Abstract
Proteomic studies with different Staphylococcus aureus isolates have shown that the cell surface-exposed and secreted proteins IsaA, LytM, Nuc, the propeptide of Atl (pro-Atl) and four phenol-soluble modulins α (PSMα) are invariantly produced by this pathogen. Therefore the present study was aimed at investigating whether these proteins can be used for active immunization against S. aureus infection in mouse models of bacteremia and skin infection. To this end, recombinant His-tagged fusions of IsaA, LytM, Nuc and pro-Atl were isolated from Lactococcus lactis or Escherichia coli, while the PSMα1-4 peptides were chemically synthesized. Importantly, patients colonized by S. aureus showed significant immunoglobulin G (IgG) responses against all eight antigens. BALB/cBYJ mice were immunized subcutaneously with a mixture of the antigens at day one (5 μg each), and boosted twice (25 μg of each antigen) with 28 days interval. This resulted in high IgG responses against all antigens although the response against pro-Atl was around one log lower compared to the other antigens. Compared to placebo-immunized mice, immunization with the octa-valent antigen mixture did not reduce the S. aureus isolate P load in blood, lungs, spleen, liver, and kidneys in a bacteremia model in which the animals were challenged for 14 days with a primary load of 3 × 105 CFU. Discomfort scores and animal survival rates over 14 days did not differ between immunized mice and placebo-immunized mice upon bacteremia with S. aureus USA300 (6 × 105 CFU). In addition, this immunization did not reduce the S. aureus isolate P load in mice with skin infection. These results show that the target antigens are immunogenic in both humans and mice, but in the used animal models do not result in protection against S. aureus infection.
Highlights
Staphylococcus aureus is a widespread Gram-positive bacterium that colonizes the skin and anterior nares of about 20–30% of the healthy human population [1]
Several strategies of passive and active immunization in S. aureus infections have been studied in experimental infection models, but until now none of these have been proved to be effective in clinical studies [9,10,11]
Using a multiplex assay to quantify antibody responses against 26 staphylococcal proteins, we found that mice with a S. aureus USA300 pneumonia or skin infection showed good immunoglobulin G (IgG) responses against Immunodominant staphylococcal antigen A (IsaA) and Nuc, while anti-LytM levels were low [25]
Summary
Staphylococcus aureus is a widespread Gram-positive bacterium that colonizes the skin and anterior nares of about 20–30% of the healthy human population [1]. Mainly a harmless colonizer, S. aureus can cause invasive diseases like skin and soft tissue infections, and can be responsible for severe infections in humans like pneumonia, endocarditis and osteomyelitis [1], which are frequently associated with S. aureus bacteremia [2]. Glycopeptides, especially vancomycin, are currently used as first-line treatment of MRSA infections. This has led to the emergence of vancomycin-intermediate and vancomycin-resistant MRSA [6]. Despite the lack of success so far, immunization approaches are still worth pursuing especially in patients admitted to the hospital for elective surgery. For this group of patients, there may be enough time for immunization prior to surgery
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