Plasmin-Mediated Processing of Clumping Factor A Impacts Bacterial Aggregation and Abscess Formation during Staphylococcus aureus Infection

The interface between pathogenic bacteria and the host plays a critical role during the progression of infection. Bacterial surface components, such as the Staphylococcus aureus cell wall-anchored protein clumping factor A (ClfA), interact with host factors. ClfA promotes bacterial aggregation in plasma by binding to fibrinogen. Here, we show that the host serine endopeptidase plasmin cleaves ClfA, disrupting its interaction with fibrinogen and promoting bloodstream survival and virulence in S. aureus. We found that plasmin cleaves ClfA between residues Arg214 and Ala215. Cleavage occurs in human serum regardless of whether plasmin becomes activated by host tissue-plasminogen activator or by the activity of the S. aureus enzyme staphylokinase. Expressing a plasmin-resistant form of ClfA, and a truncated form that mimics the plasmin-cleaved product on the bacterial cell surface, revealed that following cleavage, ClfA cannot mediate aggregation of S. aureus in fibrinogen. Truncated ClfA on the cell surface cannot bind to fibrinogen and promotes the establishment of renal abscesses in vivo. Collectively, our findings suggest that activation of plasmin during infection leads to site-specific processing of ClfA, and this not only abrogates fibrinogen binding but also facilitates enhanced S. aureus persistence in the host. Thus, we demonstrate that proteolytic processing by plasmin is a mechanism for modulating the host-pathogen interaction during infection. Author SummaryStaphylococcus aureus is a major human bacterial pathogen that binds to host factors during infection using its surface adhesins. Here we describe a novel mechanism by which host proteolytic activity modulates bacterial interaction with the plasma protein fibrinogen to influence the course of infection. The surface adhesin clumping factor A (ClfA), binds to fibrinogen, causing bacterial aggregation in the bloodstream. In this study, we show that the host enzyme plasmin cleaves ClfA at a specific site, disrupting its ability to bind fibrinogen. Cleavage eliminates ClfA-mediated aggregation in plasma fibrinogen and enhances S. aureus virulence in vivo, increasing the formation of kidney abscesses. Our work therefore demonstrates that specific protease-mediated processing of bacterial adhesins by host factors can influence the progression of infection.