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，以及患有糖尿病和肌肉骨骼创伤等共病的人。细菌病原体，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建改变的限制，这些改变限制了抗生素对感染部位的渗透。即使长期使用适当的抗菌药物治疗，骨髓炎患者的发病率也很高，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，如外科清创，在此之后，一些患者仍会进展为慢性感染。细菌病原体诱导和维持骨髓炎，触发骨骼重塑的有害变化，以及逃避骨骼中的宿主免疫反应的机制尚不清楚。同样，保护骨骼免受骨髓炎的宿主免疫反应，或有助于病原体诱导的骨重塑变化的宿主免疫反应尚未完全描述。最后，感染和炎症信号是如何调节骨骼稳态的，目前还没有很好的定义。这项建议的目标是了解细菌毒力因子如何扰乱骨骼的动态平衡(目标1)，描绘促进细菌病原体从骨骼中清除的宿主免疫反应，或促进病原体诱导的骨骼重塑变化(目标2)，并确定对骨骼内生存至关重要的细菌因素(目标3)。这些拟议目标的成功完成将显著提高对骨髓炎发病机制的了解，明确感染和炎症期间骨稳态的调控机制，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要。 詹姆斯·卡萨特博士目前是范德比尔特大学医学中心儿科传染病临床研究员。在范德比尔特接受临床培训之前，他在阿肯色大学完成了医学博士学位和博士学位。在临床研究期间，卡萨特博士致力于了解骨髓炎的发病机制，骨髓炎是儿童最常见的侵袭性细菌感染之一。卡萨特博士创造了创新的工具来模拟骨髓炎期间宿主-病原体的界面，包括一种新的动物模型，该模型利用高分辨率断层成像来量化骨髓炎期间骨重塑的变化。最近发表在《细胞宿主和微生物》上的这些工具，为本申请中概述的研究生成了大量的初步数据。在完成拟议的目标时，卡萨特博士将借鉴10多年研究金黄色葡萄球菌分子发病机制的经验，但也将在翻译成像方式、免疫学、先进的流式细胞术和骨生物学方面获得新的熟练程度。这些技能的汇编将有助于卡萨特博士发展成为一名独立资助的儿科内科医生兼科学家，并最终将使他能够在翻译研究生涯中解决一个重要的临床问题，同时寻求确定在感染和炎症背景下支配肌肉骨骼动态平衡的途径。他的专业发展将由一个跨学科的奖学金监督委员会指导，该委员会由他的导师埃里克·斯卡博士担任主席。Skaar博士是国际公认的宿主-病原体相互作用方面的专家，特别关注重要的人类病原体金黄色葡萄球菌、鲍曼不动杆菌和炭疽杆菌。卡萨特博士奖学金监督委员会的其他成员将在整个获奖期内促进新技术和知识的获得，同时促进重要的合作努力。这些成员包括针对人类病原体的先天和获得性免疫反应(John Williams博士和Buddy Creech博士)、翻译成像方式(Charles Manning博士)和基础骨生物学(Florent Elefteriou博士)方面的专家。 完成拟议的研究将需要一个多学科的方法，利用范德比尔特在宿主-病原体相互作用、翻译成像科学、免疫学和骨生物学研究方面的优势。儿科传染病科、范德比尔特骨生物学中心和范德比尔特大学影像科学研究所的杰出资源将为卡萨特博士的专业发展提供一个独特和刺激的环境。总体而言，范德比尔特是完成拟议研究的理想环境。

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.