Five birds, one stone: Neutralization of α-hemolysin and 4 bi-component leukocidins of Staphylococcus aureus with a single human monoclonal antibodyстатья из журнала
Аннотация: Staphylococcus aureus is a major human pathogen associated with high mortality. The emergence of antibiotic resistance and the inability of antibiotics to counteract bacterial cytotoxins involved in the pathogenesis of S. aureus call for novel therapeutic approaches, such as passive immunization with monoclonal antibodies (mAbs). The complexity of staphylococcal pathogenesis and past failures with single mAb products represent considerable barriers for antibody-based therapeutics. Over the past few years, efforts have focused on neutralizing α-hemolysin. Recent findings suggest that the concerted actions of several cytotoxins, including the bi-component leukocidins play important roles in staphylococcal pathogenesis. Therefore, we aimed to isolate mAbs that bind to multiple cytolysins by employing high diversity human IgG1 libraries presented on the surface of yeast cells. Here we describe cross-reactive antibodies with picomolar affinity for α-hemolysin and 4 different bi-component leukocidins that share only ∼26% overall amino acid sequence identity. The molecular basis of cross-reactivity is the recognition of a conformational epitope shared by α-hemolysin and F-components of gamma-hemolysin (HlgAB and HlgCB), LukED and LukSF (Panton-Valentine Leukocidin). The amino acids predicted to form the epitope are conserved and known to be important for cytotoxic activity. We found that a single cross-reactive antibody prevented lysis of human phagocytes, epithelial and red blood cells induced by α-hemolysin and leukocidins in vitro, and therefore had superior effectiveness compared to α-hemolysin specific antibodies to protect from the combined cytolytic effect of secreted S. aureus toxins. Such mAb afforded high levels of protection in murine models of pneumonia and sepsis.
Год издания: 2014
Авторы: Harald Rouha, Adriana Badarau, Zehra Visram, Michael B. Battles, Bianka Prinz, Zoltán Magyarics, Gábor Nagy, Irina Mirkina, Lukas Stulik, Manuel Zerbs, Michaela Jägerhofer, Barbara Maierhofer, Astrid Teubenbacher, Ivana Doležílková, Karin Groß, Srijib Banerjee, Gerhild Zauner, Stefan Malafa, Jakub Zmajkovic, Sabine Maier, Robert L. Mabry, Eric Krauland, K. Dane Wittrup, Tillman U. Gerngross, Eszter Nagy
Издательство: Landes Bioscience
Источник: mAbs
Ключевые слова: Antimicrobial Resistance in Staphylococcus, Toxin Mechanisms and Immunotoxins, Clostridium difficile and Clostridium perfringens research
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Том: 7
Выпуск: 1
Страницы: 243–254