A rat model of Staphylococcus aureus chronic osteomyelitis that provides a suitable system for studying the human infection (original) (raw)
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The American Journal of Pathology, 2012
Osteomyelitis is a serious bone infection typically caused by Staphylococcus aureus. The pathogenesis of osteomyelitis remains poorly understood, mainly for lack of experimental models that closely mimic human disease. We describe a novel murine model of metastatic chronic osteomyelitis initiated after intravenous inoculation of S. aureus microorganisms. The bacteria entered bones through the bloodstream and, after an acute phase with progressive growth (first 2 weeks after infection), they remained at constant numbers for up to 56 days (chronic phase). Clinical signs of illness and systemic inflammation were apparent only during the acute phase. Bone destruction and remodeling processes were readily detectable by magnetic resonance and X-ray imaging 3 weeks after infection, and high levels of bone deformation were observed during the chronic phase. Histological examination of infected bones demonstrated suppurative inflammation with foci of intense bacterial multiplication and necrosis during acute infection and osteoclastic resorption accompanied by new woven bone formation during chronic infection. Transmission electron microscopy revealed S. aureus microorganisms forming microcolonies within the nonmineralized collagen matrix or located intracellularly within neutrophils. In summary, our mouse model of staphylococcal hematogenous osteomyelitis precisely reproduces most features of the human disease. Although the extent of lesions in the chronic phase was subject to variation, this model is ideal for testing and monitoring novel treatment modalities via noninvasive imaging. (Am J Pathol 2012, 181:1206-1214; http://dx.
Staphylococcus aureus vs. Osteoblast: Relationship and Consequences in Osteomyelitis
Frontiers in Cellular and Infection Microbiology, 2015
Bone cells, namely osteoblasts and osteoclasts work in concert and are responsible for bone extracellular matrix formation and resorption. This homeostasis is, in part, altered during infections by Staphylococcus aureus through the induction of various responses from the osteoblasts. This includes the overproduction of chemokines, cytokines and growth factors, thus suggesting a role for these cells in both innate and adaptive immunity. S. aureus decreases the activity and viability of osteoblasts, by induction of apoptosis-dependent and independent mechanisms. The tight relationship between osteoclasts and osteoblasts is also modulated by S. aureus infection. The present review provides a survey of the relevant literature discussing the important aspects of S. aureus and osteoblast interaction as well as the ability for antimicrobial peptides to kill intra-osteoblastic S. aureus, hence emphasizing the necessity for new anti-infectious therapeutics.
A comprehensive review of bacterial osteomyelitis with emphasis on Staphylococcus aureus
Microbial Pathogenesis, 2020
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Letters in Applied Microbiology
To assess the impact of antibiotic therapy on severe osseous infections, animal models of chronic bacterial infections have been developed; however, these models suffer from many experimental limitations. The aim of this work was to develop a new model system in which high levels of bacteria are obtained within femoral bone marrow and bone tissue, and such infections are maintained for at least 14 days. Experimental osteomyelitis was induced in 25 New Zealand white rabbits. A 10(9) CFU ml(-1) suspension of methicillin-resistant Staphylococcus aureus was injected into the knee after bone trepanation. On day 3, surgical debridement was performed to mimic a surgical procedure. Animals were euthanized 1, 2, 3, 9 and 14 days post-inoculation to determine the bacterial counts in marrow and bone, and to evaluate the stability of the infection. Inoculated lesions also were assessed for changes in histological parameters on days 3 and 7 post-inoculation. At days 1, 2, 3, 9 and 14 post-inocul...
A Human Osteocyte Cell Line Model for Studying Staphylococcus aureus Persistence in Osteomyelitis
Frontiers in Cellular and Infection Microbiology, 2021
Infectious osteomyelitis associated with periprosthetic joint infections is often recalcitrant to treatment and has a high rate of recurrence. In the case of Staphylococcus aureus, the most common pathogen in all forms of osteomyelitis, this may be attributed in part to residual intracellular infection of host cells, yet this is not generally considered in the treatment strategy. Osteocytes represent a unique cell type in this context due to their abundance, their formation of a syncytium throughout the bone that could facilitate bacterial spread and their relative inaccessibility to professional immune cells. As such, there is potential value in studying the host-pathogen interactions in the context of this cell type in a replicable and scalable in vitro model. Here, we examined the utility of the human osteosarcoma cell line SaOS2 differentiated to an osteocyte-like stage (SaOS2-OY) as an intracellular infection model for S. aureus. We demonstrate that S. aureus is capable of gene...
A Model for Chronic Osteomyelitis Using Staphylococcus aureus in Goats
Clinical Orthopaedics and Related Research, 2005
The institution where the authors performed this study received funding from the Medical Material and Research Command, Ft. Detrick, MD; each author certifies that they have no commercial associations, equity interest, patent/licensing, or arrangements that might pose a conflict of interest in connection with the submitted article. Each author certifies that the institution where the study was conducted approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.
Staphylococcus aureus infects osteoclasts and replicates intracellularly
2019
Osteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. The majority of OM is caused by Staphylococcus aureus, and even with proper treatment, OM has a high rate of recurrence and chronicity. While S. aureus has been shown to infect osteoblasts, persist intracellularly, and promote the release of pro-osteoclastogenic cytokines, it remains unclear whether osteoclasts (OCs) are also a target of intracellular infection. In this study, we examined the interaction between S. aureus and OCs, demonstrating internalization of GFP-labeled bacteria by confocal microscopy, both in vitro and in vivo. Utilizing an intracellular survival assay and flow cytometry during OC differentiation from bone marrow macrophages (BMMs), we found that the intracellular burden of S. aureus increases after initial infection in cells with at least 2 days of exposure to the osteoclastogenic cytokine receptor activator of nu...
Staphylococcus aureus capsular material promotes osteoclast formation
Injury, 2006
1 Osteomyelitis, which is most frequently due to infection by Staphylococcus aureus, commonly causes bone destruction. S. aureus is known to secrete a number of surface-associated proteins that are potent stimulators of bone resorption. The precise cellular and humoral mechanisms that mediate this stimulatory effect are uncertain. In this study, we have determined whether osteoclast formation and resorption is directly promoted by surface-associated proteins. Surface-associated material (SAM) obtained from a 24-hour culture of S. aureus was added to cultures of mouse and human monocytes. Human monocyte cultures were incubated in the presence and absence of a soluble receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony stimulating factor (M-CSF). In cultures where M-CSF, RANKL, and SAM were added together, osteoclast formation did not exceed that seen in cultures with M-CSF and RANKL. In keeping with this finding, SAM did not increase osteoclast formation and resorption when mouse monocytes were cocultured with RANKL-expressing osteoblasts. In the absence of RANKL, however, SAM was capable of inducing osteoclast formation in cultures of human monocytes. This finding was evidenced by the generation of vitronectin receptor and tartrate-resistant acid phosphatasepositive multinucleated cells that were capable of lacunar resorption. Inhibitors of RANKL-dependent (RANK:Fc, OPG) and RANKL-independent (anti-TNF-α, gp130, IL-8, TGF-β) osteoclast formation did not inhibit SAM-induced osteoclast formation. SAM did not stimulate mature osteoclast resorption activity. These findings indicate that RANKL, which is present in the circulation as a soluble factor, does not play a role in osteoclast formation in the presence of S. aureus SAM and that S. aureus SAM contains a soluble factor that promotes osteoclast formation by a RANKL-independent mechanism.
Mechanisms of Internalization of Staphylococcus aureus by Cultured Human Osteoblasts
1999
Staphylococcus aureus is an important bone pathogen, and evidence shows that this organism is internalized by chick osteoblasts. Here we report that S. aureus is internalized by human osteoblasts. Internalization was inhibited by monodansylcadaverine and cytochalasin D and to a lesser extent by ouabain, monensin, colchicine, and nocodazole. We propose that internalization occurs via a receptor-mediated pathway, requiring the participation of cytoskeletal elements, principally actin.