Molecular Basis for Antibody-mediated Immunity against Iron-Binding Proteins in Staphylococcus aureus

Abstract

Nutrient acquisition is important for the survival of all living organisms. Nutrient metals such as iron, is known to play key roles in cellular metabolism, respiration, and both redox and non-redox catalysis. One particularly well-studied nutrient acquisition system is the iron-regulated surface determinant (Isd) system that scavenges iron from the human host. S. aureus utilizes the cell surface receptors IsdB and IsdH to bind hemoproteins and transfer heme to IsdA, ultimately leading to the transfer of heme-iron across the cell surface. The development of a bacterial system to sequester iron fills a fundamental metabolic requirement for the bacterial pathogen, enabling the acquisition of iron in iron-deplete conditions. The importance of this system in both nutrient acquisition and virulence to S. aureus has been validated in the laboratory, making them promising antibody targets. We hypothesize that the development of monoclonal antibodies (mAbs) specific to iron binding proteins will elucidate the importance of metal acquisition in pathogen growth, metabolism, and virulence. To investigate this further, panels of cross-reactive human mAbs specific to the surface proteins of the Staphylococcal Isd system were isolated. This includes the first panel of fully human IsdA mAbs, as well as three cross-specific mAbs each capable of binding to IsdA, IsdB, and IsdH. Two of the identified IsdA-specific mAbs worked cooperatively in a murine septic model of infection to reduce bacterial burden during staphylococcal infection. Their protection was a result of both heme-blocking and Fc-mediated effector functions, underscoring the importance of targeting S. aureus using diverse mechanisms.