Abstract
Staphylococcus aureus is an opportunistic pathogen that causes a range of serious infections associated with significant morbidity, by strains increasingly resistant to antibiotics. However, to date all candidate vaccines have failed to induce protective immune responses in humans. We need a more comprehensive understanding of the antigenic targets important in the context of human infection. To investigate infection-associated immune responses, patients were sampled at initial presentation and during convalescence from three types of clinical infection; skin and soft tissue infection (SSTI), prosthetic joint infection (PJI) and pediatric hematogenous osteomyelitis (PHO). Reactivity of serum IgG was tested with an array of recombinant proteins, representing over 2,652 in-vitro-translated open reading frames (ORFs) from a community-acquired methicillin-resistant S. aureus USA300 strain. High-level reactivity was demonstrated for 104 proteins with serum IgG in all patient samples. Overall, high-level IgG-reactivity was most commonly directed against a subset of secreted proteins. Although based on limited surveys, we found subsets of S. aureus proteins with differential reactivity with serum samples from patients with different clinical syndromes. Together, our studies have revealed a hierarchy within the diverse proteins of the S. aureus “immunome”, which will help to advance efforts to develop protective immunotherapeutic agents.
Highlights
Staphylococcus aureus is an opportunistic bacterial pathogen that causes a range of serious infections associated with significant morbidity, with 10,000 deaths per year in the US alone[1,2,3]
We prioritized male patients from each of the three clinical cohorts for further study based on detection of increased IgG-reactivity with three or more S. aureus antigens in the short-term follow-up blood sample compared to the baseline sample (Supplementary Fig. S1)
Using an antigen array of all open reading frames (ORFs) in a USA300 CA-methicillin-resistant S. aureus (MRSA) clinical strain, we measured serologic IgG reactivity against every potential staphylococcal protein and found that only a small subset of total ORFs encoded for proteins that are immunologically-recognized across all infection types
Summary
Staphylococcus aureus is an opportunistic bacterial pathogen that causes a range of serious infections associated with significant morbidity, with 10,000 deaths per year in the US alone[1,2,3]. Mobile genetic elements enable efficient horizontal transfer of antibiotic resistance genes and other virulence factors[9,10], resulting in the rapid genetic diversification of S. aureus strains[11] Due to this genomic plasticity[12], coupled with the slow development of new antibiotics for clinical use, there has been greatly increased interest in the development of vaccines and therapeutic immunotherapies directed against S. aureus. Despite extensive efforts to develop vaccines against S. aureus, a broadly protective clinical vaccine has not been validated in controlled clinical trials[16], as none has imparted protective immunity from serious infections, while in some cases vaccination has led to worse outcomes[17] In part, this may be due to our current incomplete understanding of host-commensal/pathogen relationships and the range of S. aureus products that can represent antigenic targets for host immune defenses. We postulated that the results from these simple surveys would in part provide an essential step in the assembly of an effective combinatorial vaccine
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