Differential Inflammasome Regulation in the pathogenesis of S. aureus osteomyelitis

金黄色葡萄球菌骨髓炎发病机制中的差异炎症小体调节

• 批准号: 10493396
• 负责人: JAMES E CASSAT
• 金额: $ 68.67万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493396
• 关键词: Address; Affect; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Architecture; Bacteria; Bone Diseases; Bone Tissue; Cell Differentiation process; Cell Lineage; Cells; Chronic; Clinical; Complex; Data; Disease; Disease Management; Equilibrium; Event; Family member; Genetic; Genus staphylococcus; Goals; Hematogenous; Hematogenous Spread; Homeostasis; Host Defense; Hypoxia; Immune; Immune system; Immunity; Implant; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-1 beta; Knowledge; Lead; Learning; Link; Methods; Microbial Biofilms; Modeling; Multiprotein Complexes; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Osteocytes; Osteomyelitis; Pain; Pathogenesis; Pathologic; Population; Process; Public Health; Refractory; Regulation; Reporter; Resolution; Role; Route; Signal Transduction; Source; Staphylococcal Infections; Staphylococcus aureus; Testing; Tissues; Tumor necrosis factor receptor 11b; Work; antimicrobial; bone; bone cell; bone loss; immune clearance; in vivo; innovation; macrophage; microorganism; monocyte; mouse model; neutrophil; pathogen; response; skeletal; soft tissue; success; tool

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.

抽象的 传染性骨髓炎 (OM) 是一种炎症驱动的骨疾病，最终导致病理性骨髓炎 骨骼结构的改变是多因素的，反映了之间复杂的相互作用。 微生物和宿主细胞金黄色葡萄球菌，一种已经产生抗生素耐药性的病原体， 是细菌引起的 OM 的主要原因，并已被确定为对人类最大的细菌威胁之一 这些感染是痛苦的、使人衰弱的，并且可能会变成慢性病或在感染后数年复发。 病原体破坏骨组织并逃避免疫系统清除的能力。 使用适当的抗生素，对 OM 的治疗造成重大障碍。 宿主抵抗金黄色葡萄球菌感染的防御是先天免疫，主要是成熟的骨髓谱系细胞，例如 中性粒细胞和巨噬细胞；这种病原体的成功取决于其逃避和利用这些细胞的能力 虽然人们对骨髓细胞和金黄色葡萄球菌之间的相互作用了解很多，但相对较少。 该工作特别关注骨感染。这种微环境具有独特的特征，包括 相对缺氧、丰富的未成熟骨髓细胞以及独特的骨细胞——破骨细胞（OC）的存在， 成骨细胞和骨细胞 - 与细菌和先天免疫细胞相互作用。此外，该途径 感染 - 通过损伤或直接软组织延伸、手术植入或血行传播 - 可以 显着改变细菌和骨骼之间的相互作用，尤其是在感染的早期阶段。 OC 与单核细胞前体细胞分化，提供未成熟骨髓谱系细胞之间的内在联系 该应用的总体目标是了解宿主与病原体的相互作用。 骨的 OC 和中性粒细胞谱系细胞与金黄色葡萄球菌之间的建立、进展和 我们的初步研究强烈表明白介素 1 (IL-1) 信号轴是 OM 的驱动因素。 OM 期间的抗菌免疫和病理性骨骼变化，例如金黄色葡萄球菌感染后， IL-1 家族成员（包括 IL-1β）通常是通过多蛋白复合物的激活产生的 然而，人们对炎症小体在 OM 发病机制中的作用知之甚少。 我们发现，与其未承诺的前体相比，OCs 的炎性体激活较低，并且 我们已经捕获了炎性体活性的差异。 骨中存在的骨髓谱系细胞影响 OM 的发病机制，金黄色葡萄球菌利用这些细胞 具有较弱的炎症体和抗菌反应作为增殖生态位，同时导致宿主细胞具有 过度炎症反应导致组织损伤 目标 1：确定宿主和病原体的决定因素。 OM 中 OC 谱系的炎症小体激活 目标 2：定义炎症小体的机制和影响。 通过检查和操纵宿主病原体，金黄色葡萄球菌激活中性粒细胞谱系。 特定骨髓细胞群中的相互作用，我们将学习如何使平衡朝着 OM 的解决方向倾斜。