IsdA and IsdB antibodies protect mice against Staphylococcus aureus abscess formation and lethal challenge

Abstract

Staphylococcus aureus is the most frequent cause of bacteremia and hospital-acquired infection, however a vaccine that prevents staphylococcal disease is currently not available. Two sortase-anchored surface proteins, IsdA and IsdB, have been identified as subunit vaccines that, following active immunization, protect experimental animals against intravenous challenge with staphylococci. Here we investigate the molecular basis of this immunity and report that, when passively transferred to naïve mice, purified antibodies directed against IsdA or IsdB protected against staphylococcal abscess formation and lethal intravenous challenge. When added to mouse blood, IsdA- or IsdB-specific antibodies did not promote rapid opsonophagocytic killing of wild-type staphylococci. Antibodies directed against IsdA interfered with heme-binding and IsdB antibodies perturbed the ability of this surface protein to bind hemoglobin. As the structural genes for isdA and isdB are required for heme-iron scavenging during the pathogenesis of infection, we hypothesize that IsdA and IsdB antibodies may at least in part provide protection against staphylococci by interfering with the pathogen's heme-iron scavenging mechanisms.

Regulation of Host Hemoglobin Binding by the Staphylococcus aureus Clp Proteolytic System

“…Moreover, the IsdB-hemoglobin interaction is critical to staphylococcal pathogenesis in a murine model of infection (10,42,49). Consistent with this, IsdB is highly immunogenic and has garnered attention as a potential staphylococcal vaccine target (53,54). Data presented here suggest that hemoglobin-dependent heme acquisition through IsdB is driven not only by Fur-mediated repression but also by an additional level of proteolytic regulation.…”

The Five Near-iron Transporter (NEAT) Domain Anthrax Hemophore, IsdX2, Scavenges Heme from Hemoglobin and Transfers Heme to the Surface Protein IsdC

“…More recent studies highlight the potential utilization of NEAT proteins in vaccine assembly. For example, the vaccination of mice with antibodies raised against two recombinant NEAT proteins, IsdA and IsdB from S. aureus, protected mice against abscess formation and a lethal challenge of Staphylococci (19). This suggests that individual NEAT domains can serve as immunogens for induction of neutralizing antibodies, and protection is probably due to inhibition of NEAT function by the antibody binding to the heme binding structure.…”

The Near-iron Transporter (NEAT) Domains of the Anthrax Hemophore IsdX2 Require a Critical Glutamine to Extract Heme from Methemoglobin

“…A second potential use of these results could be to make a better vaccine against Gram-positive bacteria. There are numerous reports on the use of IsdB as a vaccine for S. aureus, a leading cause of communityacquired and nosocomial infections worldwide (53)(54)(55). Based on this success, Merck initiated clinical trials to develop this NEAT protein as a vaccine (56).…”