A Novel Mouse Model of Staphylococcus aureus Chronic Osteomyelitis That Closely Mimics the Human Infection

Abstract

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.

CD11chighCD8+ Regulatory T Cell Feedback Inhibits CD4 T Cell Immune Response via Fas Ligand–Fas Pathway

“…These data revealed that CD11c + T cells are restricted to L. monocytogenes infection, we created the murine model of metastatic chronic osteomyelitis initiated after i.v. inoculation of S. aureus microorganism, which mimics human osteomyelitis caused by S. aureus (31). We found that S. aureus infection also induced CD11c high CD8 + T cells that appeared on day 20 after infection and disappeared on day 30 ( Fig.…”

“…For infection, aliquots were thawed and appropriately diluted in PBS, and 1 3 10 6 bacteria were injected in a volume of 150 ml PBS into the lateral tail veins of mice as described previously (31).…”

Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

“…When animals were infected with a fully virulent organism with a wild-type phenotype and developed a septic stage, the bac-teria disseminated to various organs. In particular, in bone tissue, bacterial persistence was observed for up to 2 months and was accompanied by a high rate of SCV formation (142). Antibiotic treatment with different compounds was always less effective in the chronic than in the acute stage of the infection (33).…”

A Major Role for Myeloid-Derived Suppressor Cells and a Minor Role for Regulatory T Cells in Immunosuppression during Staphylococcus aureus Infection

“…For this purpose, we used an exper-imental model of chronic osteomyelitis (bone infection) that closely resembles the pathological features of the chronic human disease (34). In this experimental infection model, osteomyelitis is established after i.v.…”