Protein A-Specific Monoclonal Antibodies and Prevention of Staphylococcus aureus Disease in Mice

Abstract

Staphylococcus aureusis a leading cause of human soft tissue infections and bacterial sepsis. The emergence of antibiotic-resistant strains (methicillin-resistantS. aureus[MRSA]) has prompted research into staphylococcal vaccines and preventive measures. The envelope ofS. aureusis decorated with staphylococcal protein A (SpA), which captures the Fcγ portion of immunoglobulins to prevent opsonophagocytosis and associates with the Fab portion of V_H3-type B cell receptors to trigger B cell superantigen activity. Nontoxigenic protein A (SpA_KKAA), when used as an immunogen in mice, stimulates humoral immune responses that neutralize the Fcγ and the V_H3⁺Fab binding activities of SpA and provide protection from staphylococcal abscess formation in mice. Here, we isolated monoclonal antibodies (MAbs) against SpA_KKAAthat, by binding to the triple-helical bundle fold of its immunoglobulin binding domains (IgBDs), neutralize the Fcγ and Fab binding activities of SpA. SpA_KKAAMAbs promoted opsonophagocytic killing of MRSA in mouse and human blood, provided protection from abscess formation, and stimulated pathogen-specific immune responses in a mouse model of staphylococcal disease. Thus, SpA_KKAAMAbs may be useful for the prevention and therapy of staphylococcal disease in humans.