Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus

Abstract

<i>Staphylococcus aureus</i> is a major cause of skin and soft tissue infection. The bacterium expresses four major proteases that are emerging as virulence factors: aureolysin (Aur), V8 protease (SspA), staphopain A (ScpA), and staphopain B (SspB). We hypothesized that human galectin-3, a β-galactoside-binding lectin involved in immune regulation and antimicrobial defense, is a target for these proteases and that proteolysis of galectin-3 is a novel immune evasion mechanism. Indeed, supernatants from laboratory strains and clinical isolates of <i>S. aureus</i> caused galectin-3 degradation. Similar proteolytic capacities were found in <i>Staphylococcus epidermidis</i> isolates but not in <i>Staphylococcus saprophyticus</i> Galectin-3-induced activation of the neutrophil NADPH oxidase was abrogated by bacterium-derived proteolysis of galectin-3, and SspB was identified as the major protease responsible. The impact of galectin-3 and protease expression on <i>S. aureus</i> virulence was studied in a murine skin infection model. In galectin-3^+/+ mice, SspB-expressing <i>S. aureus</i> caused larger lesions and resulted in higher bacterial loads than protease-lacking bacteria. No such difference in bacterial load or lesion size was detected in galectin-3^-/- mice, which overall showed smaller lesion sizes than the galectin-3^+/+ animals. In conclusion, the staphylococcal protease SspB inactivates galectin-3, abrogating its stimulation of oxygen radical production in human neutrophils and increasing tissue damage during skin infection.