 plaque-forming units (PFU) with the parental virus to just 150 PFU with the mutant virus. The survival of mice challenged with the mutant virus was significantly decreased when compared with the parental virus (P < 0.0001). Significantly higher viral titers and elevated proinflammatory cytokines in lung homogenates of mice infected with the mutant virus were found, which were compatible with severe histopathological changes of pneumonitis. The only consistent mutation in the genomes of viral clones obtained from dying mice was D225G substitution. Copyright © 2010 by the Society for Experimental Biology and Medicine.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationExperimental Biology And Medicine, 2010, v. 235 n. 8, p. 981-988 [How to Cite?]
DOI: http://dx.doi.org/10.1258/ebm.2010.010071
 
dc.identifier.doihttp://dx.doi.org/10.1258/ebm.2010.010071
 
dc.identifier.epage988
 
dc.identifier.hkuros180532
 
dc.identifier.isiWOS:000280586600011
Funding AgencyGrant Number
Providence Foundation Limited
HKSAR Research Grant Council
Food and Health Bureau of the HKSAR
Shaw Foundation
Funding Information:

This work is partly supported by the Providence Foundation Limited in memory of the late Dr Lui Hac Minh, the HKSAR Research Grant Council, Research Fund for the Control of Infectious Diseases of the Food and Health Bureau of the HKSAR and The Shaw Foundation.

 
dc.identifier.issn1535-3702
2012 Impact Factor: 2.803
2012 SCImago Journal Rankings: 0.932
 
dc.identifier.issue8
 
dc.identifier.openurl
 
dc.identifier.pmid20660098
 
dc.identifier.scopuseid_2-s2.0-77955688829
 
dc.identifier.spage981
 
dc.identifier.urihttp://hdl.handle.net/10722/125135
 
dc.identifier.volume235
 
dc.languageeng
 
dc.publisherSociety for Experimental Biology and Medicine. The Journal's web site is located at http://www.ebmonline.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofExperimental Biology and Medicine
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshDisease Outbreaks
 
dc.subject.meshHemagglutinin Glycoproteins, Influenza Virus - genetics - metabolism
 
dc.subject.meshInfluenza A Virus, H1N1 Subtype - genetics - pathogenicity
 
dc.subject.meshInfluenza, Human - epidemiology - virology
 
dc.subject.meshMutation - genetics
 
dc.subjectAdaptation
 
dc.subjectD222G
 
dc.subjectD225G
 
dc.subjectH1N1
 
dc.subjectHemagglutinin
 
dc.subjectInfluenza
 
dc.subjectPandemic
 
dc.subjectSialic acid
 
dc.titleD225G mutation in hemagglutinin of pandemic influenza H1N1 (2009) virus enhances virulence in mice
 
dc.typeArticle
 
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<description.abstract>Although the majority of infections by the pandemic influenza H1N1 (2009) virus is mild, a higher mortality occurs in young adults with no risk factors for complications. Some of these severe cases were infected by the virus with an aspartate to glycine substitution at 225 position (D225G, H3 numbering) in the hemagglutinin (HA). Previous studies with the highly virulent 1918 pandemic H1N1 virus suggested that such substitution was associated with a dual binding specificity of the virus for both &#945;2,3- and &#945;2,6-linked sialic acid receptors on host cells. Thus, the D225G mutant may cause more severe disease with its increased predilection for the lower respiratory tract, where the &#945;2,3 sialic acid receptor is more prevalent, but this hypothesis has not been investigated. We obtained a mutant virus after four sequential passages in lungs of BALB/c mice with a wild-type pandemic influenza A H1N1 (2009) virus. One plaque purified mutant virus had a single non-synonymous D225G mutation in the HA gene. This mutant was more lethal to chick embryo and produced a viral load of about two log higher than that of the wild-type parental virus during the first 24 h. A pathogenicity test showed that the 50% lethal dose in mice (LD50) was reduced from over 2 &#215; 10 6 plaque-forming units (PFU) with the parental virus to just 150 PFU with the mutant virus. The survival of mice challenged with the mutant virus was significantly decreased when compared with the parental virus (P &lt; 0.0001). Significantly higher viral titers and elevated proinflammatory cytokines in lung homogenates of mice infected with the mutant virus were found, which were compatible with severe histopathological changes of pneumonitis. The only consistent mutation in the genomes of viral clones obtained from dying mice was D225G substitution. Copyright &#169; 2010 by the Society for Experimental Biology and Medicine.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong