Journal article
Glycosylations in the globular head of the hemagglutinin protein modulate the virulence and antigenic properties of the H1N1 influenza viruses
Science translational medicine, Vol.5(187), pp.187ra70-187ra70
05/29/2013
DOI: 10.1126/scitranslmed.3005996
PMCID: PMC3940933
PMID: 23720581
Abstract
The global spread of the 2009 pandemic H1N1 (pH1N1) virus in humans increases the likelihood that this influenza virus strain could undergo antigenic drift in the coming years. Previous seasonal H1N1 and H3N2 influenza strains acquired additional glycosylations in the globular head of their hemagglutinin (HA) proteins as they evolved over time; these are believed to shield antigenically relevant regions. We used influenza A/Netherlands/602/2009 recombinant (rpH1N1) viruses to which we added additional HA glycosylation sites reflecting their temporal appearance in previous seasonal H1N1 viruses. Additional glycosylations resulted in substantial attenuation in mice and ferrets, while deleting HA glycosylation sites from a pre-pandemic 1991 seasonal H1N1 influenza virus resulted in increased pathogenicity in mice. Sera from mice infected with wild type (WT) rpH1N1 virus showed a considerable loss of HA inhibitory (HI) activity against rpH1N1 viruses glycosylated at sites 144 or 144-172, indicating that the polyclonal antibody response elicited by WT rpH1N1 HA seems to be directed against an immunodominant region, likely site Sa, shielded by glycosylation at 144. Sera from humans vaccinated with the pH1N1 inactivated vaccine also showed reduced activity against the 144 and 144-172 mutant viruses. Remarkably, the HI activity of sera from virus-infected mice demonstrated that glycosylation at position 144 resulted in the induction of a broader polyclonal response able to cross-neutralize all WT and glycosylation mutant pH1N1 viruses. Mice infected with a recent seasonal virus in which glycosylation sites 71, 142 and 177 were removed, elicited antibodies that protected against challenge with the antigenically distant pH1N1 virus. Thus, acquisition of glycosylation sites in the HA of H1N1 human influenza viruses not only affects their pathogenicity and ability to escape from polyclonal antibodies elicited by previous influenza virus strains, but also their ability to induce cross-reactive antibodies against drifted antigenic variants. These findings provide the basis for designing improved vaccines and immunization strategies capable of protecting against a broader range of influenza virus strains.
Details
- Title: Subtitle
- Glycosylations in the globular head of the hemagglutinin protein modulate the virulence and antigenic properties of the H1N1 influenza viruses
- Creators
- Rafael A Medina - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USASilke Stertz - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USABalaji Manicassamy - University of Iowa, Microbiology and ImmunologyPetra Zimmermann - Institute of Medical Virology, University of Zurich, Winterthurerstr. 190, 8057 Zurich, SwitzerlandXiangjie Sun - University of Iowa, Anatomy and Cell BiologyRandy A Albrecht - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USAHanni Uusi-Kerttula - Laboratory of Molecular Virology, Millennium Institute on Immunology and Immunotherapy, Centro de Investigaciones Médicas y División de Pediatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, ChileOsvaldo Zagordi - Institute of Medical Virology, University of Zurich, Winterthurerstr. 190, 8057 Zurich, SwitzerlandRobert B Belshe - Saint Louis University School of Medicine, Saint Louis University, St. Louis, MO, USASharon E Frey - Saint Louis University School of Medicine, Saint Louis University, St. Louis, MO, USADirk Eggink - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USATerrence M Tumpey - Influenza Division, National Center for Immunization and Respiratory Disease, Centers for Disease Control and Prevention, Atlanta, GA, USAAdolfo García-Sastre - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.5(187), pp.187ra70-187ra70
- DOI
- 10.1126/scitranslmed.3005996
- PMID
- 23720581
- PMCID
- PMC3940933
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Language
- English
- Date published
- 05/29/2013
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984083887902771
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