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.

Author summary

Osteomyelitis is a common, debilitating infection of bone that rarely resolves without prolonged antibiotics and invasive surgical procedures. This study explores the role of host inflammation during osteomyelitis. Our findings highlight innate immune responses that are critical for control of S. aureus burdens in bone, prevention of bacterial dissemination, and death. Conversely, these same immune pathways were found to contribute to disease pathogenesis by activating infection-associated bone loss. Such bone loss is associated with detrimental outcomes during osteomyelitis, including pathologic fractures and irreversible changes in bone growth plates. Alterations in bone remodeling that occur during S. aureus osteomyelitis are multifaceted, driven by bacterial toxins and inflammation-mediated changes. We found that inflammation incited by S. aureus in bone contributes to pathologic bone loss. We highlight a mechanism by which S. aureus stimulates formation of bone-resorbing osteoclasts both in vitro and in vivo. Our data illustrate connections between innate immune signaling pathways and bone homeostasis. These connections may be relevant to other autoinflammatory bone and joint conditions characterized by bone loss, such as rheumatoid arthritis. Collectively, this work outlines the fine balance between promotion of bacterial clearance and protection from collateral tissue damage.