Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate

ABSTRACT Influenza viruses expressing chimeric hemagglutinins (HAs) are important tools in the quest for a universal vaccine. Using cryo-electron tomography, we have determined the structures of a chimeric HA variant that comprises an H1 stalk and an H5 globular head domain (cH5/1 HA) in native and...

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Autores principales:	Erin E. H. Tran, Kira A. Podolsky, Alberto Bartesaghi, Oleg Kuybeda, Giovanna Grandinetti, Teddy John Wohlbold, Gene S. Tan, Raffael Nachbagauer, Peter Palese, Florian Krammer, Sriram Subramaniam
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/35be324109e04a4faa66b8868fe3368c
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spelling	oai:doaj.org-article:35be324109e04a4faa66b8868fe3368c2021-11-15T15:41:41ZCryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate10.1128/mBio.00257-162150-7511https://doaj.org/article/35be324109e04a4faa66b8868fe3368c2016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00257-16https://doaj.org/toc/2150-7511ABSTRACT Influenza viruses expressing chimeric hemagglutinins (HAs) are important tools in the quest for a universal vaccine. Using cryo-electron tomography, we have determined the structures of a chimeric HA variant that comprises an H1 stalk and an H5 globular head domain (cH5/1 HA) in native and antibody-bound states. We show that cH5/1 HA is structurally different from native HA, displaying a 60° rotation between the stalk and head groups, leading to a novel and unexpected “open” arrangement of HA trimers. cH5/1N1 viruses also display higher glycoprotein density than pH1N1 or H5N1 viruses, but despite these differences, antibodies that target either the stalk or head domains of hemagglutinins still bind to cH5/1 HA with the same consequences as those observed with native H1 or H5 HA. Our results show that a large range of structural plasticity can be tolerated in the chimeric spike scaffold without disrupting structural and geometric aspects of antibody binding. IMPORTANCE Chimeric hemagglutinin proteins are set to undergo human clinical trials as a universal influenza vaccine candidate, yet no structural information for these proteins is available. Using cryo-electron tomography, we report the first three-dimensional (3D) visualization of chimeric hemagglutinin proteins displayed on the surface of the influenza virus. We show that, unexpectedly, the chimeric hemagglutinin structure differs from those of naturally occurring hemagglutinins by displaying a more open head domain and a dramatically twisted head/stalk arrangement. Despite this unusual spatial relationship between head and stalk regions, virus preparations expressing the chimeric hemagglutinin are fully infectious and display a high glycoprotein density, which likely helps induction of a broadly protective immune response.Erin E. H. TranKira A. PodolskyAlberto BartesaghiOleg KuybedaGiovanna GrandinettiTeddy John WohlboldGene S. TanRaffael NachbagauerPeter PaleseFlorian KrammerSriram SubramaniamAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Erin E. H. Tran Kira A. Podolsky Alberto Bartesaghi Oleg Kuybeda Giovanna Grandinetti Teddy John Wohlbold Gene S. Tan Raffael Nachbagauer Peter Palese Florian Krammer Sriram Subramaniam Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate
description	ABSTRACT Influenza viruses expressing chimeric hemagglutinins (HAs) are important tools in the quest for a universal vaccine. Using cryo-electron tomography, we have determined the structures of a chimeric HA variant that comprises an H1 stalk and an H5 globular head domain (cH5/1 HA) in native and antibody-bound states. We show that cH5/1 HA is structurally different from native HA, displaying a 60° rotation between the stalk and head groups, leading to a novel and unexpected “open” arrangement of HA trimers. cH5/1N1 viruses also display higher glycoprotein density than pH1N1 or H5N1 viruses, but despite these differences, antibodies that target either the stalk or head domains of hemagglutinins still bind to cH5/1 HA with the same consequences as those observed with native H1 or H5 HA. Our results show that a large range of structural plasticity can be tolerated in the chimeric spike scaffold without disrupting structural and geometric aspects of antibody binding. IMPORTANCE Chimeric hemagglutinin proteins are set to undergo human clinical trials as a universal influenza vaccine candidate, yet no structural information for these proteins is available. Using cryo-electron tomography, we report the first three-dimensional (3D) visualization of chimeric hemagglutinin proteins displayed on the surface of the influenza virus. We show that, unexpectedly, the chimeric hemagglutinin structure differs from those of naturally occurring hemagglutinins by displaying a more open head domain and a dramatically twisted head/stalk arrangement. Despite this unusual spatial relationship between head and stalk regions, virus preparations expressing the chimeric hemagglutinin are fully infectious and display a high glycoprotein density, which likely helps induction of a broadly protective immune response.
format	article
author	Erin E. H. Tran Kira A. Podolsky Alberto Bartesaghi Oleg Kuybeda Giovanna Grandinetti Teddy John Wohlbold Gene S. Tan Raffael Nachbagauer Peter Palese Florian Krammer Sriram Subramaniam
author_facet	Erin E. H. Tran Kira A. Podolsky Alberto Bartesaghi Oleg Kuybeda Giovanna Grandinetti Teddy John Wohlbold Gene S. Tan Raffael Nachbagauer Peter Palese Florian Krammer Sriram Subramaniam
author_sort	Erin E. H. Tran
title	Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate
title_short	Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate
title_full	Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate
title_fullStr	Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate
title_full_unstemmed	Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate
title_sort	cryo-electron microscopy structures of chimeric hemagglutinin displayed on a universal influenza vaccine candidate
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/35be324109e04a4faa66b8868fe3368c
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Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate

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