Nature: Germline-encoded Neutralization of a Staphylococcus aureus Virulence Factor by the Human Antibody Repertoire

Nature Communications. 2016 Nov 18; doi: 10.1038/ncomms13376.

Y. Yeung, D. Foletti, X. Deng, Y. Abdiche, P. Strop, J. Glanville, S. Pitts, K. Lindquist, P. Sundar, M. Sirota, A. Hasa-Moreno, A. Pham, J. Melton Witt, I. Ni, J. Pons, D. Shelton, A. Rajpal, J. Chaparro-Riggers

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.