Host response to Staphylococcus aureus cytotoxins in children with cystic fibrosis

Abstract

Background Staphylococcus aureus is one of the earliest bacterial pathogens to colonize the lungs of children with cystic fibrosis and is an important contributor to pulmonary exacerbations. The adaptive host response to S. aureus in cystic fibrosis remains inadequately defined and has important implications for pathogenesis and potential interventions. The objectives of this study were to determine the functional antibody response to select staphylococcal exotoxins (LukAB, alpha-hemolysin, and PVL) in children with cystic fibrosis and to evaluate the relationship of this response with pulmonary exacerbations. Methods Fifty children with cystic fibrosis were enrolled and followed prospectively for 12 months. Clinical characteristics and serologic profiles were assessed at routine visits and during pulmonary exacerbations, and functional antibody assessments were performed to measure neutralization of LukAB-mediated cytotoxicity. Results For each antigen, geometric mean titers were significantly higher if S. aureus was detected at the time of exacerbation. For LukAB, GMTs were significantly higher at exacerbation follow-up compared to titers during the exacerbation, consistent with expression during human disease, and the humoral response capably neutralized LukAB-mediated cytotoxicity. Moreover, the presence of a positive S. aureus culture during a pulmonary exacerbation was associated with a 31-fold higher odds of having a LukA titer ≥1:160, suggesting potential diagnostic capability of this assay. Conclusions The leukotoxin LukAB is expressed by S. aureus and recognized by the human adaptive immune response in the setting of pulmonary infection in cystic fibrosis. Anti-LukAB antibodies were not only predictive of positive staphylococcal culture during exacerbation, but also functional in the neutralization of this toxin.

Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent Staphylococcus aureus

“…The latter confirms and expands on another recent study that demonstrated a significant inverse association between S . aureus toxin-specific IgG-levels and lung function in CF patients [25]. In contrast to our results, this previous study also showed a significant association between the culture of S .…”

“…aureus toxin-specific IgG-levels has been associated with the presence of S . aureus in airway specimens of CF patients, the severity of exacerbations and with FEV 1 % predicted [25]. To expand on these results, we measured IgG-levels against 44 different virulence factors of S .…”

Commercial Intravenous Immunoglobulin Preparations Contain Functional Neutralizing Antibodies against the Staphylococcus aureus Leukocidin LukAB (LukGH)

“…Our group has shown that children with invasive S. aureus infection produce a high titer of anti-LukAB antibodies under acute-phase conditions that increases in convalescence and that B cells obtained from children following invasive infection produce potently neutralizing anti-LukAB antibodies (5), strongly suggesting that the toxin is produced during invasive human disease. Additionally, all clinical isolates of S. aureus identified by our group to date harbored lukAB (5,15). These characteristics of immunogenicity, and its universal presence in isolates causing human disease, make LukAB an interesting preventive or therapeutic target.…”

“…Diep et al showed IVIg to have a protective effect against death in a rabbit model of necrotizing pneumonia and were able to characterize two specific IVIg antibodies that neutralized the toxic effects of ␣-hemolysin and PVL (14). No studies, however, have assessed the neutralization capacity of IVIg against LukAB, despite its ubiquitous presence in all clinical isolates tested to date (5,15) and its clear role in pathogenesis in vivo (2,7,8). Thus, the primary aim of this study was to assess the binding and neutralization potential of commercially available IVIg against LukAB.…”

Antibody-based intervention against the pore-forming toxins of Staphylococcus aureus

“…Infection of human neutrophils with diverse S. aureus strains indicates that LukAB/LukGH is the dominant toxin responsible for neutrophil targeting and killing [ 12 ]. This toxin is also highly conserved, being present in the genome of all known clinical isolates tested to date [ 20 , 21 ]. Finally, LukAB/LukGH is clearly produced during human infection, as evidenced by its recognition by the humoral response following invasive human disease [ 21 , 22 ].…”