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

Obesity and associated type 2 diabetes (T2D) are important risk factors for infection following orthopedic implant surgery. , the most common pathogen in bone infections, adapts to multiple environments to survive and evade host immune responses. Whether adaptation of 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 that infection was more severe, including increases in bone abscesses relative to nondiabetic controls. isolated from bone of obese/T2D mice displayed marked upregulation of four adhesion genes (, , , and ), all with binding affinity for fibrin(ogen). Immunostaining of infected bone revealed increased fibrin deposition surrounding bacterial abscesses in obese/T2D mice. coagulation assays demonstrated a hypercoagulable state in obese/T2D mice that was comparable to that of diabetic patients. with an inactivating mutation in clumping factor A () 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), expression and fibrin-encapsulated abscess communities in bone were also increased, further linking fibrin deposition to expression of and infection severity. Together, these results demonstrate an adaptation by to obesity/T2D with increased expression of that is associated with the hypercoagulable state of the host and increased virulence of .