title: Monitoring immune responses in a mouse model of fracture fixation with and without Staphylococcus aureus osteomyelitis.
abstract: Post-traumatic bone fractures are commonly fixed with implanted devices to restore the anatomical position of bone fragments and aid in the healing process. Bacterial infection in this situation is a challenge for clinicians due to the need for aggressive antibiotic therapy, debridement of infected tissues, and the need to maintain fracture stability. The aim of this study was to monitor immune responses that occur during healing and during Staphylococcus aureus infection, in a clinically relevant murine model of fracture fixation. Skeletally mature C57bl/6 mice received a transverse osteotomy of the femur, which was treated with commercially available titanium fracture fixation plates and screws. In the absence of infection, healing of the fracture was complete within 35days and was characterized by elevated Interleukin (IL)-4 and Interferon-gamma secretion from bone-derived cells and expression of these same genes. In contrast, mice inoculated with S. aureus could not heal the fracture within the observation period and were found to develop typical signs of implant-associated bone infection, including biofilm formation on the implant and osteolysis of surrounding bone. The immune response to infection was characterized by a TH17-led bone response, and a pro-inflammatory cytokine-led Tumor necrosis factor (TNF)-α, Interleukin (IL)-1β) soft tissue response, both of which were ineffectual in clearing implant related bone and soft tissue infections respectively. In this murine model, we characterize the kinetics of pro-inflammatory responses to infection, secondary to bone trauma and surgery. A divergent local immune polarization is evident in the infected versus non-infected animals, with the immune response ultimately unable to clear the S. aureus infection.
authors.affiliation: AO Research Institute Davos, Switzerland.
authors.forename: Edward T J
authors.initials: ETJ
authors.lastname: Rochford
authors.affiliation: AO Research Institute Davos, Switzerland; Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
authors.forename: Marina
authors.initials: M
authors.lastname: Sabaté Brescó
authors.affiliation: AO Research Institute Davos, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zeiter
authors.affiliation: AO Research Institute Davos, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kluge
authors.affiliation: AO Research Institute Davos, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Poulsson
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Ziegler
authors.affiliation: AO Research Institute Davos, Switzerland.
authors.forename: R Geoff
authors.initials: RG
authors.lastname: Richards
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
authors.forename: Liam
authors.initials: L
authors.lastname: O'Mahony
authors.affiliation: AO Research Institute Davos, Switzerland. Electronic address: fintan.moriarty@aofoundation.org.
authors.forename: T Fintan
authors.initials: TF
authors.lastname: Moriarty
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D002452:Cell Count; D002469:Cell Separation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005592:Fracture Fixation; D017102:Fracture Healing; D005786:Gene Expression Regulation; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D015166:Monitoring, Immunologic; D010019:Osteomyelitis / Q000150:complications / Q000000981:diagnostic imaging / Q000276:immunology* / Q000382:microbiology*; D010027:Osteotomy; D011859:Radiography; D060888:Real-Time Polymerase Chain Reaction; D013203:Staphylococcal Infections / Q000150:complications / Q000000981:diagnostic imaging / Q000276:immunology* / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000502:physiology*
chemical_list: D016207:Cytokines
keywords: Biofilm; Fracture; Host responses; Implant associated infections; Osteomyelitis; Osteosynthesis; Pathogenesis; S. aureus; Trauma