Abstract
Staphylococcus aureus is both an important pathogen and a human commensal. To explore this ambivalent relationship between host and microbe, we analysed the memory humoral response against IsdB, a protein involved in iron acquisition, in four healthy donors. Here we show that in all donors a heavily biased use of two immunoglobulin heavy chain germlines generated high affinity (pM) antibodies that neutralize the two IsdB NEAT domains, IGHV4-39 for NEAT1 and IGHV1-69 for NEAT2. In contrast to the typical antibody/antigen interactions, the binding is primarily driven by the germline-encoded hydrophobic CDRH-2 motifs of IGHV1-69 and IGHV4-39, with a binding mechanism nearly identical for each antibody derived from different donors. Our results suggest that IGHV1-69 and IGHV4-39, while part of the adaptive immune system, may have evolved under selection pressure to encode a binding motif innately capable of recognizing and neutralizing a structurally conserved protein domain involved in pathogen iron acquisition.
Highlights
Staphylococcus aureus is both an important pathogen and a human commensal
We found the majority of the antibodies to be directed against epitopes on the conserved core of IsdB (NEAT1–Linker–NEAT2) (Fig. 1c; Supplementary Fig. 8a) with two prominent sets of antibodies that block haemoglobin binding to IsdB, targeting NEAT1 and NEAT2, respectively
Among the antibodies that bind NEAT1, there is a strong bias (7 out of 12 antibodies) towards using the immunoglobulin heavy chain variable gene (IGHV) 4-39 and immunoglobulin kappa light chain variable gene (IGKV) (Supplementary Fig. 9a), whereas the antibodies that bind NEAT2 are invariably derived from the IGHV1-69 germline and IGKV light chains (Supplementary Fig. 9b), irrespective of the donor of origin
Summary
Staphylococcus aureus is both an important pathogen and a human commensal To explore this ambivalent relationship between host and microbe, we analysed the memory humoral response against IsdB, a protein involved in iron acquisition, in four healthy donors. To gain a better understanding of the functionality of these antibodies and to explore the relationship between the human immune system and the commensal pathogen S. aureus, we used single-B cell cloning, phage display libraries, high-throughput sequencing and epitope mapping[17], structural and mutagenesis methodologies to characterize in detail the humoral immune response to the staphylococcal protein IsdB
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