A protective and heterosubtypic antibody lineage targeting the influenza A virus neuraminidase active site
Ty A. Sornberger, Rachael M. Wolters, Iuliia M. Gilchuk, Luke Myers, Elad Binshtein, Ryan Irving, Elaine C. Chen, Pavlo Gilchuk, Rachel S. Nargi, Rachel E. Sutton, Bethany N. Howard, Laura S. Handal, Andrew Trivette, Katherine E. Webb, Chandrahaas Kona, Eduardo Villalobos, Lauren E. Williamson, James E. Crowe Jr., Seth J. Zost
Ty A. Sornberger, Rachael M. Wolters, Iuliia M. Gilchuk, Luke Myers, Elad Binshtein, Ryan Irving, Elaine C. Chen, Pavlo Gilchuk, Rachel S. Nargi, Rachel E. Sutton, Bethany N. Howard, Laura S. Handal, Andrew Trivette, Katherine E. Webb, Chandrahaas Kona, Eduardo Villalobos, Lauren E. Williamson, James E. Crowe Jr., Seth J. Zost
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Research Article Immunology Infectious disease

A protective and heterosubtypic antibody lineage targeting the influenza A virus neuraminidase active site

Abstract

Influenza type A viruses (IAVs) remain an extraordinary burden to global public health and regularly circulate through human populations. This investigation describes the isolation of human mAbs from an individual with a substantial history of influenza exposure via vaccination and natural infection. From these mAbs, a clonally expanded B cell lineage was identified that recognizes the IAV neuraminidase (NA) glycoprotein and binds near the NA active site of H3N2 viruses to inhibit sialidase activity. Further characterization found that some somatically mutated members of this lineage exhibited cross-reactive binding to recombinant N1 and N9 antigens, suggesting that heterosubtypic reactivity was acquired through somatic mutation. Two candidate mAbs from this family — FluA-168 and FluA-173 — potently inhibited IAV replication in vitro and protected against lethality in vivo. The results of this study contribute to our understanding of cross-reactivity between IAV subtypes in response to diverse exposure patterns and identified 2 mAbs as potential therapeutic candidates for IAV infection.

Authors

Ty A. Sornberger, Rachael M. Wolters, Iuliia M. Gilchuk, Luke Myers, Elad Binshtein, Ryan Irving, Elaine C. Chen, Pavlo Gilchuk, Rachel S. Nargi, Rachel E. Sutton, Bethany N. Howard, Laura S. Handal, Andrew Trivette, Katherine E. Webb, Chandrahaas Kona, Eduardo Villalobos, Lauren E. Williamson, James E. Crowe Jr., Seth J. Zost

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Figure 1

Identification and characterization of a FluA B cell lineage.

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Identification and characterization of a FluA B cell lineage. (A) Timeli...
(A) Timeline illustrating the exposure history of the donor with types of exposures and sequencing indicated. (B) Illustration of the general antibody discovery process in which plasmablasts are isolated and sequenced using single-cell sequencing techniques, and the antibodies are recombinantly expressed. Illustrations in A and B created in BioRender. (C) ELISA heatmap indicating mAb binding potency to rN2 and rN9. Columns represent mAbs used, and rows represent the indicated IAV strains. Phylogenetic trees indicate the divergence of (top) full-length heavy-chain nucleotide sequences of the FluA B cell lineage from the germline heavy-chain variable gene or (left) the relatedness of the NA nucleotide sequence between each IAV strain shown in the heatmap over time. Scale bars: average number of nucleotide substitutions between each node. Binding potency is represented as an EC50 value. Black indicates IAV N2 strains without an N-linked glycan motif at position 245 of NA (S245/S247), and green indicates IAV N2 strains containing an N-linked glycan motif at position 245 of NA (N245/T247). Candidate mAbs FluA-168 and FluA-173 are highlighted. All mAbs were assessed in triplicate, and data are representative of 2 biological replicates.