| dc.description.abstract | Inflammation of bone, or osteomyelitis, is most commonly caused by infection with the Gram-positive bacterium Staphylococcus aureus. During S. aureus osteomyelitis, the homeostasis-maintaining activities of bone cells are perturbed, resulting in aberrant bone formation and net bone loss. Pathologic changes to bone homeostasis contribute to treatment challenges and increase the risk of complications, including pathologic fracture. Bone-resorbing osteoclasts are implicated as major drivers of dysregulated bone homeostasis during osteomyelitis. This dissertation focuses on how inflammation generated by the host response to S. aureus causes bone damage by perturbing osteoclast differentiation (osteoclastogenesis) and function. The immune response to S. aureus is facilitated by receptors that detect bacterial components. This includes pathogen-sensing by Toll-like receptors (TLRs) and activation of the inflammasome, which cleaves the pro-inflammatory cytokine interleukin-1β (IL-1β) into its active form. In this dissertation, I define the roles of TLR2 and TLR9, which sense bacterial lipoproteins and CpG-DNA, respectively, in promoting host bacterial burden control and dysregulation of bone homeostasis during osteomyelitis. I also explore how IL-1β activation by the inflammasome influences bacterial burden control and bone damage during osteomyelitis. My results show that while TLR2 and TLR9 promote osteoclastogenesis in response to S. aureus supernatant and live infection in vitro, these receptors do not significantly alter bacterial burden control or bone homeostasis during S. aureus osteomyelitis in vivo. Moreover, studies of IL-1β activating pathways show this cytokine is a driver of osteoclast-associated bone loss during S. aureus osteomyelitis. Cell culture experiments further reveal that osteoclasts can activate the inflammasome to generate mature IL-1β, highlighting the inflammatory potential of this cell population. However, inflammasome activation may not occur in osteoclasts during osteomyelitis, as IL-1β release does not readily occur when these cells are infected with S. aureus. Thus, the findings presented in this dissertation show that redundancy in innate immune pathways promotes bacterial burden control and inflammation-mediated bone destruction in S. aureus osteomyelitis even when TLR2 and TLR9 are absent. This work supports greater study of pathways leading to IL-1β-activation during osteomyelitis with continued consideration for the potential role of the osteoclast inflammasome in inflammatory bone loss. | |
