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IsdB antibody-mediated sepsis following S. aureus surgical site infection.

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.

SUBMITTER: Nishitani K

PROVIDER: S-EPMC7566716 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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IsdB antibody-mediated sepsis following S. aureus surgical site infection.

Nishitani Kohei K Ishikawa Masahiro M Morita Yugo Y Yokogawa Noriaki N Xie Chao C de Mesy Bentley Karen L KL Ito Hiromu H Kates Stephen L SL Daiss John L JL Schwarz Edward M EM

JCI insight 20201002 19

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 ...[more]

PMID: 33004694

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Project description:Staphylococcus aureus is a well-recognized, clinically important cause of nosocomial infections, and as such, a vaccine to prevent S. aureus infections would be an important achievement. A Phase IIB/III study of V710, a vaccine containing iron-regulated surface determinant B (IsdB), demonstrated significant sero-conversion rates in cardiovascular surgery patients following a single pre-surgery immunization. However, the vaccine was not efficacious in preventing bacteremia or deep sternal wound infection post-surgery, thus raising the possibility that IsdB might not be available for immune recognition during infection. The purpose of the work described herein was to evaluate and quantify the naturally occurring anti-IsdB levels at baseline and over time during infection, to understand whether IsdB is expressed during a S. aureus infection in hospitalized non-vaccinated patients. We evaluated baseline and follow-up titers in 3 populations: (1) healthy subjects, (2) hospitalized patients with non-S. aureus infections, and (3) hospitalized patients with S. aureus infections. Baseline anti-IsdB levels generally overlapped between the 3 groups, but were highly variable within each group. In healthy subjects, baseline and follow-up levels were highly correlated (Spearman's rho = 0.93), and the geometric mean fold-rise (GMFR) in anti-IsdB levels between study entry and last value was 0.9-fold (95% confidence interval (CI): 0.8 to 1.0 ; p = 0.09), showing no trend over time. The convalescent GMFR in anti-IsdB levels from baseline was 1.7-fold (95% CI: 1.3 to 2.2, p = 0.0008) during S. aureus infection, significantly different from the 1.0-fold GMFR (95% CI: 0.9-1.2, p = 0.60) in non-S. aureus infection, p = 0.005. Additionally, S. aureus isolates (51) obtained from the hospitalized patient group expressed the IsdB protein in vitro. Collectively, these data suggest that IsdB expression levels rise substantially following infection with S. aureus, but not with other pathogens, and IsdB is likely well-conserved across S. aureus strains.

Project description:BackgroundThe rate of cesarean delivery is increasing in North America. Surgical site infection following this operation can make it difficult to recover, care for a baby and return home. We aimed to determine the incidence of surgical site infection to 30 days following cesarean delivery, associated risk factors and whether risk factors differed for predischarge versus postdischarge infection.MethodsWe identified a retrospective cohort in Nova Scotia by linking the provincial perinatal database to hospital admissions and physician billings databases to follow women for 30 days after they had given birth by cesarean delivery between Jan. 1, 1997 and Dec. 31, 2012. Logistic regression with generalized estimating equations was used to determine risk factors for infection.ResultsA total of 25 123 women had 33 991 cesarean deliveries over the study period. Of the 25 123, 923 had surgical site infections, giving an incidence rate of 2.7% (95% CI 2.54%-2.89%); the incidence decreased over time. Risk factors for infection (adjusted odds ratios ≥ 1.5) were prepregnancy weight 87.0 kg or more, gaining 30.0 kg or more during pregnancy, chorioamnionitis, maternal blood transfusion, anticoagulation therapy, alcohol or drug abuse, second stage of labour before surgery, delivery in 1997-2000 and delivery in a hospital performing 130-1249 cesarean deliveries annually. Women who gave birth earlier in the study period, those who gave birth in a hospital with 130-949 cesarean deliveries per year and those with more than 1 fetus were at a significantly higher risk for surgical site infection before discharge; women who smoked were at significantly higher risk for surgical site infection after discharge.InterpretationMost risk factors are known before delivery, and some are potentially modifiable. Although the incidence of surgical site infection decreased over time, targeted clinical and infection prevention and control interventions could further reduce the burden of illness associated with this health-care-related infection.

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IsdB antibody-mediated sepsis following S. aureus surgical site infection.

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IsdB antibody-mediated sepsis following S. aureus surgical site infection.

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