Differential Inflammasome Regulation in the pathogenesis of S. aureus osteomyelitis

摘要 感染性骨髓炎（OM）是一种炎症驱动的骨疾病，其最终表现为病理性骨髓炎。 骨骼结构的改变骨感染是多因素的，并反映了一个复杂的相互作用， 微生物和宿主细胞。葡萄球菌（S.）金黄色葡萄球菌，一种已经产生抗生素耐药性的病原体， 是细菌引起OM的主要原因，已被确定为对人类最大的细菌威胁之一。 全球公共卫生。这些感染是痛苦的，使人衰弱的，并且可以成为慢性或在治疗后数年复发。 初始事件。病原体破坏骨组织和逃避免疫系统清除的能力， 与适当的抗生素一起使用，对OM的治疗造成了重大障碍。第一个也是最关键的水平， 宿主对S.金黄色葡萄球菌是先天免疫，主要是成熟的骨髓谱系细胞，如 嗜中性粒细胞和巨噬细胞;这种病原体的成功取决于它逃避和利用这些细胞的能力。 应答虽然已经了解了很多关于骨髓细胞和S。金黄色葡萄球菌，相对较少 工作特别集中在骨感染上。这种微环境具有独特的功能，包括 相对缺氧，大量未成熟的骨髓细胞，以及存在独特的骨细胞-破骨细胞（OC）， 成骨细胞和骨细胞，它们与细菌和先天免疫细胞相互作用。此外，路线 感染-通过损伤或直接软组织延伸，外科植入物或血源性传播-可以 显著改变细菌和骨之间的相互作用，特别是在感染的早期阶段。值得注意的是， OC从单核细胞前体分化，提供未成熟髓系细胞之间的内在联系 和骨内稳态。本应用程序的总体目标是了解宿主-病原体相互作用 骨OC和中性粒细胞系细胞与S.金黄色葡萄球菌在建立，进展， OM的分辨率。我们的初步研究强烈暗示白细胞介素-1（IL-1）信号轴作为一个驱动因素， 抗菌免疫和病理性骨变化在OM。感染后，如S。金黄色， 包括IL-1β在内的IL-1家族成员是通过激活多蛋白复合物而产生的 称为炎性小体。然而，关于炎性小体在OM发病机制中的作用知之甚少。 我们已经发现，与它们未定型的前体相比，OC具有较低的炎性小体激活， 允许细胞内S.金黄色葡萄球菌增殖。我们假设炎性小体活性的差异 骨中存在的髓系细胞影响OM的发病机制，S.金黄色葡萄球菌利用这些细胞 较弱的炎性小体和抗菌反应作为增殖小生境，同时导致宿主细胞具有 过度的炎症反应导致组织损伤。目标1：确定感染的宿主和病原体决定因素 OM中OC谱系中的炎性小体活化。目的2：明确炎性小体的机制和影响 嗜中性粒细胞系中的S.金黄色葡萄球菌通过检查和操纵宿主病原体 通过研究特定骨髓细胞群体中的相互作用，我们将学习如何使平衡向OM的解决倾斜。

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.