Host-pathogen interactions during osteomyelitis

描述（由申请人提供）：骨髓炎是一种常见的、使人衰弱的骨骼感染，影响健康的儿童和成人，以及那些患有糖尿病和肌肉骨骼创伤等合并症的人。细菌性病原体，特别是金黄色葡萄球菌，是骨髓炎最常见的原因。骨感染的治疗选择受到多重耐药细菌病原体日益流行以及病原体诱导的骨重塑变化的限制，这些变化限制了抗生素进入感染部位。即使长期给予适当的抗菌药物治疗，患有骨髓炎的患者往往会出现显著的发病率，包括骨折、深静脉血栓形成和败血症。因此，骨髓炎需要积极的干预措施，如手术清创，之后一些患者仍进展为慢性感染。细菌病原体诱导和维持骨髓炎的机制，引发骨重塑的有害变化，以及逃避骨宿主免疫反应的机制尚不清楚。同样，宿主免疫反应保护骨骼免受骨髓炎，或促成病原体诱导的骨重塑变化尚未完全描述。最后，骨稳态是如何被感染和炎症信号调节的还没有很好的定义。本研究的目标是了解细菌毒力因子如何扰乱骨稳态（目的1），描述宿主免疫反应，这些免疫反应要么促进骨中细菌病原体的清除，要么促进病原体诱导的骨重塑变化（目的2），并定义对骨内存活至关重要的细菌因子（目的3）。该研究的成功完成将显著提高对骨髓炎发病机制的理解，明确感染和炎症期间骨稳态的控制机制，并满足治疗骨髓炎和对抗病原体诱导的骨重塑变化的新疗法的需求。

DESCRIPTION (provided by applicant): Osteomyelitis is a common and debilitating infection of bone that affects healthy children and adults, as well as those with comorbidities such as diabetes and musculoskeletal trauma. Bacterial pathogens, notably Staphylococcus aureus, are the most common causes of osteomyelitis. Treatment options for bone infections are limited by both the increasing prevalence of multi-drug resistant bacterial pathogens, as well as pathogen- induced changes in bone remodeling that limit antibiotic penetration into the infection site. Even with prolonged administration of appropriate antimicrobial therapy, patients suffering from osteomyelitis often experience significant morbidity, including bone fractures, deep venous thrombosis, and septicemia. Osteomyelitis therefore necessitates aggressive interventions such as surgical debridement, after which some patients still progress to chronic infection. The mechanisms by which bacterial pathogens induce and sustain osteomyelitis, trigger detrimental changes in bone remodeling, and evade host immune responses in the bone are poorly understood. Likewise, the host immune responses that protect bone from osteomyelitis, or that contribute to pathogen-induced changes in bone remodeling have not been fully delineated. Finally, how bone homeostasis is modulated by infectious and inflammatory signals is not well defined. The goals of this proposal are to understand how bacterial virulence factors perturb bone homeostasis (Aim 1), to delineate host immune responses that either promote clearance of bacterial pathogens from bone, or contribute to pathogen-induced changes in bone remodeling (Aim 2), and to define bacterial factors that are critical for survival within the bone (Aim 3). Successful completion of the proposed Aims will significantly enhance an understanding of the pathogenesis of osteomyelitis, define mechanisms governing bone homeostasis during infection and inflammation, and meet the need for new therapies that treat osteomyelitis and counteract pathogen-induced changes in bone remodeling. Dr. James Cassat is currently a Clinical Fellow in Pediatric Infectious Diseases at Vanderbilt University Medical Center. He completed the M.D. and Ph.D. degrees at the University of Arkansas for Medical Sciences prior to his clinical training at Vanderbilt. During clinical fellowship, Dr. Cassat has focused his research efforts on understanding the pathogenesis of osteomyelitis, one of the most common invasive bacterial infections in children. Dr. Cassat has created innovative tools to model the host-pathogen interface during osteomyelitis, including a new animal model that utilizes high resolution tomographic imaging to quantify changes in bone remodeling during osteomyelitis. These tools, recently published in Cell Host and Microbe, enabled generation of substantial preliminary data for the studies outlined in this application. In completion of the proposed Aims, Dr. Cassat will draw upon greater than 10 years of experience studying the molecular pathogenesis of S. aureus, but will also gain new proficiencies in translational imaging modalities, immunology, advanced flow cytometry, and bone biology. The compilation of these skills will facilitate Dr. Cassat's development into an independently-funded pediatric physician-scientist, and will ultimately enable a translational research career that addresses an important clinical problem while seeking to define the pathways that govern musculoskeletal homeostasis in the setting of infection and inflammation. His professional development will be guided by an inter-disciplinary scholarship oversight committee, chaired by his mentor Dr. Eric Skaar. Dr. Skaar is an internationally recognized expert in host-pathogen interactions, with a specific focus on the important human pathogens S. aureus, Acinetobacter baumannii, and Bacillus anthracis. Additional members of Dr. Cassat's scholarship oversight committee will facilitate the acquisition of new techniques and knowledge throughout the award period, while fostering important collaborative efforts. These members include experts in the innate and adaptive immune responses to human pathogens (Dr. John Williams and Dr. Buddy Creech), translational imaging modalities (Dr. Charles Manning), and fundamental bone biology (Dr. Florent Elefteriou). Completion of the proposed studies will require a multi-disciplinary approach that capitalizes on Vanderbilt's strengths in the study of host-pathogen interactions, translational imaging sciences, immunology, and bone biology. The outstanding resources of the Division of Pediatric Infectious Diseases, The Vanderbilt Center for Bone Biology, and the Vanderbilt University Institute of Imaging Sciences will provide Dr. Cassat a unique and stimulating environment for professional development. In total, Vanderbilt is the ideal environment for completion of the proposed studies.