Differential Inflammasome Regulation in the pathogenesis of S. aureus osteomyelitis

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Abstract Infectious osteomyelitis (OM) is an inflammation-driven disease of bone that culminates in pathological alterations in skeletal architecture. Bone infections are multifactorial and reflect a complex interaction between microorganisms and host cells. Staphylococcus (S.) aureus, a pathogen that has developed antibiotic resistance, is the leading cause of bacterial-induced OM and has been identified as one of the greatest bacterial threats to global public health. These infections are painful, debilitating and can become chronic or recur years after the initial event. The pathogen’s ability to damage bone tissue and evade clearance by the immune system, even with appropriate antibiotics, impose significant obstacles to treatment of OM. The first and most critical level of host defense against infection by S. aureus is innate immunity, primarily mature myeloid lineage cells such as neutrophils and macrophages; the success of this pathogen is dependent on its ability to evade and exploit these responses. While much has been learned about interactions between myeloid cells and S. aureus, relatively little work has specifically focused on infections of bone. This microenvironment presents unique features, including relative hypoxia, abundant immature myeloid cells, and the presence of unique bone cells – osteoclasts (OCs), osteoblasts, and osteocytes - that interact with both the bacteria and innate immune cells. Furthermore, the route of infection - via injury or direct soft tissue extension, surgical implants, or hematogenously spread – can significantly alter the interactions between bacteria and bone, especially during early stages of infection. Notably, OCs differentiate from monocytic precursors, providing an inherent link between immature myeloid lineage cells and bone homeostasis. The overall goal of this application is to understand the host-pathogen interactions between the bone’s OC and neutrophil lineage cells and S. aureus during the establishment, progression, and resolution of OM. Our preliminary studies strongly implicate the interleukin-1 (IL-1) signaling axis as a driver of both antibacterial immunity and pathologic bone changes during OM. Following infections such as with S. aureus, IL-1 family members including IL-1β are canonically generated through the activation of multi-protein complexes known as inflammasomes. However, little is known about the role of inflammasomes in the pathogenesis of OM. We have found that, compared to their uncommitted precursors, OCs have lower inflammasome activation and are permissive of intracellular S. aureus proliferation. We hypothesize that differences in inflammasome activity within myeloid lineage cells present in bone affect the pathogenesis of OM, with S. aureus exploiting those cells with weaker inflammasome and antimicrobial responses as a proliferative niche while leading host cells with an excessive inflammatory response to cause tissue damage. Aim 1: Define host and pathogen determinants of inflammasome activation in the OC lineage in OM. Aim 2: Define the mechanisms and impact of inflammasome activation in the neutrophil lineage by S. aureus in OM. By examining and manipulating the host-pathogen interactions in specific myeloid cell populations, we will learn how to tip the balance towards resolution of OM.