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

这项研究计划的重点是加强对螺旋体细菌所使用的致病策略的理解，螺旋体细菌是梅毒和莱姆病等疾病的病原体，在人类宿主内的多菌环境中生存和繁衍。目前发现拨款申请中包含的研究计划的方向集中于调查一种假说，即高度成功的螺旋体细菌梅毒螺旋体是梅毒的病原体，其致病成功部分归功于其基因组编码的抗菌肽的补充。生物信息学分析显示，多达4%的梅毒螺旋体基因组编码推测的抗菌肽，这是一组小电荷蛋白质，通过直接和间接方式杀死竞争细菌物种。当考虑到梅毒螺旋体的小基因组，它经历了广泛的基因组削减，只保留最基本的基因，如此大比例的基因组致力于这一预测的功能类蛋白质表明，这组蛋白质对病原体的成功至关重要。在这项提案中，将确定由梅毒螺旋体基因组编码的预测抗菌肽的全长(目标1)，将确定这些抗菌肽在梅毒螺旋体感染期间遇到的多微生物环境中杀死生物相关竞争细菌物种的能力(目标2)，并将确定这些抗菌肽调节宿主免疫反应的能力，以提高对竞争细菌的杀灭和梅毒螺旋体的生存(目标3)。这些研究代表了以前在螺旋体领域从未进行过的一条新的研究路线。通过这些研究，我们将获得基础知识，这将加强对梅毒螺旋体成功感染机制的理解，并将为未来的研究提供机会，通过靶向这一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.