The Staphylococcus aureus Host Cell Genetic Adhesion Network

Adhesion of Staphylococcus aureus to the host’s skin and mucosae enables asymptomatic colonization and the establishment of infections. This process is facilitated by cell wall-anchored (CWA) adhesins that are covalently attached to the bacterial cell wall and exhibit affinity for host ligands. To gain insight into the cellular factors contributing to adhesion, we developed a sensitive and robust assay to enable the large-scale profiling of S. aureus adhesion to host ligands. Using this assay, we profiled a sequence defined transposon mutant library of the community-associated methicillin-resistant S. aureus (CA-MRSA) isolate USA300, to identify mutant strains with attenuated adhesion to human derived keratin, fibronectin and fibrinogen. Overall, we identified 21 adhesion defective mutants and we used this information to construct ‘The S. aureus Genetic Adhesion Network’. Importantly, we identified a core gene set involved in adhesion to all three host ligands and we delineated unique genetic signatures. In addition, we demonstrate a central requirement for autolysin-mediated daughter cell separation in S. aureus CWA protein-mediated adhesion to host ligands, which contributes to virulence in murine skin and soft tissue infection. This comprehensive study will inform strategies to inhibit S. aureus host cell adhesion, potentially enabling the development of anti-adhesive therapeutics to complement traditional antibacterial chemotherapy.