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：
8951509
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/8951509
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 Hematogenous In Vitro Indium Infection Knowledge Life Mediating Methods Microbial Biofilms Modeling Mus Mutation Operative Surgical Procedures Orthopedics Osteoblasts Osteoclasts Osteomyelitis Pathogenesis Pathological fracture Peptide Hydrolases Phenols Phenotype Physiology Play Positioning Attribute Prevention Process Production Proteins Proteomics Relative (related person)Resistance Risk Factors Role Septicemia Site Staging Staphylococcus aureus System Therapeutic Time Toxic effect Venous Thrombosis Virulence Virulence Factors antimicrobial base bone bone cell effective therapy extracellular functional status in vivo interdisciplinary approach interest mutant novel novel strategies novel therapeutics pathogen public health relevance research study skeletal soft tissue

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（由申请人提供）：骨髓炎是一种破坏性的骨感染，其治疗需要复杂的跨学科方法，这通常涉及强化、长期的全身抗生素治疗和手术清创，并辅以额外的局部抗生素给药，以克服这一问题。这些危及生命的感染的内在抵抗力，同时避免全身毒性，导致骨髓炎和其他形式的骨科感染的主要原因是金黄色葡萄球菌。金黄色葡萄球菌骨科感染需要清楚地了解导致这些感染的发展、成熟、持久性和治疗顽固性的细菌毒力因素，以及这些因素对宿主骨细胞生理学的影响。这方面的一个关键因素是葡萄球菌辅助调节因子 (sarA) 和 saeRS 调节系统相对于彼此的功能状态。具体来说，我们已经确定这些基因座相对于彼此的功能状态可以。用于定义血源性骨髓炎的“毒力梯度”，其定义为特定毒力因子的产生与其蛋白酶介导的降解之间的平衡，前者主要由 saeRS 的功能状态介导，后者主要由 saeRS 的功能状态介导。在本提案中，我们将使用在 USA300 克隆谱系 (LAC) 的当代临床分离株中产生的突变体，这些突变体在这两个调节位点的功能状态上有所不同。在经过验证的急性血源性骨髓炎、急性术后原位骨髓炎和慢性骨髓炎动物模型中质疑这一假设，这将使我们能够识别特定的毒力因子，其丰度变化与体内定义的毒力梯度一致。识别并优先考虑可能在骨髓炎各个阶段发挥重要作用的金黄色葡萄球菌毒力因子然后，我们将确定这些毒力因子在体内的作用，并研究这些毒力因子影响宿主骨细胞生理学的机制基础。总的来说，所提出的研究的完成将为开发新策略奠定基础。用于预防和治疗金黄色葡萄球菌骨科感染。