Impact of Staphylococcus aureus in osteomyelitis and bone physiology

金黄色葡萄球菌对骨髓炎和骨生理学的影响

基本信息

批准号：
9089872
负责人：
MARK S SMELTZER
金额：
$ 36.9万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089872
关键词：
Acute Address Animal Model Antibiotic Therapy Antibiotics Bone Marrow Cell physiology Chronic Clinical Complex Data Debridement Development Disease Equilibrium Exhibits Failure Genes Goals Health Hematogenous In Vitro Indium Infection Knowledge Life Mediating Methods Microbial Biofilms Mutation Operative Surgical Procedures Orthopedics Osteoblasts Osteoclasts Osteomyelitis Pathogenesis Pathological fracture Peptide Hydrolases Phenols Phenotype Physiology Play Positioning Attribute Prevention Process Production Proteins Proteomics Resistance Risk Factors Role Septicemia Site Staging Staphylococcus aureus System Therapeutic Time Venous Thrombosis Virulence Virulence Factors antimicrobial base bone bone cell effective therapy extracellular functional status in vivo interdisciplinary approach interest mouse model mutant novel novel strategies novel therapeutics pathogen research study skeletal soft tissue systemic toxicity

项目摘要

DESCRIPTION (provided by applicant): Osteomyelitis is a devastating bone infection, the treatment of which requires a complicated, interdisciplinary approach. This most often involves intensive, long-term systemic antibiotic therapy and surgical debridement accompanied by additional local antibiotic delivery aimed at overcoming the intrinsic resistance of these life- threatening infections while avoiding systemic toxicity. The leading cause of osteomyelitis and other forms of orthopaedic infection is Staphylococcus aureus. Our hypothesis is that overcoming the growing problem of S. aureus orthopaedic infections will require a clear understanding of the bacterial virulence factors that contribute to the development, maturation, persistence, and therapeutic recalcitrance of these infections, as well as the impact these factors have on host bone cell physiology. Our results demonstrate that a key element in this regard is the functional status of the staphylococcal accessory regulator (sarA) and the saeRS regulatory system relative to each other. Specifically, we have established that the functional status of these loci relative to each other can be used to define a "virulence gradient" in hematogenous osteomyelitis that is defined by the balance between the production of specific virulence factors and their protease-mediated degradation, with the former mediated primarily by the functional status of saeRS and the latter mediated primarily by the functional status of sarA. In this proposal, we will use mutants generated in a contemporary clinical isolate of the USA300 clonal lineage (LAC) that differ in the functional status of these two regulatory loci to fully interrogate this hypothesis in validated animal models of acute hematogenous osteomyelitis, acute post-surgical orthotopic osteomyelitis, and chronic osteomyelitis. This will position us to identify specific virulence factors whose abundance varies in a manner consistent with the virulence gradient defined in vivo, thereby allowing us to identify and prioritize the S. aureus virulence factors that are likely to play important roles in all stages of the osteomyelitis disease process. We will then determine the role of these virulence factors in vivo and investigate the mechanistic basis by which these virulence factors impact host bone cell physiology. Collectively, completion of the proposed studies will set the stage for the development of novel strategies that can be used for the prevention and treatment of S. aureus orthopaedic infections.

描述（由适用提供）：骨髓炎是一种毁灭性的骨骼感染，其治疗需要复杂的跨学科方法。这通常涉及密集的，长期的全身抗生素治疗和手术调试，该疗法通过额外的局部抗生素递送来克服这些威胁到生命的感染的内在抗药性，同时避免系统性毒性。骨髓炎和其他形式的正交感染的主要原因是金黄色葡萄球菌。我们的假设是，克服金黄色金黄色葡萄球菌骨科感染的日益严重的问题将需要清楚地了解这些感染的发育，成熟，持久性和治疗性恢复性的细菌病毒因素，以及这些因素对宿主骨细胞生理学的影响。我们的结果表明，这方面的关键要素是葡萄球菌附件调节器（SARA）和SAERS调节系统相对于彼此的功能状态。具体而言，我们已经确定，这些局部相对于彼此的功能状态可用于定义血源性骨髓炎中的“毒力梯度”，这是由特定病毒因子的产生与蛋白酶介导的降解之间的平衡所定义的，其蛋白酶介导的降解是由Saers的功能和后来的Primartial Prienditial the saraara介导的原发性。 In this proposal, we will use mutants generated in a contemporary clinical isolate of the USA300 clonal lineage (LAC) that differ in the functional status of these two regulatory locale to fully interrogate this hypothesis in validated animal models of acute hematogenous osteomyelitis, acute post-surgical orthotopic osteomyelitis, and chronic osteomyelitis.这将使我们确定以与病毒一致的方式差异的特定病毒因素。体内定义的梯度，从而使我们能够识别和优先考虑在骨髓炎的所有阶段中起重要作用的金黄色葡萄球菌病毒因子疾病过程。然后，我们将确定这些病毒因子在体内的作用，并研究这些病毒因素影响宿主骨细胞生理的机械基础。总的来说，拟议的研究的完成将为开发新策略的发展奠定了基础，这些策略可用于预防和治疗金黄色葡萄球菌骨科感染。