B cells develop receptor specificity--over the course of many delicate rounds of clonal selection and recombination--to a single antigen. However, recent advances in cellular immunology have revealed that mature BCRs (B Cell Receptors) are not always limited to one target for the duration of their lives.
Our lab is presently investigating an instance of BCR cross-reactivity in which B cells adapted to recognize the S2 region of endemic coronavirus hCoV-OC43 also display reactivity to the S2 region of pandemic strain SARS-CoV-2. The S2 region is a subunit of the viral spike protein: a highly-conserved structure critical to the successful infection of a human host cell. Other portions of these viruses, such as the FP (fusion peptide) and HR2 regions, are also very similar in structure across strains. This observation, along with existing knowledge of the mechanisms controlling BCR specificity, leads us to posit:
1) Individual HR2-reactive antibodies that arise/expand in COVID-19 convalescent subjects bind both the SARS-CoV-2 and hCoV-OC43 antigen variants
2) The breadth of cross-reactivity is determined by sequence features of the IgH/L (immunoglobulin heavy and light chains)
3) Pre-existing antibodies against the OC43 antigen develop increased affinity for the SARS-CoV-2 variant by acquiring IgH/L mutations following SARS-CoV-2 exposure
Our targets are long-lived memory B cells possessing BCRs able to bind to an array of viral peptides. We are using a combination of density gradient separation, magnetic bead enrichment, and fluorescent tagging to isolate B cells of interest before loading them into a 10X Genomics sequencing pipeline. Long-read sequencing and future-barcoding provide us with precise mapping of BCRs to the cells that express them--enabling us to identify individual memory B cells with ideal antigen specificities.