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Modulating the immunodominance hierarchy of immunoglobulin germline-encoded structural motifs targeting the influenza hemagglutinin stem

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Ataca, Sila ; Sangesland, Maya ; Rocha, Rebeca de Paiva Froes ; de la Pena, Alba Torrents ; Ronsard, Larance ; Boyoglu-Barnum, Seyhan ; Gillespie, Rebecca A. ; Tsybovsky, Yaroslav ; Stephens, Tyler ; Moin, Syed M. ; Lederhofer, Julia ; Creanga, Adrian ; Andrews, Sarah F. ; Barnes, Ralston M. ; Rohrer, Daniel ; Lonberg, Nils ; Graham, Barney S. ; Ward, Andrew B. ; Lingwood, Daniel ; Kanekiyo, Masaru
Número total de Autores: 20
Tipo de documento: Artigo Científico
Fonte: CELL REPORTS; v. 43, n. 12, p. 17-pg., 2024-11-22.
Resumo

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 IGHV1-69*01 germline-encoded antibody response to the conserved stem epitope on group 1 hemagglutinin (HA) of influenza A virus to show that this germlineendowed 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. (AU)

Processo FAPESP: 19/20772-4 - Análise da resposta de anticorpos policlonais no contexto de infecção e imunização por Influenza A vírus
Beneficiário:Rebeca de Paiva Froes Rocha
Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado