Host-derived protease promotes aggregation ofStaphylococcus aureusby cleaving the surface protein SasG

AbstractStaphylococcus aureusis one of the leading causes of hospital acquired infections, many of which begin following attachment and accumulation on indwelling medical devices or diseased tissue. These infections are often linked to establishment of biofilms, but another often overlooked key characteristic allowingS. aureusto establish persistent infection is formation of planktonic aggregates. Such aggregates are physiologically similar to biofilms and protect pathogen from innate immune clearance and increase its antibiotic tolerance. The cell wall-associated protein SasG has been implicated in biofilm formation via mechanisms of intercellular aggregation, but the mechanism in the context of disease is largely unknown. We have previously shown that expression of cell wall-anchored proteins involved in biofilm formation is controlled by the ArlRS-MgrA regulatory cascade. In this work, we demonstrate that the ArlRS two-component system controls aggregation, by repressing expression ofsasGby activation of the global regulator MgrA. We also demonstrate that SasG must be proteolytically processed by a non-native protease to induce aggregation, and that strains expressing functional full-lengthsasGaggregate significantly upon proteolysis by a mucosal-derived host protease found in human saliva. We used fractionation and N-terminal sequencing to demonstrate that human trypsin within saliva cleaves within the A domain of SasG to expose the B domain and induce aggregation. Finally, we demonstrated that SasG is involved in virulence during mouse lung infection. Together, our data point to SasG, its processing by host proteases, and SasG-driven aggregation as important elements ofS. aureusadaptation to host environment.