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Obesity and associated type 2 diabetes (T2D) are important risk factors for infection following orthopedic implant surgery.Staphylococcus aureus , the most common pathogen in bone infections, adapts to multiple environments to survive and evade host immune responses. Whether adaptation ofS. aureus to the unique environment of the obese/T2D host accounts for its increased virulence and persistence in this population is unknown. Thus, we assessed implant-associated osteomyelitis in normal versus high-fat-diet obese/T2D mice and found thatS. aureus infection was more severe, including increases in bone abscesses relative to nondiabetic controls.S. aureus isolated from bone of obese/T2D mice displayed marked upregulation of four adhesion genes (clfA ,clfB ,bbp , andsdrC ), all with binding affinity for fibrin(ogen). Immunostaining of infected bone revealed increased fibrin deposition surrounding bacterial abscesses in obese/T2D mice.In vitro coagulation assays demonstrated a hypercoagulable state in obese/T2D mice that was comparable to that of diabetic patients.S. aureus with an inactivating mutation in clumping factor A (clfA ) showed a reduction in bone infection severity that eliminated the effect of obesity/T2D, while infections in control mice were unchanged. In infected mice that overexpress plasminogen activator inhibitor-1 (PAI-1),S. aureus clfA expression and fibrin-encapsulated abscess communities in bone were also increased, further linking fibrin deposition toS. aureus expression ofclfA and infection severity. Together, these results demonstrate an adaptation byS. aureus to obesity/T2D with increased expression ofclfA that is associated with the hypercoagulable state of the host and increased virulence ofS. aureus .

Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence