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Structure paper

TitleLassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection.
Journal, issue, pagesCell Host Microbe, Vol. 30, Issue 12, Page 1759-1772.e12, Year 2022
Publish dateDec 14, 2022
AuthorsPhilip J M Brouwer / Aleksandar Antanasijevic / Adam J Ronk / Helena Müller-Kräuter / Yasunori Watanabe / Mathieu Claireaux / Hailee R Perrett / Tom P L Bijl / Marloes Grobben / Jeffrey C Umotoy / Angela I Schriek / Judith A Burger / Khadija Tejjani / Nicole M Lloyd / Thijs H Steijaert / Marlies M van Haaren / Kwinten Sliepen / Steven W de Taeye / Marit J van Gils / Max Crispin / Thomas Strecker / Alexander Bukreyev / Andrew B Ward / Rogier W Sanders /
PubMed AbstractThe Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been hampered by the instability of ...The Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here, we use two-component protein nanoparticles consisting of trimeric and pentameric subunits to stabilize GPC in a trimeric conformation. These GPC nanoparticles present twenty prefusion GPC trimers on the surface of an icosahedral particle. Cryo-EM studies of GPC nanoparticles demonstrated a well-ordered structure and yielded a high-resolution structure of an unliganded GPC. These nanoparticles induced potent humoral immune responses in rabbits and protective immunity against the lethal Lassa virus challenge in guinea pigs. Additionally, we isolated a neutralizing antibody that mapped to the putative receptor-binding site, revealing a previously undefined site of vulnerability. Collectively, these findings offer potential approaches to vaccine and therapeutic design for the Lassa virus.
External linksCell Host Microbe / PubMed:36400021 / PubMed Central
MethodsEM (single particle)
Resolution3.67 - 4.41 Å
Structure data

EMDB-25107, PDB-7sgd:
Lassa virus glycoprotein construct(Josiah GPCysR4) recovered from GPC-I53-50 nanoparticle by localized reconstruction
Method: EM (single particle) / Resolution: 3.97 Å

EMDB-25108, PDB-7sge:
I53-50 nanoparticle core reconstructed from GPC-I53-50NP by focused refinement
Method: EM (single particle) / Resolution: 3.67 Å

EMDB-25109, PDB-7sgf:
Lassa virus glycoprotein construct (Josiah GPC-I53-50A) in complex with LAVA01 antibody
Method: EM (single particle) / Resolution: 4.41 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • lassa mammarenavirus
  • synthetic construct (others)
  • oryctolagus cuniculus (rabbit)
KeywordsVIRAL PROTEIN / glycoprotein / Lassa / Josiah / vaccine design / nanoparticle / protein design / VIRAL PROTEIN/IMMUNE SYSTEM / VIRAL PROTEIN-IMMUNE SYSTEM complex

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