MyD88 and IL-1R signaling drive antibacterial immunity and osteoclast-driven bone loss during Staphylococcus aureus osteomyelitis

Abstract

Staphylococcus aureus is able to infect virtually all organ systems and is a frequently isolated etiologic agent of osteomyelitis, a common and debilitating invasive infection of bone. Treatment of osteomyelitis requires invasive surgical procedures and prolonged antibiotic therapy, yet is frequently unsuccessful due to extensive pathogen-induced bone damage that can limit antibiotic penetration and immune cell influx to the infectious focus. We previously established that S . aureus triggers profound alterations in bone remodeling in a murine model of osteomyelitis, in part through the production of osteolytic toxins. However, staphylococcal strains lacking osteolytic toxins still incite significant bone destruction, suggesting that host immune responses are also major drivers of pathologic bone remodeling during osteomyelitis. The objective of this study was to identify host immune pathways that contribute to antibacterial immunity during S . aureus osteomyelitis, and to define how these immune responses alter bone homeostasis and contribute to bone destruction. We specifically focused on the interleukin-1 receptor (IL-1R) and downstream adapter protein MyD88 given the prominent role of this signaling pathway in both antibacterial immunity and osteo-immunologic crosstalk. We discovered that while IL-1R signaling is necessary for local control of bacterial replication during osteomyelitis, it also contributes to bone loss during infection. Mechanistically, we demonstrate that S . aureus enhances osteoclastogenesis of myeloid precursors in vitro , and increases the abundance of osteoclasts residing on bone surfaces in vivo . This enhanced osteoclast abundance translates to trabecular bone loss, and is dependent on intact IL-1R signaling. Collectively, these data define IL-1R signaling as a critical component of the host response to S . aureus osteomyelitis, but also demonstrate that IL-1R-dependent immune responses trigger collateral bone damage through activation of osteoclast-mediated bone resorption.

Impact of Bacterial Infections on Osteogenesis: Evidence From In Vivo Studies

“…The same cytokines that are needed for efficient antibacterial immune responses may also drastically affect the activity of bone cells . It can be reasoned that the inflammatory response in bacterial infection is a double‐edge sword in terms of its opposite effects on osteogenesis.…”

“…In this context, the activation of various pattern recognition receptors (PRRs) in osteomyelitis may be an important shared feature of the different, sometimes paradoxical, cellular responses seen in osteomyelitis. In recent years, it has been shown that PRRs not only play a key role in the antibacterial immune response, but that they also modulate the osteoblastic and osteoclastic responses …”

“…41 The same cytokines that are needed for efficient antibacterial immune responses may also drastically affect the activity of bone cells. 99 It can be reasoned that the inflammatory response in bacterial infection is a double-edge sword in terms of its opposite effects on osteogenesis. On the one hand, a mild inflammatory milieu distant from the infection site may stimulate osteogenesis, 50,100,101 resembling the normal bone healing response after injury.…”

“…In recent years, it has been shown that PRRs not only play a key role in the antibacterial immune response, 106 but that they also modulate the osteoblastic and osteoclastic responses. 49,99 SUMMARY Animal studies collectively show a strong negative association between bacterial infection and bone regeneration. In the long bones, callus formation is impaired and the defect is instead replaced by fibrous tissue formation characteristic of an atrophic nonunion, even in the case of non-critical size defects.…”

Staphylococcus aureus infects osteoclasts and replicates intracellularly

“…Investigation into the role of OCs in OM has focused mainly on determining the effects of S. aureus infection on bone resorption, while neglecting to examine whether OCs could be the target of infection, as well. [17, 18, 19, 20].…”