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Monoclonal Antibodies Against the Staphylococcus aureus Bicomponent Leukotoxin AB Isolated Following Invasive Human Infection Reveal Diverse Binding and Modes of Action.
- Source :
-
The Journal of infectious diseases [J Infect Dis] 2017 Apr 01; Vol. 215 (7), pp. 1124-1131. - Publication Year :
- 2017
-
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.<br /> (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Subjects :
- Animals
B-Lymphocytes immunology
Child
Female
Humans
Hybridomas
Male
Mice
Mice, Inbred BALB C
Regression Analysis
Staphylococcus aureus
Antibodies, Bacterial blood
Antibodies, Monoclonal blood
Bacterial Proteins immunology
Leukocidins immunology
Neutrophils immunology
Staphylococcal Infections microbiology
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6613
- Volume :
- 215
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of infectious diseases
- Publication Type :
- Academic Journal
- Accession number :
- 28186295
- Full Text :
- https://doi.org/10.1093/infdis/jix071