Identification and Functional Characterization of Antimicrobial Peptides from the Bacterium Treponema pallidum

该研究项目的重点是加强对螺旋体细菌（梅毒和莱姆病等疾病的病原体）在人类宿主内的多微生物环境中生存和繁衍的致病策略的理解。目前的发现基金申请中包含的研究项目的方向集中在调查一个假设，即梅毒螺旋体细菌梅毒螺旋体（梅毒的病原体）的致病成功部分归功于其基因组编码的抗菌肽的补体。生物信息学分析表明，高达4%的白螺旋体基因组编码假定的抗菌肽，这是一组小的带电蛋白，其功能是通过直接和间接的手段杀死竞争的细菌物种。当考虑到小苍白球绦虫基因组的背景下，它经历了广泛的基因组缩减，只保留了最重要的基因，将如此大比例的基因组奉献给这类预测的功能蛋白质表明，这组蛋白质对病原体的成功至关重要。在这项提议中，将鉴定由苍白球绦虫基因组编码的预测抗菌肽的完整互补（目的1），这些抗菌肽在苍白球绦虫感染过程中遇到的多微生物环境中杀死生物学相关竞争细菌物种的能力将被确定（目的2）。这些抗菌肽调节宿主免疫反应的能力，以增强对竞争细菌的杀死和苍白球绦虫的存活，将被确定（目标3）。这些调查代表了一个新的研究路线，以前没有在螺旋体领域进行。通过这些研究，我们将获得基础知识，这将增强对T. pallidum建立成功感染的机制的理解，并将为未来的研究提供机会，通过靶向这种致病策略来预防感染。

This research program focuses upon enhancing understanding of the pathogenic strategies used by spirochete bacteria, causative agents of diseases such as syphilis and Lyme Disease, to survive and flourish in polymicrobial environments within a human host. The direction of the research program contained within the current Discovery Grant application is focused upon investigating the hypothesis that the highly successful spirochete bacterium Treponema pallidum, causative agent of syphilis, owes its pathogenic success in part to the complement of antimicrobial peptides encoded by its genome. Bioinformatic analyses show that up to 4% of the T. pallidum genome encodes for putative antimicrobial peptides, a group of small charged proteins that function to kill competing bacterial species via both direct and indirect means. When considered in the context of the small T. pallidum genome, which has undergone extensive genome reduction to retain only the most essential genes, dedication of such a large proportion of the genome to this predicted functional class of proteins suggest this group of proteins is critical to the success of the pathogen. In this proposal the full complement of predicted antimicrobial peptides encoded by the T. pallidum genome will be identified (Aim 1), the ability of these antimicrobial peptides to kill biologically relevant competing bacterial species in the polymicrobial environment encountered by T. pallidum during infection will be determined (Aim 2), and the ability of these antimicrobial peptides to modulate the host immune response to enhance killing of competing bacteria and survival of T. pallidum will be determined (Aim 3). These investigations represent a novel line of study that has not been previously performed in the spirochete field. Through these studies we will gain fundamental knowledge that will enhance understanding of the mechanism employed by T. pallidum to establish successful infection, and will provide opportunities in future studies to prevent infection by targeting this pathogenic strategy.