PMID- 28320836 OWN - NLM STAT- MEDLINE DCOM- 20170731 LR - 20190610 IS - 1098-5522 (Electronic) IS - 0019-9567 (Print) IS - 0019-9567 (Linking) VI - 85 IP - 6 DP - 2017 Jun TI - Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence. LID - 10.1128/IAI.01005-16 [doi] LID - e01005-16 AB - 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. aureusclfA expression and fibrin-encapsulated abscess communities in bone were also increased, further linking fibrin deposition to S. aureus expression of clfA and infection severity. Together, these results demonstrate an adaptation by S. aureus to obesity/T2D with increased expression of clfA that is associated with the hypercoagulable state of the host and increased virulence of S. aureus. CI - Copyright (c) 2017 American Society for Microbiology. FAU - Farnsworth, Christopher W AU - Farnsworth CW AD - Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA. AD - Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA. FAU - Schott, Eric M AU - Schott EM AD - Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA. AD - Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA. FAU - Jensen, Sarah E AU - Jensen SE AD - Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA. AD - Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA. FAU - Zukoski, Jacob AU - Zukoski J AD - Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA. AD - Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA. FAU - Benvie, Abigail M AU - Benvie AM AD - Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA. FAU - Refaai, Majed A AU - Refaai MA AD - Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA. FAU - Kates, Stephen L AU - Kates SL AD - Department of Orthopaedic Surgery, Virginia Commonwealth University, Richmond, Virginia, USA. FAU - Schwarz, Edward M AU - Schwarz EM AD - Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA. FAU - Zuscik, Michael J AU - Zuscik MJ AD - Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA. FAU - Gill, Steven R AU - Gill SR AD - Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA. FAU - Mooney, Robert A AU - Mooney RA AD - Department of Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, USA robert_mooney@urmc.rochester.edu. AD - Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA. LA - eng GR - P30 AR069655/AR/NIAMS NIH HHS/United States GR - T32 AR053459/AR/NIAMS NIH HHS/United States GR - TL1 TR000096/TR/NCATS NIH HHS/United States GR - UL1 TR002001/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20170523 PL - United States TA - Infect Immun JT - Infection and immunity JID - 0246127 RN - 0 (Antibodies, Bacterial) RN - 0 (ClfA protein, Staphylococcus aureus) RN - 0 (Coagulase) RN - 9001-32-5 (Fibrinogen) SB - IM MH - Abscess/pathology MH - Animals MH - Antibodies, Bacterial/genetics/metabolism MH - Coagulase/genetics/*metabolism MH - Diabetes Mellitus, Type 2/*complications/microbiology MH - Disease Models, Animal MH - Fibrinogen/metabolism MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Obesity/*complications/microbiology MH - Osteomyelitis/microbiology/*pathology MH - Sequence Analysis, RNA MH - Staphylococcal Infections/*microbiology MH - Transcriptional Activation MH - Up-Regulation MH - Virulence PMC - PMC5442639 OTO - NOTNLM OT - Staphylococcus aureus OT - clumping factor A OT - fibrinogen OT - obesity OT - osteomyelitis OT - type 2 diabetes EDAT- 2017/03/23 06:00 MHDA- 2017/08/02 06:00 PMCR- 2017/11/23 CRDT- 2017/03/22 06:00 PHST- 2016/12/06 00:00 [received] PHST- 2017/03/09 00:00 [accepted] PHST- 2017/03/23 06:00 [pubmed] PHST- 2017/08/02 06:00 [medline] PHST- 2017/03/22 06:00 [entrez] PHST- 2017/11/23 00:00 [pmc-release] AID - IAI.01005-16 [pii] AID - 01005-16 [pii] AID - 10.1128/IAI.01005-16 [doi] PST - epublish SO - Infect Immun. 2017 May 23;85(6):e01005-16. doi: 10.1128/IAI.01005-16. Print 2017 Jun.