Abstract
Staphylococcus aureus is prevalent in surgical site infections (SSI) and leads to death in approximately 1% of patients. Phase IIB/III clinical trial results have demonstrated that vaccination against the iron-regulated surface determinant protein B (IsdB) is associated with an increased mortality rate in patients with SSI. Thus, we hypothesized that S. aureus induces nonneutralizing anti-IsdB antibodies, which facilitate bacterial entry into leukocytes to generate “Trojan horse” leukocytes that disseminate the pathogen. Since hemoglobin (Hb) is the primary target of IsdB, and abundant Hb-haptoglobin (Hb-Hp) complexes in bleeding surgical wounds are normally cleared via CD163-mediated endocytosis by macrophages, we investigated this mechanism in vitro and in vivo. Our results demonstrate that active and passive IsdB immunization of mice renders them susceptible to sepsis following SSI. We also found that a multimolecular complex containing S. aureus protein A–anti-IsdB–IsdB–Hb-Hp mediates CD163-dependent bacterial internalization of macrophages in vitro. Moreover, IsdB-immunized CD163–/– mice are resistant to sepsis following S. aureus SSI, as are normal healthy mice given anti-CD163–neutralizing antibodies. These genetic and biologic CD163 deficiencies did not exacerbate local infection. Thus, anti-IsdB antibodies are a risk factor for S. aureus sepsis following SSI, and disruption of the multimolecular complex and/or CD163 blockade may intervene.
Highlights
Despite advances in prophylaxis, surgical protocols, and postoperative care, surgical site infections (SSI) remain a serious complication, and the majority are caused by Staphylococcus aureus [1]
Consistent with prior studies in a murine tail vein sepsis model [14], we found that recombinant IsdB protein (rIsdB) was a potent immunogen, inducing high titers of anti-iron-regulated surface determinant protein B (IsdB) IgG antibodies in all immunized mice, and this immunization was protective against the primary infection, as assessed by bioluminescent imaging (BLI) (Figure 1, A and C)
In order to investigate the direct effects of anti-IsdB humoral immunity on methicillin-resistant S. aureus (MRSA) dissemination following SSI, we generated anti-IsdB mAbs and assessed their ability to block rIsdB binding to hemoglobin (Hb) in vitro (Figure 2)
Summary
Surgical protocols, and postoperative care, surgical site infections (SSI) remain a serious complication, and the majority are caused by Staphylococcus aureus [1]. As immunization is a cost-effective intervention for the prevention of some infections, there have been major efforts to develop a vaccine against S. aureus; there has been essentially no success in human clinical trials [7]. Results from other experiments showed that IsdB-specific antibodies may promote opsonophagocytosis of S. aureus [12, 13] Despite this rigorous preclinical research demonstrating V710 safety and efficacy in mice and rhesus macaques [12, 14], the vaccine was associated with an increased mortality rate from S. aureus infections among immunized human subjects following elective heart surgery in a phase IIB/III clinical trial [15]
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