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.Staphylococcus aureus, the most common pathogen in bone infections, adapts to multiple environments to survive and evade host immune responses. Whether adaptation ofS. aureusto 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. aureusinfection was more severe, including increases in bone abscesses relative to nondiabetic controls.S. aureusisolated 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 vitrocoagulation assays demonstrated a hypercoagulable state in obese/T2D mice that was comparable to that of diabetic patients.S. aureuswith 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. aureusclfAexpression and fibrin-encapsulated abscess communities in bone were also increased, further linking fibrin deposition toS. aureusexpression ofclfAand infection severity. Together, these results demonstrate an adaptation byS. aureusto obesity/T2D with increased expression ofclfAthat is associated with the hypercoagulable state of the host and increased virulence ofS. aureus.
Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA.|Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA.
Christopher W
CW
Farnsworth
Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA.|Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA.
Eric M
EM
Schott
Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA.|Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA.
Sarah E
SE
Jensen
Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA.|Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA.
Jacob
J
Zukoski
Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA.
Abigail M
AM
Benvie
Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA.
Majed A
MA
Refaai
Department of Orthopaedic Surgery, Virginia Commonwealth University, Richmond, Virginia, USA.
Stephen L
SL
Kates
Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA.
Edward M
EM
Schwarz
Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA.
Michael J
MJ
Zuscik
Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA.
Steven R
SR
Gill
Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA robert_mooney@urmc.rochester.edu.|Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA.
Robert A
RA
Mooney
D000038:Abscess / Q000473:pathology; D000818:Animals; D000907:Antibodies, Bacterial / Q000235:genetics / Q000378:metabolism; D003030:Coagulase / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000382:microbiology; D004195:Disease Models, Animal; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000382:microbiology; D010019:Osteomyelitis / Q000382:microbiology / Q000473:pathology*; D017423:Sequence Analysis, RNA; D013203:Staphylococcal Infections / Q000382:microbiology*; D015533:Transcriptional Activation; D015854:Up-Regulation; D014774:Virulence
D000907:Antibodies, Bacterial; C515944:ClfA protein, Staphylococcus aureus; D003030:Coagulase; D005340:Fibrinogen
Staphylococcus aureus; clumping factor A; fibrinogen; obesity; osteomyelitis; type 2 diabetes