Functional antibodies targeting IsaA of Staphylococcus aureus augment host immune response and open new perspectives for antibacterial therapy.
Staphylococcus aureus is the most common cause of nosocomial infections. Multiple antibiotic resistance and severe clinical outcomes provide a strong rationale for development of immunoglobulin-based strategies. Traditionally, novel immunological approaches against bacterial pathogens involve antibodies directed against cell surface-exposed virulence-associated epitopes or toxins. In this study, we generated a monoclonal antibody targeting the housekeeping protein IsaA, a suggested soluble lytic transglycosylase of S. aureus, and tested its therapeutic efficacy in two experimental mouse infection models. A murine anti-IsaA antibody of the IgG1 subclass (UK-66P) showed the highest binding affinity in Biacore analysis. This antibody recognized all S. aureus strains tested, including hospital-acquired and community-acquired methicillin-resistant S. aureus strains. Therapeutic efficacy in vivo in mice was analyzed using a central venous catheter-related infection model and a sepsis survival model. In both models, anti-IsaA IgG1 conferred protection against staphylococcal infection. Ex vivo, UK-66P activates professional phagocytes and induces highly microbicidal reactive oxygen metabolites in a dose-dependent manner, resulting in bacterial killing. The study provides proof of concept that monoclonal IgG1 antibodies with high affinity to the ubiquitously expressed, single-epitope-targeting IsaA are effective in the treatment of staphylococcal infection in different mouse models. Anti-IsaA antibodies might be a useful component in an antibody-based therapeutic for prophylaxis or adjunctive treatment of human cases of S. aureus infections.
Department of General, Visceral, Vascular and Paediatric Surgery, University Clinic of Würzburg, Wuerzburg, Germany. u.lorenz@mail.uni-wuerzburg.de
Udo
U
Lorenz
Birgit
B
Lorenz
Tim
T
Schmitter
Karin
K
Streker
Christian
C
Erck
Jürgen
J
Wehland
Joachim
J
Nickel
Bastian
B
Zimmermann
Knut
K
Ohlsen
D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology* / Q000627:therapeutic use*; D000942:Antigens, Bacterial / Q000276:immunology*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D008297:Male; D051379:Mice; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000276:immunology* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000276:immunology*
D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; C417673:IsaA antigen, staphylococcus