Identifying Borrelia turicatae genes needed for colonization and transmission fro

鉴定Borrelia turicatae定植和传播所需的基因

• 批准号: 8188983
• 负责人: Job E Lopez
• 金额: $ 16.2万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8188983
• 关键词: Address; Affect; Arthropod Vectors; Biological; Biology; Black-legged Tick; Blood; Blood-Borne Pathogens; Borrelia; Borrelia turicatae; Code; Country; Data; Developing Countries; Development; Disease; Enabling Factors; Gene Deletion; Gene Expression Profile; Gene Expression Regulation; Gene Family; Gene Silencing; Genes; Genetic; Genetic Determinism; Goals; Human; Human body; In Vitro; Infection; Laboratories; Left; Life Cycle Stages; Longevity; Lyme Disease; Mammals; Membrane Proteins; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Names; Order Spirochaetales; Ornithodoros; Pediculus humanus humanus; Plasmids; Proteins; Relapsing Fever; Resources; Rocky Mountain Spotted Fever; Role; System; Testing; Tick Control; Tick-Borne Diseases; Ticks; Time; Up-Regulation; base; density; disease transmission; feeding; gene complementation; global health; immunogenic; improved; mortality; novel strategies; novel therapeutics; pathogen; prevent; therapeutic development; transmission process; vector

DESCRIPTION (provided by applicant): Relapsing fever spirochetosis is a global disease transmitted by argasid (soft-shelled) ticks or the human body louse. Throughout the world, this disease causes severe morbidity and mortality if left untreated, primarily affecting those in resource poor countries. However, little is known regarding the molecular mechanisms involved with transmission of the spirochetes from the tick vector to the vertebrate host. Therefore, to address NIAID's role in improving global health, my goal for this proposal is to identify the genetic factors that enable a species of relapsing fever spirochetes, Borrelia turicatae, to colonize the tick and to be subsequently transmitted to the mammalian host. Furthermore, there are several distinctions between B. turicatae and Lyme disease-causing spirochetes which make B. turicatae advantageous for studying spirochete-host interactions. These differences include plasmid stability and retention of infectivity after prolonged in vitro cultivation, and the ability to reach high bacterial densities in mammalian blood. These distinctions have aided in the development of the proposed studies focusing on determining the necessity of outer membrane proteins (Omps) during tick colonization and transmission of B. turicatae from its tick vector, Ornithodoros turicata. The importance of a family of genes which code for Omps has been established in a different species of relapsing fever spirochetes, Borrelia hermsii. However, little is known about the role of Omps in other species that cause disease. Therefore, I propose to identify genes which code for Omps that are up-regulated within B. turicatae during tick infection. A microarray based approach will be used to identify these genetic determinants, and their necessity for tick colonization and transmission to the mammal will be determined. To accomplish this, I have developed the first system in B. turicatae for gene inactivation and complementation, and have established the only known laboratory tick colony for these studies. These findings will have a broad impact enabling the development of therapeutics blocking transmission of this disease, and will increase our understanding of the adaptation and transmission mechanisms of vector-borne pathogens. PUBLIC HEALTH RELEVANCE (provided by applicant): Relapsing fever spirochetes are a blood-borne pathogen that are distributed throughout the world and are transmitted by ticks or the human body louse. It is poorly understood how these spirochetes are transmitted from their tick-vector. Identifying the genetic factors which aid in spirochete colonization in tick and transmission to the mammal will aid in developing novel therapeutics preventing transmission.

描述（申请人提供）：回归热螺旋体病是一种由软壳蜱或人体虱子传播的全球性疾病。在世界各地，如果不及时治疗，这种疾病会导致严重的发病率和死亡率，主要影响资源匮乏国家的人们。然而，人们对螺旋体从蜱载体传播到脊椎动物宿主的分子机制知之甚少。因此，为了解决 NIAID 在改善全球健康方面的作用，我提出此提案的目标是确定使回归热螺旋体（Borrelia turicatae）能够在蜱中定植并随后传播给哺乳动物宿主的遗传因素。此外，B. turicatae 和引起莱姆病的螺旋体之间存在一些区别，这使得 B. turicatae 有利于研究螺旋体与宿主的相互作用。这些差异包括质粒稳定性和长期体外培养后感染性的保留，以及在哺乳动物血液中达到高细菌密度的能力。这些区别有助于拟议研究的发展，重点是确定蜱虫定殖和从其蜱虫媒介 Ornithodoros turicata 传播 B. turicatae 期间外膜蛋白 (Omps) 的必要性。编码 Omps 的基因家族的重要性已在另一种回归热螺旋体——赫氏疏螺旋体中得到证实。然而，人们对 Omps 在其他引起疾病的物种中的作用知之甚少。因此，我建议鉴定编码 Omp 的基因，这些 Omp 在蜱感染期间在 B. turicatae 中上调。基于微阵列的方法将用于识别这些遗传决定因素，并确定它们对蜱定植和传播给哺乳动物的必要性。为了实现这一目标，我在 B. turicatae 中开发了第一个用于基因失活和互补的系统，并为这些研究建立了唯一已知的实验室蜱群体。这些发现将产生广泛的影响，促进开发阻止这种疾病传播的疗法，并将增加我们对媒介传播病原体的适应和传播机制的了解。 公共卫生相关性（由申请人提供）：回归热螺旋体是一种血源性病原体，分布于世界各地，通过蜱或人体虱子传播。人们对这些螺旋体如何从蜱虫媒介传播的了解甚少。鉴定有助于螺旋体在蜱中定植并传播给哺乳动物的遗传因素将有助于开发预防传播的新疗法。