Role of Staphylococcus aureus SpA in Microbial Competition and Host Colonization

描述（由申请人提供）：本提案详细介绍了一个全面的5年计划，为博士保罗J行星的职业发展在传染病基础研究。行星设计了他的指导研究计划，以提供额外的科学培训和技能，使他能够成功地作为一个独立的调查员和医生科学家。Planet博士的科学培训目标是通过获得宿主病原体免疫学，流行病学和微生物组学研究领域的经验来增加他在分子微生物学和微生物遗传学方面的背景。他的职业目标是成功地过渡到成为一名独立调查员。爱丽丝·普林斯医学博士将成为行星博士科学和职业发展的主要导师。普林斯博士是宿主-病原体相互作用、先天免疫和传染病领域的领导者。Planet博士成立了一个咨询委员会，指导他的科学进步和职业发展，该委员会由微生物学家（Noah Fierer博士，富兰克林Lowy博士，巴里Kreisperth博士）组成，他们在微生物生态学，免疫学，流行病学，基因组学，动物模型和发病机理方面具有专业知识。他还将利用哥伦比亚大学的大量资源进行职业发展和科学合作。Planet博士的项目重点是金黄色葡萄球菌在人体皮肤和粘膜组织上定植和持续存在的非凡能力。殖民地S。金黄色葡萄球菌是疾病传播的关键，也是感染的主要危险因素。中心假设是，金黄色葡萄球菌通过触发宿主的先天免疫应答来优先消除其他肠道细菌竞争者，从而提高其定殖能力。在一个小鼠模型中，Planet博士最近发现S。金黄色 操纵宿主的免疫反应部分是由于蛋白A（SpA）的产生。他还表明，SpA的可变串联重复区（Xr）似乎对这种效应至关重要。初步数据表明，SpA可能通过增加宿主上皮细胞产生的抗菌肽的表达而起作用。该提案的具体目的是：（1）在小鼠模型中检验SpA的Xr区域影响常驻植物群定殖的假设，并描绘发生的特定生态变化。(2)确定由Xr触发的导致其他植物群清除的人类先天免疫应答的主要要素。

DESCRIPTION (provided by applicant): This proposal details a comprehensive 5-year program for Dr. Paul J Planet's career development in basic research in Infectious Diseases. Dr. Planet has designed his mentored research program to provide both additional scientific training and skills that will allow him to succeed as an independent investigator and physician-scientist. Dr. Planet's scientific training objective is to add to his background in molecular microbiology and phylogenetics by gaining experience in the areas of host-pathogen immunology, epidemiology, and microbiome studies. His career objective is to successfully make the transition to being an independent investigator. Alice Prince M.D. will be Dr. Planet's primary mentor for scientific and career development. Dr. Prince is a leader in the fields of host-pathogen interactions, innate immunity, and infectious diseases. Dr. Planet has established an advisory committee that will guide his scientific progress and career development that is composed of microbiologists (Dr. Noah Fierer, Dr. Franklin Lowy, Dr. Barry Kreiswirth) with expertise in microbial ecology, immunology, epidemiology, genomics, animal models, and pathogenesis. He will also utilize the considerable resources for career development and scientific collaboration at Columbia University. Dr. Planet's project focuses on the remarkable ability of Staphylococcus aureus to colonize and persist on human skin and mucosal tissues. Colonization by S. aureus is critical for the spread of disease, and it is a major risk factor for infection. The central hypothesis is that Staphylococcus aureus improves its ability to colonize by triggering the host's innate immune response to preferentially eliminate other commensal bacterial competitors. In a mouse model, Dr. Planet recently found that the ability of S. aureus to manipulate the host's immune response is due, in part, to production of Protein A (SpA). He has also shown that the variable tandem repeat region (Xr) of SpA appears to be critical for this effect. Preliminary data suggests that SpA may act by increasing expression of antimicrobial peptides produced by the host epithelium. The specific aims of the proposal are to: (1) Test the hypothesis that the Xr region of SpA affects colonization of resident flora in a mouse model, and delineate the specific ecological shifts that occur. (2) Determine the primary elements of the human innate immune response that are triggered by Xr leading to clearance of other flora.