title: Staphylococcus aureus protein A binding to osteoblast tumour necrosis factor receptor 1 results in activation of nuclear factor kappa B and release of interleukin-6 in bone infection.
abstract: Staphylococcus aureus is the major pathogen among the staphylococci and the most common cause of bone infections. These infections are mainly characterized by bone destruction and inflammation, and are often debilitating and very difficult to treat. Previously we demonstrated that S. aureus protein A (SpA) can bind to osteoblasts, which results in inhibition of osteoblast proliferation and mineralization, apoptosis, and activation of osteoclasts. In this study we used small interfering RNA (siRNA) to demonstrate that osteoblast tumour necrosis factor receptor-1 (TNFR-1) is responsible for the recognition of and binding to SpA. TNFR-1 binding to SpA results in the activation of nuclear factor kappa B (NFκB). In turn, NFκB translocates to the nucleus of the osteoblast, which leads to release of interleukin 6 (IL-6). Silencing TNFR-1 in osteoblasts or disruption of the spa gene in S. aureus prevented both NFκB activation and IL-6 release. As well as playing a key role in proinflammatory reactions, IL-6 is also an important osteotropic factor. Release of IL-6 from osteoblasts results in the activation of the bone-resorbing cells, the osteoclasts. Consistent with our results described above, both silencing TNFR-1 in osteoblasts and disruption of spa in S. aureus prevented osteoclast activation. These studies are the first to demonstrate the importance of the TNFR-1-SpA interaction in bone infection, and may help explain the mechanism through which osteoclasts become overactivated, leading to bone destruction. Anti-inflammatory drug therapy could be used either alone or in conjunction with antibiotics to treat osteomyelitis or for prophylaxis in high-risk patients.
authors.affiliation: Microbial Infection Group, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.
authors.forename: Tânia
authors.initials: T
authors.lastname: Claro
authors.affiliation: Department of Anatomy, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.|Microbial Infection Group, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.
authors.forename: Amro
authors.initials: A
authors.lastname: Widaa
authors.affiliation: Microbial Infection Group, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.
authors.forename: Cormac
authors.initials: C
authors.lastname: McDonnell
authors.affiliation: Department of Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Foster
authors.affiliation: Trinity Centre for Bioengineering, Trinity College Dublin, Dublin 2, Ireland.|Department of Anatomy, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.
authors.forename: Fergal J
authors.initials: FJ
authors.lastname: O'Brien
authors.affiliation: School of Pharmacy, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.|Microbial Infection Group, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Kerrigan
mesh_terms: D000818:Animals; D002460:Cell Line; D054884:Host-Pathogen Interactions; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010006:Osteoblasts / Q000382:microbiology*; D011485:Protein Binding; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D013205:Staphylococcal Protein A / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000472:pathogenicity*
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D013205:Staphylococcal Protein A; C506236:Tnfrsf1a protein, mouse