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TitleModulating the immunodominance hierarchy of immunoglobulin germline-encoded structural motifs targeting the influenza hemagglutinin stem.
Journal, issue, pagesCell Rep, Vol. 43, Issue 12, Page 114990, Year 2024
Publish dateNov 22, 2024
AuthorsSila Ataca / Maya Sangesland / Rebeca de Paiva Fróes Rocha / Alba Torrents de la Peña / Larance Ronsard / Seyhan Boyoglu-Barnum / Rebecca A Gillespie / Yaroslav Tsybovsky / Tyler Stephens / Syed M Moin / Julia Lederhofer / Adrian Creanga / Sarah F Andrews / Ralston M Barnes / Daniel Rohrer / Nils Lonberg / Barney S Graham / Andrew B Ward / Daniel Lingwood / Masaru Kanekiyo /
PubMed AbstractAntibodies targeting epitopes through germline-encoded motifs can be found in different individuals. While these public antibodies are often beneficial, they also pose hurdles for subdominant ...Antibodies targeting epitopes through germline-encoded motifs can be found in different individuals. While these public antibodies are often beneficial, they also pose hurdles for subdominant antibodies to emerge. Here, we use transgenic mice that reproduce the human IGHV1-6901 germline-encoded antibody response to the conserved stem epitope on group 1 hemagglutinin (HA) of influenza A virus to show that this germline-endowed response can be overridden by a subdominant yet cross-group reactive public antibody response. Immunization with a non-cognate group 2 HA stem enriched B cells harboring the IGHD3-9 gene, thereby switching from IGHV1-69- to IGHD3-9-encoded motif-dependent epitope recognition. These IGHD3-9 antibodies bound, neutralized, and conferred cross-group protection in mice against influenza A viruses. A cryoelectron microscopy (cryo-EM) structure of an IGHD3-9 antibody resembled the human broadly neutralizing antibody FI6v3, which uses IGHD3-9. Together, our findings offer insights into vaccine regimens that engage an immunoglobulin repertoire with broader cross-reactivity to influenza A viruses.
External linksCell Rep / PubMed:39580804 / PubMed Central
MethodsEM (single particle)
Resolution3.09 Å
Structure data

44112

9b2m

EMDB-44112, PDB-9b2m:
Hemagglutinin H1 New Caledonia 1999 in complex with monoclonal antibody Fab 43_S0008
Method: EM (single particle) / Resolution: 3.09 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • Homo sapiens (human)
  • influenza a virus
  • mus sp. (mice)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / influenza virus; broadly neutralizing antibody; bnAb; VH1-69; DH3-9; hemagglutinin; HA; stem; stalk; germline-targeting / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex

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