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感染，影响健康儿童和成人，以及患有糖尿病和肌肉骨骼创伤等合并症的患者。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增加的流行率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渗透到感染部位。即使长期给予适当的抗微生物治疗，患有骨髓炎的患者也经常经历显著的发病率，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，一些患者仍然进展为慢性感染。细菌性病原体诱导和维持骨髓炎、触发骨重建的有害变化以及逃避骨中宿主免疫反应的机制知之甚少。同样地，保护骨免受骨髓炎的宿主免疫应答，或有助于病原体诱导的骨重建变化的宿主免疫应答尚未完全阐明。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。本提案的目标是了解细菌毒力因子如何扰乱骨稳态（目标1），描述宿主免疫反应，促进细菌病原体从骨中清除，或有助于病原体诱导的骨重建变化（目标2），并定义对骨内生存至关重要的细菌因子（目标3）。成功完成所提出的目标将显著提高对骨髓炎发病机制的理解，确定感染和炎症期间控制骨稳态的机制，并满足对治疗骨髓炎和对抗病原体诱导的骨重建变化的新疗法的需求。 博士James Cassat目前是范德比尔特大学医学中心的儿科传染病临床研究员。他完成了医学博士学位。和博士在范德比尔特接受临床培训之前，他在阿肯色州大学获得医学学位。在临床研究期间，Cassat博士的研究重点是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。Cassat博士创造了创新的工具来模拟骨髓炎期间的宿主-病原体界面，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建的变化。这些工具最近发表在Cell Host和Microbe上，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，博士卡萨特将借鉴超过10年的经验，研究分子致病性的S。金黄色葡萄球菌，但也将获得新的专业知识，在翻译成像模式，免疫学，先进的流式细胞术和骨生物学。这些技能的汇编将促进Cassat博士发展成为一名独立资助的儿科医生-科学家，并最终实现转化研究职业生涯，解决重要的临床问题，同时寻求定义在感染和炎症环境中控制肌肉骨骼稳态的途径。他的专业发展将由跨学科奖学金监督委员会指导，由他的导师Eric Skaar博士担任主席。Skaar博士是国际公认的宿主-病原体相互作用专家，特别关注重要的人类病原体S。金黄色葡萄球菌、鲍曼不动杆菌和炭疽杆菌。Cassat博士奖学金监督委员会的其他成员将在整个颁奖期间促进新技术和知识的获得，同时促进重要的合作努力。这些成员包括对人类病原体的先天性和适应性免疫反应的专家（John威廉姆斯博士和Buddy Creech博士），翻译成像模式（Charles Manning博士）和基础骨生物学（Florent Elefteriou博士）。 完成拟议的研究将需要一个多学科的方法，利用范德比尔特的优势，在宿主-病原体相互作用，翻译成像科学，免疫学和骨生物学的研究。儿科感染性疾病部、范德比尔特骨生物学中心和范德比尔特大学成像科学研究所的优秀资源将为Cassat博士的专业发展提供独特而刺激的环境。总之，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.