Mechanisms of intraspecies Competition in Streptococcus pneumoniae.

描述（由申请方提供）：鼻咽定植是病原体肺炎链球菌疾病的先决条件。对于>90种不同的荚膜血清型，7价缀合肺炎球菌疫苗（PCV 7）的初步成功已经被导致先前罕见菌株的定殖和疾病的血清型替换的报告所掩盖。这表明肺炎球菌之间的种内竞争发生在鼻咽部，并且通过PCV 7诱导的群体免疫丧失竞争菌株导致先前竞争菌株的出现。本项目采用两个目标来解决由S. pneumoniae的一种名为pneumocins的细菌对种内竞争的抑制作用。第一个目的是解决机制的调节，涉及在转录和转录后水平上的修改的肺炎菌素的表达。调节电路将进行研究，特别强调在殖民化过程中的表达状态。第二个目标将集中在影响各种肺炎菌素MN同种型的活性谱的因素，以及描述这些肽在多菌株同时定植的小鼠模型中清除易感菌株定植的能力。该申请描述了一个为期4年的计划，旨在为Suzanne Dawid博士提供成为微生物发病机理领域独立科学家所需的技能。Dawid博士已经完成了儿科感染性疾病的研究，并将由Jeffrey Weiser博士指导，Jeffrey Weiser博士是细菌发病机制领域的领导者，特别关注S。肺炎菌定植。该项目涉及遗传学和微生物发病机理领域的教学研究，以及分子生物学，生物化学和体内建模方面的深入实验室经验。相关性：S分离株之间预先存在的种内竞争。通过产生被称为细菌素的抗微生物肽介导的肺炎可能解释了在人群广泛接种疫苗后出现以前罕见的菌株。对这种竞争驱动力的详细研究将有助于我们理解微生物生态学和成功定植所涉及的复杂相互作用，这是这种主要病原体引起所有疾病的第一步。

DESCRIPTION (provided by applicant): Colonization of the nasopharynx is a prerequisite to disease with the pathogen Streptococcus pneumoniae. With >90 different capsular serotypes, the initial success of the 7-valent conjugate pneumococcal vaccine (PCV7) has been overshadowed by reports of serotype replacement resulting in colonization and disease with previously rare strains. This suggests that intraspecies competition among pneumococci occurs in the nasopharynx, and the loss of competitive strains through PCV7 induced herd immunity has resulted in the emergence of previously out competed strains. This project uses two aims to address the contribution of antimicrobial peptides made by S. pneumoniae called pneumocins to intraspecies competition. The first aim addresses the mechanism of regulation of pneumocin expression which involves modifications at the transcriptional and post transcriptional level. The regulatory circuit will be studied with a particular emphasis on the state of expression during colonization. The second aim will focus on factors influencing the spectrum of activity of the various pneumocin MN isotypes as well as describing the ability of these peptides to clear colonization by suseptible strains in a mouse model of simultaneous colonization by mutliple strains. This application describes a 4-year program designed to provide Dr. Suzanne Dawid with the skills required to become an independent scientist in the field of microbial pathogenesis. Dr. Dawid has completed a fellowship in pediatric infectious diseases and will be mentored by Dr. Jeffrey Weiser, a leader in the field of bacterial pathogenesis with a particular focus on S. pneumoniae colonization. The project involves didactic study in the fields of genetics and microbial pathogenesis as well as in-depth laboratory experience in molecular biology, biochemistry and in vivo modeling. Relevance: Preexisting intraspecies competition between isolates of S. pneumoniae mediated by the production of antimicrobial peptides called pneumocins may explain the emergence of previously rare strains following widespread vaccination of the population. This detailed study of the forces driving this competition will aid in our understanding of microbial ecology and complex interactions involved in successful colonization, the initial step in all disease by this major pathogen.