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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jul 28, 2022 |
| Title |
Antibody from Single Human VH-rearranging Mouse Potently Neutralizes All SARS-CoV-2 Variants Through BA.5 by Inhibiting Membrane Fusion |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
Here, we describe a mouse model in which the primary B cell receptor (BCR) repertoire is generated solely through V(D)J recombination of a human VH1-2 heavy chain (HC) and, substantially, a human Vk1-33 light chain (LC). Thus, primary humanized BCR repertoire diversity in these mice derives from immensely diverse HC and LC antigen-contact complementarity-region-3 (CDR3) sequences generated de novo by non-templated junctional modifications during V(D)J recombination. We assayed the V usage and CDR3 diversity in this mouse model by HTGTS-repertoire sequencing. Immunizing this human VH1-2/Vk1-33-rearranging model with prototype SARS-CoV-2 spike protein immunogens elicited several VH1-2/Vk1-33-based nAbs. Of these, SP1-77 potently and broadly neutralized all SARS-CoV-2 variants through BA.5. Cryo-EM studies revealed that SP1-77 binds RBD away from the ACE2 receptor-binding-motif via a striking CDR3-dominated mode of recognition. Lattice-light-sheet-microscopy-based studies confirmed that SP1-77 did not block ACE2-mediated viral attachment or subsequent endocytosis, but rather blocked membrane fusion. The SP1-77 binding epitope and neutralization mechanism may offer additional strategies for designing vaccines that robustly neutralize emerging SARS-CoV-2 variants.
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| Overall design |
High-thoughput sequencing of splenic B cell receptor repertoire
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| Contributor(s) |
Luo S, Zhang J, Kreutzberger A, Eaton A, Edwards RJ, Jing C, Dai H, Sempowski GD, Cronin K, Parks R, Ye AY, Mansouri K, Barr M, Pishesha N, Williams AC, Francisco LV, Saminathan A, Peng H, Batra H, Bellusci L, Khurana S, Alam SM, Montefiori DC, Saunders KO, Tian M, Ploegh H, Kirchhausen T, Chen B, Haynes BF, Alt FW |
| Citation(s) |
35951767, 36574685 |
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| Submission date |
Feb 23, 2022 |
| Last update date |
Feb 24, 2023 |
| Contact name |
Frederick W Alt |
| E-mail(s) |
alt@enders.tch.harvard.edu
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| Organization name |
Boston Children's Hospital
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| Department |
Program in Cellular and Molecular Medicine
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| Lab |
Frederick Alt
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| Street address |
1 Blackfan Circle
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (3) |
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| Samples (15)
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| GSM5911642 |
VH1-2, mVHdel, VK1-33-CS, SP, IgH1 |
| GSM5911643 |
VH1-2, mVHdel, VK1-33-CS, SP, IgH2 |
| GSM5911644 |
VH1-2, mVHdel, VK1-33-CS, SP, IgH3 |
| GSM5911645 |
VH1-2, mVHdel, VK1-33-CS, SP, IgK1 |
| GSM5911646 |
VH1-2, mVHdel, VK1-33-CS, SP, IgK2 |
| GSM5911647 |
VH1-2, mVHdel, VK1-33-CS, SP, IgK3 |
| GSM6412352 |
129Sv_SP_IgH_1 |
| GSM6412353 |
129Sv_SP_IgH_2 |
| GSM6412354 |
129Sv_SP_IgH_3 |
| GSM6412355 |
129Sv_SP_IgK_1 |
| GSM6412356 |
129Sv_SP_IgK_2 |
| GSM6412357 |
129Sv_SP_IgK_3 |
| GSM6412358 |
VH1_2_mVHdel_VK1_33_SP_IgK_1 |
| GSM6412359 |
VH1_2_mVHdel_VK1_33_SP_IgK_2 |
| GSM6412360 |
VH1_2_mVHdel_VK1_33_SP_IgK_3 |
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| Relations |
| BioProject |
PRJNA809561 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE197255_RAW.tar |
147.9 Mb |
(http)(custom) |
TAR (of TXT, XLS) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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