Children with Invasive Staphylococcus aureus Disease Exhibit a Potently Neutralizing Antibody Response to the Cytotoxin LukAB

Abstract

c Despite the importance of Staphylococcus aureus as a common invasive bacterial pathogen, the humoral response to infection remains inadequately defined, particularly in children. The purpose of this study was to assess the humoral response to extracellular staphylococcal virulence factors, including the bicomponent leukotoxins, which are critical for the cytotoxicity of S. aureus toward human neutrophils. Children with culture-proven S. aureus infection were prospectively enrolled and stratified by disease type. Fifty-three children were enrolled in the study, of which 90% had invasive disease. Serum samples were obtained during the acute (within 48 h) and convalescent (4 to 6 weeks postinfection) phases, at which point both IgG titers against S. aureus exotoxins were determined, and the functionality of the generated antibodies was evaluated. Molecular characterization of clinical isolates was also performed. We observed a marked rise in antibody titer from acute-phase to convalescent-phase sera for LukAB, the most recently described S. aureus bicomponent leukotoxin. LukAB production by the isolates was strongly correlated with cytotoxicity in vitro, and sera containing anti-LukAB antibodies potently neutralized cytotoxicity. Antibodies to S. aureus antigens were detectable in healthy pediatric controls but at much lower titers than in sera from infected subjects. The discovery of a high-titer, neutralizing antibody response to LukAB during invasive infections suggests that this toxin is produced in vivo and that it elicits a functional humoral response.

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

“…However, like PVL, whether this antibody response to LukAB/HG alone is capable of conferring protection against infection with S. aureus remains to be determined. In this study, the titers of LukAB/HG antibody were higher than those of any other leucocidin tested, implying that it may be a dominant antigen seen during infection (330).…”

“…In an additional study of children with S. aureus infection, it was found that those with invasive disease generated a high-titer antibody response to LukAB/HG. The antibodies generated have significant neutralizing capabilities in vitro (330). However, like PVL, whether this antibody response to LukAB/HG alone is capable of conferring protection against infection with S. aureus remains to be determined.…”

Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

“…This toxin appears to be encoded in most sequenced strains of S. aureus [7, 90], yet another study noted that three out of ten clinical isolates failed to express LukAB protein [9]. Higher titers of LukAB neutralizing antibodies were found in convalescent patient sera compared to that of acutely ill patients in the setting of pediatric invasive S. aureus , indicating that LukAB is produced during human disease [91]. …”

Host response to Staphylococcus aureus cytotoxins in children with cystic fibrosis

“…S. aureus virulence relies, in part, on the production of a group of cytolytic toxins 10 including alpha-hemolysin and the bicomponent leukotoxins, notably Panton-Valentine leukocidin (PVL) and the recently described LukAB 11,12 . Recent work from our group demonstrated that invasive staphylococcal infection elicits a functional and potent humoral response to LukAB 13 . Data regarding the adaptive response to S. aureus in children with CF are limited, and the antibody response to key staphylococcal antigens, particularly those with vaccine or therapeutic potential, remains largely unknown 14-16 .…”