Thursday, May 9, 2024
5/9/2024
PROJECT SUMMARY Bone disorders such as osteomyelitis that result from bacterial infection are associated with severe inflammation and progressive bone loss. Staphylococcus aureus is the most common causative agent of osteomyelitis and the incidence and severity of staphylococcal osteomyelitis appears to be increasing despite improvements in prophylaxis and diagnosis. Dysregulation of osteoclast formation and activity results in bone destruction and/or abnormal bone remodeling at sites of infection, and osteoblasts play an essential role in the regulation of these bone-resorbing cells. In addition, bacterially infected osteoblasts and osteoclasts are capable of producing an array of immune mediators that could promote the recruitment and activation of inflammatory leukocytes in bone tissue. While type I interferons, such as IFN-a and IFN-b, are best known for their antiviral effects, it is becoming increasingly apparent that they can impact susceptibility to bacterial pathogens including S. aureus. Furthermore, IFN-a and IFN-b have been shown to affect bone homeostasis and are potent inhibitors of osteoclastogenesis. We have intriguing preliminary data indicating that osteoblasts express IFN-b, select IFN-stimulated genes, and key intracellular mediators of interferon effects, in response to S. aureus infection. In this R03 pilot project, we will begin to test the hypothesis that S. aureus infected bone cells are a significant source of type I interferons and that such production serves to limit the intracellular bacterial burden and/ or pro-osteoclastogenic responses associated with conditions such as osteomyelitis. We will characterize the type I interferon responses of isolated bone cells to S. aureus infection and perform an initial determination of the effects of IFN-a and IFN-b on bacterial burden and bone cell formation and function in S. aureus-infected osteoblasts and osteoclasts. These studies will provide critical preliminary data for future studies to fully define the role played by type I interferons in such infections for which R01 mechanism support will be sought.
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