Mechanisms of intraspecies Competition in Streptococcus pneumoniae.

描述（由申请人提供）：鼻咽部的定植是病原体肺炎链球菌疾病的先决条件。对于bbbb90不同的荚膜血清型，7价结合肺炎球菌疫苗（PCV7）的初步成功已经被血清型替代导致定植和疾病的报道所掩盖。这表明，肺炎球菌之间的种内竞争发生在鼻咽部，通过PCV7诱导的群体免疫导致竞争菌株的丧失，导致先前竞争菌株的出现。该项目有两个目的，以解决由肺炎链球菌产生的抗菌肽（称为肺炎素）对种内竞争的贡献。第一个目标是解决肺炎素表达的调控机制，包括转录和转录后水平的修饰。调控电路将被研究，特别强调在殖民化期间的表达状态。第二个目标将集中在影响各种肺炎素MN同型活性谱的因素，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。这个应用程序描述了一个为期4年的计划，旨在为苏珊娜·大卫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。david博士已经完成了儿科传染病的研究，并将接受Jeffrey Weiser博士的指导，Jeffrey Weiser博士是细菌发病机制领域的领导者，特别关注肺炎链球菌的定植。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：肺炎链球菌分离株之间先前存在的种内竞争是由被称为肺炎素的抗菌肽的产生介导的，这可能解释了在人群广泛接种疫苗后出现以前罕见菌株的原因。对这种竞争驱动力量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在所有疾病中的第一步。

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.