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.
Highlights
Osteomyelitis, or inflammation of bone, is most commonly caused by invasive bacterial infection [1]
Alterations in bone remodeling that occur during S. aureus osteomyelitis are multifaceted, driven by bacterial toxins and inflammationmediated changes
Our findings reveal that while MyD88 and IL-1R signaling are necessary for antibacterial responses in bone, they contribute to S. aureusstimulated osteoclastogenesis and host-mediated bone loss during osteomyelitis
Summary
Osteomyelitis, or inflammation of bone, is most commonly caused by invasive bacterial infection [1]. S. aureus is the most frequently isolated etiologic agent of both acute and chronic bacterial osteomyelitis [2, 3]. Bone represents a unique niche for invading bacterial pathogens as it is constantly undergoing turnover by bone-forming osteoblasts and boneresorbing osteoclasts. Bone represents a distinctive immunological niche, as bone marrow houses hematopoietic stem cells that give rise to lymphocytes and myeloid cells [5]. Bone infections rarely resolve without medical intervention, and are difficult to treat due to the widespread antimicrobial resistance of S. aureus as well as induction of bone damage that effectively limits antibiotic delivery and immune cell influx [2, 3]
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