Induction of protective interferon-β responses in murine osteoblasts following S. aureus infection and the use of nucleic acid nanoparticles to enhance bacterial killing

Abstract Staphylococcus aureus is the primary causative agent of osteomyelitis, a severe inflammatory bone infection. Treatment for osteomyelitis includes long-term antibiotic treatment, surgical debridement of necrotic bone, or even amputation. Treatment is challenging due to an inability of antibiotics to penetrate bone tissue and resident bone cells that harbor intracellular bacteria, and the increased incidence of infections associated with antibiotic-resistant S. aureus strains. Following S. aureus infection, resident bone cells including osteoblasts produce immune mediators and bone regulatory factors. While type I interferons (IFNs) are best known for their antiviral effects, it is becoming apparent that they impact susceptibility to many pathogens. Here, we report elevated IFN-β levels in infected femurs in a mouse model of osteomyelitis. RNA Tag-Seq analysis of S. aureus infected osteoblasts showed elevated expression of mRNA encoding IFN-β and ISGs. We confirmed rapid and robust release of IFN-β protein production by osteoblasts following S. aureus challenge. Furthermore, we showed increased protein expression of ISGs by infected osteoblasts and demonstrate that this occurs secondary to the release of IFN-β by these cells. Importantly, we have determined that exposure of S. aureus-infected osteoblasts to IFN-β markedly reduces the viable bacteria harbored by these cells. Finally, we have demonstrated delivery of immunomodulatory nucleic acid nanoparticle (NANPs) scaffolds using lipid-based carriers to murine osteoblasts. These NANPs are promising agents that could induce protective IFNs during S. aureus infection of bone tissue and be further functionalized with antimicrobials to kill intracellular S. aureus. This work was supported by grant 1R01AI170012-01 to IM and MBJ from the National Institute for Arthritis and Musculoskeletal and Skin Diseases.