Identification of biologic agents to neutralize the bicomponent leukocidins of Staphylococcus aureus

• Published in: Science translational medicine 2019-01, Vol.11 (475)
• Main Authors: Chan, Rita, Buckley, Peter T, O'Malley, Aidan, Sause, William E, Alonzo, 3rd, Francis, Lubkin, Ashira, Boguslawski, Kristina M, Payne, Angela, Fernandez, Jeffrey, Strohl, William R, Whitaker, Brian, Lynch, Anthony Simon, Torres, Victor J
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biological Factors - pharmacology; Cell culture; Cytolysis; Cytoprotection - drug effects; Cytotoxicity, Immunologic; Fibronectin; Hemolysis - drug effects; Humans; Immune response; Intoxication; Leukocidins - chemistry; Leukocidins - metabolism; Mice; Neutralization Tests; Neutrophils - drug effects; Neutrophils - metabolism; Phagocytes - drug effects; Staphylococcal Infections - microbiology; Staphylococcal Infections - pathology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - metabolism; Tenascin; Tenascin C; Tissue culture; Virulence factors
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aat0882

A key aspect underlying the severity of infections caused by is the abundance of virulence factors that the pathogen uses to thwart critical components of the human immune response. One such mechanism involves the destruction of host immune cells by cytolytic toxins secreted by , including five bicomponent leukocidins: PVL, HlgAB, HlgCB, LukED, and LukAB. Purified leukocidins can lyse immune cells ex vivo, and systemic injections of purified LukED or HlgAB can acutely kill mice. Here, we describe the generation and characterization of centyrins that bind leukocidins with high affinity and protect primary human immune cells from toxin-mediated cytolysis. Centyrins are small protein scaffolds derived from the fibronectin type III-binding domain of the human protein tenascin-C. Although centyrins are potent in tissue culture assays, their short serum half-lives limit their efficacies in vivo. By extending the serum half-lives of centyrins through their fusion to an albumin-binding consensus domain, we demonstrate the in vivo efficacy of these biologics in a murine intoxication model and in models of both prophylactic and therapeutic treatment of live systemic infections. These biologics that target virulence factors have potential for treating and preventing serious staphylococcal infections.