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Article: D225G mutation in hemagglutinin of pandemic influenza H1N1 (2009) virus enhances virulence in mice

TitleD225G mutation in hemagglutinin of pandemic influenza H1N1 (2009) virus enhances virulence in mice
Authors
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/
Citation
Experimental Biology And Medicine, 2010, v. 235 n. 8, p. 981-988 How to Cite?
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 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.
Persistent Identifierhttp://hdl.handle.net/10722/125135
ISSN
2013 Impact Factor: 2.226
2013 SCImago Journal Rankings: 1.150
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorZheng, Ben_HK
dc.contributor.authorChan, KHen_HK
dc.contributor.authorZhang, AJXen_HK
dc.contributor.authorZhou, Jen_HK
dc.contributor.authorChan, CCSen_HK
dc.contributor.authorPoon, VKMen_HK
dc.contributor.authorZhang, Ken_HK
dc.contributor.authorLeung, VHCen_HK
dc.contributor.authorJin, DYen_HK
dc.contributor.authorWoo, PCYen_HK
dc.contributor.authorChan, JFWen_HK
dc.contributor.authorTo, KKWen_HK
dc.contributor.authorChen, Hen_HK
dc.contributor.authorYuen, KYen_HK
dc.date.accessioned2010-10-31T11:13:23Z-
dc.date.available2010-10-31T11:13:23Z-
dc.date.issued2010en_HK
dc.identifier.citationExperimental Biology And Medicine, 2010, v. 235 n. 8, p. 981-988en_HK
dc.identifier.issn1535-3702en_HK
dc.identifier.urihttp://hdl.handle.net/10722/125135-
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.en_HK
dc.languageengen_HK
dc.publisherSociety for Experimental Biology and Medicine. The Journal's web site is located at http://www.ebmonline.org/en_HK
dc.relation.ispartofExperimental Biology and Medicineen_HK
dc.subjectAdaptationen_HK
dc.subjectD222Gen_HK
dc.subjectD225Gen_HK
dc.subjectH1N1en_HK
dc.subjectHemagglutininen_HK
dc.subjectInfluenzaen_HK
dc.subjectPandemicen_HK
dc.subjectSialic aciden_HK
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.titleD225G mutation in hemagglutinin of pandemic influenza H1N1 (2009) virus enhances virulence in miceen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1535-3702&volume=235&issue=8&spage=981&epage=988&date=2010&atitle=D225G+mutation+in+haemagglutinin+of+pandemic+Influenza+H1N1+(2009)+virus+enhances+virulence+in+mice-
dc.identifier.emailZheng, B: bzheng@hkucc.hku.hken_HK
dc.identifier.emailZhang, AJX: zhangajx@hkucc.hku.hken_HK
dc.identifier.emailZhou, J: jiezhou@hku.hken_HK
dc.identifier.emailJin, DY: dyjin@hku.hken_HK
dc.identifier.emailWoo, PCY: pcywoo@hkucc.hku.hken_HK
dc.identifier.emailChan, JFW: jfwchan@hku.hken_HK
dc.identifier.emailTo, KKW: kelvinto@hkucc.hku.hken_HK
dc.identifier.emailChen, H: hlchen@hku.hken_HK
dc.identifier.emailYuen, KY: kyyuen@hkucc.hku.hken_HK
dc.identifier.authorityZheng, B=rp00353en_HK
dc.identifier.authorityZhang, AJX=rp00413en_HK
dc.identifier.authorityZhou, J=rp01412en_HK
dc.identifier.authorityJin, DY=rp00452en_HK
dc.identifier.authorityWoo, PCY=rp00430en_HK
dc.identifier.authorityChan, JFW=rp01736en_HK
dc.identifier.authorityTo, KKW=rp01384en_HK
dc.identifier.authorityChen, H=rp00383en_HK
dc.identifier.authorityYuen, KY=rp00366en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1258/ebm.2010.010071en_HK
dc.identifier.pmid20660098en_HK
dc.identifier.scopuseid_2-s2.0-77955688829en_HK
dc.identifier.hkuros180532en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77955688829&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume235en_HK
dc.identifier.issue8en_HK
dc.identifier.spage981en_HK
dc.identifier.epage988en_HK
dc.identifier.isiWOS:000280586600011-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridZheng, B=7201780588en_HK
dc.identifier.scopusauthoridChan, KH=7406034307en_HK
dc.identifier.scopusauthoridZhang, AJX=12752135600en_HK
dc.identifier.scopusauthoridZhou, J=7405550443en_HK
dc.identifier.scopusauthoridChan, CCS=16021156900en_HK
dc.identifier.scopusauthoridPoon, VKM=54934161900en_HK
dc.identifier.scopusauthoridZhang, K=8685813400en_HK
dc.identifier.scopusauthoridLeung, VHC=36612082100en_HK
dc.identifier.scopusauthoridJin, DY=7201973614en_HK
dc.identifier.scopusauthoridWoo, PCY=7201801340en_HK
dc.identifier.scopusauthoridChan, JFW=24278817900en_HK
dc.identifier.scopusauthoridTo, KKW=14323807300en_HK
dc.identifier.scopusauthoridChen, H=26643315400en_HK
dc.identifier.scopusauthoridYuen, KY=36078079100en_HK

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