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

作者：Christopher W Farnsworth, Eric M. Schott, Sarah E. Jensen, Jacob Zukoski, Abigail M. Benvie, Majed A. Refaai, Stephen L. Kates, Edward M. Schwarz, Michael J. Zuscik, Steven R. Gill, Robert A. Mooney · 发表于：Infection and Immunity · 年份：2017 · DOI：10.1128/iai.01005-16 · 被引用次数：53 · 研究领域：Antimicrobial Resistance in Staphylococcus、Streptococcal Infections and Treatments、Infective Endocarditis Diagnosis and Management

ABSTRACT 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 of S. 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 that S. 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 , and sdrC ), 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...