Monoclonal Antibodies Against the Staphylococcus aureus Bicomponent Leukotoxin AB Isolated Following Invasive Human Infection Reveal Diverse Binding and Modes of Action. (13th April 2017)

• Record Type: Journal Article
• Authors: Thomsen, Isaac P.; Sapparapu, Gopal; James, David B. A.; Cassat, James E.; Nagarsheth, Meera; Kose, Nurgun; Putnam, Nicole; Boguslawski, Kristina M.; Jones, Lauren S.; Wood, James B.; Creech, Clarence B.; Torres, Victor J.; Crowe, James E.
• Is Part Of: Journal of infectious diseases. Volume 215:Number 7(2017:Apr. 01)
• Page Start: 1124
• Page End: 1131
• Publication Date: 2017-04-13
• Subjects: Staphylococcus aureus -- leukocidin -- LukAB -- monoclonal -- hybridoma -- toxins.; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jix071
• Languages: English
• ISSNs: 0022-1899

Abstract

Brief Summary: Human monoclonal antibodies targeting the leukotoxin LukAB were isolated and purified from a boy with invasive Staphylococcus aureus infection. Characterization of these antibodies revealed diverse potency and modes of neutralization against toxin-mediated cytotoxicity, and they exhibited partial protection in vivo. Abstract: The 2-component leukotoxin LukAB is critical for Staphylococcus aureus targeting and killing of human neutrophils ex vivo and is produced in the setting of human infection. We report 3 LukAB-specific human monoclonal antibodies (mAbs) with distinct mechanisms of toxin neutralization and in vivo efficacy. Three hybridomas secreting mAbs with anti-LukAB activity (designated SA-13, -15, and -17) were generated from B cells obtained from a 12-year-old boy with S. aureus osteomyelitis. Each of the 3 mAbs neutralized LukAB-mediated neutrophil toxicity, exhibited differing levels of potency, recognized different antigenic sites on the toxin, and displayed at least 2 distinct mechanisms for cytotoxic inhibition. SA-15 bound exclusively to the dimeric form of the toxin, suggesting that human B cells recognize epitopes on the dimerized form of LukAB during natural infection. Both SA-13 and SA-17 bound the LukA monomer and the LukAB dimer. Although all 3 mAbs potently neutralized cytotoxicity, only SA-15 and SA-17 significantly inhibited toxin association with the cell surface. Treatment with a 1:1 mixture of mAbs SA-15 and SA-17 resulted in significantly lower bacterial colony counts in heart, liver, and kidneys in a murine model of S. aureus sepsis. These data describe the isolation of diverse and efficacious antitoxin mAbs.