The impact of host hypoxic signaling on antibacterial immunity and bone repair during Staphylococcus aureus osteomyelitis

金黄色葡萄球菌骨髓炎期间宿主缺氧信号对抗菌免疫和骨修复的影响

基本信息

批准号：
9883705
负责人：
Caleb Anthony Ford
金额：
$ 5.05万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883705
关键词：
Adjuvant Affect Anti-Bacterial Agents Anti-Infective Agents Antibiotic Therapy Antibiotics Architecture Bacteria Bacterial Infections Biocompatible Materials Biomedical Engineering Blood Vessels Bone Diseases Bone Regeneration Bone Resorption Bone remodeling Cell Lineage Cells Cellular biology Clinical Coculture Techniques Cytokine Receptors Data Exposure to Fracture Healing Future Genes Genetic Transcription Goals Gram-Positive Bacteria Homeostasis Human Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway Immune Immune response Immunity In Vitro Infection Infiltration Inflammatory Innate Immune Response Ligands Measurement Measures Mediating Mentorship Metabolic Metabolism Modeling Mus NF-kappa B Necrosis Osteoblasts Osteoclasts Osteolytic Osteomyelitis Oxygen Pathogenesis Pathologic Pattern recognition receptor Physicians Production Regulation Research Research Personnel Research Proposals Risk Role Science Scientist Shapes Signal Transduction Site Staphylococcal Infections Staphylococcus aureus Structure Testing Therapeutic Agents Tissues Toxin Training Tumor necrosis factor receptor 11b Vascular Endothelial Growth Factors Vascular blood supply angiogenesis bone bone healing bone loss career cell behavior chronic infection combat comorbidity conditional knockout cytokine experimental study fracture risk human disease immunoregulation in vivo mineralization mouse genetics mouse model osteoblast differentiation osteoclastogenesis pathogen pathogen exposure pathogenic bacteria receptor repaired response skeletal targeted treatment therapeutic evaluation tissue oxygenation

项目摘要

PROJECT SUMMARY/ABSTRACT Osteomyelitis is an inflammatory state of bone most commonly triggered by the Gram-positive bacterium Staphylococcus aureus. Staphylococcal infection of bone is both common and highly morbid. During osteomyelitis, the structural matrix and vascular architecture of bone is destroyed, resulting in regions of necrotic, avascular tissue that increase risk of chronic infection. Extreme hypoxia occurs during osteomyelitis due to an altered vascular supply, inflammatory infiltration, and the metabolism of invasive S. aureus. The host responds to hypoxia by initiating hypoxia-inducible factor (HIF) signaling. HIF signaling, in turn, modulates bone remodeling. Beyond bone homeostasis and repair, HIF signaling is implicated in the regulation of antibacterial immunity. However, the role of hypoxia and HIF signaling during osteomyelitis is unknown and may serve as an important clinical target for optimizing immune responses to combat invasive infection. We have developed a powerful murine model of osteomyelitis that recapitulates the pathogenesis of human disease. Using this model, we demonstrated that extreme hypoxia is present at the infectious focus in a manner independent of non-infectious fracture healing. Our preliminary data demonstrate that VEGF, a well- characterized target of HIF signaling, is increased during osteomyelitis relative to mock-infected bone, consistent with the notion that HIF signaling is activated during invasive infection of bone. Under normoxia, we also observed that osteoblasts (bone-building cells) sense and respond to S. aureus stimulation in vitro by increasing the transcription of genes that regulate HIF signaling, control host-mediated bone remodeling, and mediate innate immune responses. The overarching hypothesis of this proposal is that tissue oxygenation and host hypoxic signaling responses influence antibacterial immunity and bone repair during S. aureus osteomyelitis. I will test this hypothesis with two integrated Specific Aims. In Specific Aim 1, I will define the role of oxygenation in mediating osteoblast innate immune responses and bone homeostasis in response to S. aureus stimulation in vitro. In Specific Aim 2, I will determine the impact of HIF signaling on antibacterial immunity and bone remodeling during S. aureus osteomyelitis. Within the experiments of Aim 2, I will use in vivo analyses that will harness both mouse genetics and biomaterial science to alter HIF signaling during osteomyelitis and investigate the impact of HIF on immune responses and bone repair. Together these studies will 1) define the role of oxygenation in dictating the innate immune and bone remodeling responses of osteoblasts, 2) define the impact of osteoblast HIF signaling on antibacterial immunity and bone repair during S. aureus osteomyelitis, and 3) test the potential of HIF-targeted therapies as an anti-infective adjuvant for invasive infection of bone. Collectively, this proposal will elucidate how oxygenation impacts skeletal cell biology and the innate immune responses to bacterial pathogens while providing ideal training and mentorship to develop my future career as an independent investigator and physician-scientist.

项目摘要/摘要骨髓炎是骨骼的炎症状态，最常见于革兰氏阳性细菌触发金黄色葡萄球菌。骨骼的葡萄球菌感染既常见又高病态。期间骨髓炎，骨骼的结构基质和血管结构被破坏，导致区域坏死的血管组织增加了慢性感染的风险。极端缺氧发生在骨髓炎期间由于血管供应改变，炎症性浸润和侵入性金黄色葡萄球菌的代谢。主人通过引发缺氧诱导因子（HIF）信号传导来应对缺氧。 HIF信令反过来调节骨骼重塑。除了骨稳态和修复之外，HIF信号与调节有关抗菌免疫。但是，缺氧和HIF信号在骨髓炎中的作用尚不清楚并可以作为优化免疫反应以对抗侵入性的重要临床目标感染。我们开发了强大的骨髓炎的鼠模型，该模型概括了人类疾病。使用该模型，我们证明了在感染力的关注点中存在极端缺氧与非感染性断裂愈合无关的方式。我们的初步数据表明，VEGF是一个很好的在骨髓炎期间，相对于模拟感染的骨骼，在骨髓炎期间的特征靶标的靶标有增加与在骨骼侵入性感染过程中激活HIF信号传导的概念一致。在常规状态下，我们还观察到成骨细胞（骨建造细胞）感知并在体外对金黄色葡萄球菌刺激作出反应增加调节HIF信号传导，控制宿主介导的骨重塑的基因转录，并调解先天免疫反应。该提议的总体假设是组织氧合和宿主缺氧信号反应影响金黄色葡萄球菌期间的抗菌免疫和骨修复骨髓炎。我将以两个集成的特定目的来检验这一假设。在特定目标1中，我将定义氧合在介导成骨细胞先天免疫反应和骨体内平衡中的作用。金黄色的体外刺激。在特定的目标2中，我将确定HIF信号对抗菌的影响金黄色葡萄球菌骨髓炎期间的免疫力和骨骼重塑。在AIM 2的实验中，我将使用体内分析将利用小鼠遗传学和生物材料科学来改变HIF信号传导骨髓炎并研究HIF对免疫反应和骨修复的影响。共同研究会1）定义氧合在决定先天免疫和骨骼重塑反应中的作用成骨细胞，2）定义成骨细胞HIF信号传导对抗菌免疫和骨修复的影响金黄色葡萄球菌骨髓炎和3）测试以HIF为靶向疗法的潜力骨骼的侵入性感染。总的来说，该建议将阐明氧合如何影响骨骼细胞生物学以及对细菌病原体的先天免疫反应，同时提供理想的培训和指导为了发展我作为独立调查员和医师科学家的未来职业。