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）是一种炎症疾病的骨骼，最终导致病理学 骨骼建筑的改变。骨感染是多因素的，反映了复杂的相互作用 微生物和宿主细胞。葡萄球菌（S.）金黄色葡萄球菌，一种已经发展出抗生素耐药性的病原体 是细菌引起的OM的主要原因，已被确定为最大的细菌威胁之一 全球公共卫生。这些感染是痛苦的，令人衰弱的，并且可能会在 初始事件。病原体损害骨组织和逃避免疫系统的能力，甚至 使用适当的抗生素，对OM的治疗施加了重大障碍。第一个也是最关键的水平 金黄色葡萄球菌的宿主防御感染是先天免疫，主要成熟的髓样谱系细胞，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病原体的能力 回答。尽管已经了解了髓样细胞与金黄色葡萄球菌之间的相互作用的知识，但相对较少 工作专门针对骨骼感染。这种微环境提出了独特的功能，包括 相对缺氧，丰富的未成熟髓样细胞以及独特的骨细胞的存在 - 破骨细胞（OCS）， 成骨细胞和骨细胞 - 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，手术叉或血源性传播 - 可以 特别是改变细菌与骨骼之间的相互作用，尤其是在感染的早期。尤其， OC与单核细胞前体区分开，提供了未成熟的髓样谱系细胞之间的固有联系 和骨体内平衡。该应用程序的总体目标是了解宿主病原体的相互作用 在建立，进展和 OM的解决方案。我们的初步研究强烈暗示白介素-1（IL-1）信号轴是 OM期间的抗菌免疫学和病理骨变化。诸如金黄色葡萄球菌等感染后， 包括IL-1β在内的IL-1家族成员是通过多蛋白复合物的激活来产生的 被称为炎症。然而，关于炎性症在OM发病机理中的作用知之甚少。 我们发现，与其未承诺的前体相比，OC具有较低的炎性体激活，并且 允许细胞内金黄色葡萄球菌增殖。我们假设炎性体活动的差异 在骨骼中存在的髓样谱系细胞内部影响OM的发病机理，金黄色葡萄球菌利用这些细胞 以较弱 过度炎症反应会导致组织损伤。 AIM 1：定义宿主和病原体决定者 OM中的OC谱系中的炎症体激活。目标2：定义炎症体的机制和影响 金黄色葡萄球菌在OM中的中性粒细胞谱系中的激活。通过检查和操纵宿主病原 在特定的髓样细胞群体中的相互作用，我们将学习如何将平衡倾斜到分辨率。