Defining the role of toxin-antitoxin systems in persistence of Burkholderia pseudomallei

项目总结/摘要 迫切需要对抗由细菌病原体类鼻疽伯克霍尔德氏菌引起的感染 导致了类鼻疽病类鼻疽是世界上热带流行地区的一种健康威胁 并且现在被认为是在非流行性地区的紧急疾病。除了引起急性 感染被认为是致命的，如果不治疗，细菌可以坚持在主机和产生非常 很难治疗潜伏感染。因此，我们的长期目标是开发有效的治疗方法， 类鼻疽和预防潜伏或慢性疾病的结果。在这个项目中，我们将评估一个 毒素-抗毒素系统的子集，已被鉴定为感知应激的细菌开关之一 并激活一种持久性表型。我们将确定它们与细菌持久性的关系， 体外和体内。我们的中心假设是，选择性毒素在体内上调，以响应特定的 条件下，其功能的丧失导致宿主相关持久性降低。必须指出 目前针对B的抗生素。假鼻疽产生的持续感染率高达50%。因为 由于B的倾向，目前的治疗持续数月。该研究称，假鼻疽会产生潜伏感染， 毒素-抗毒素系统的研究可以帮助确定新的药物靶点，从而提高抗生素的疗效。我们 拟议的实验方法将集中在两个具体目标：首先，我们将评估选定的作用， 毒素在存活和诱导过程中的一个持续阶段B。巨噬细胞的假鼻疽感染， 这种细胞类型可能促进潜伏感染;其次，我们将评估B中毒素的作用。 假鼻疽在宿主相关的体内条件下持续存在的能力。我们的建议意义重大，因为它 有望阐明与持久性有很强关联的特定毒素的作用 表型，这可能会导致替代治疗方法的发展，以防止潜在的 由B引起的感染。类鼻疽，CDC类别B 1级选择生物威胁剂和一种待研究的 新兴病原体

Project Summary/Abstract There is an urgent need to combat infections caused by Burkholderia pseudomallei, the bacterial agent responsible for the disease melioidosis. Melioidosis is a health threat in tropical endemic regions of the world and is now recognized as an emergent disease in areas considered non-endemic. In addition to causing acute infections that are considered lethal if left untreated, the bacteria can persist in the host and produce very difficult to treat latent infections. Therefore, our long-term goal is to develop effective treatments against melioidosis and prevent latent or chronic disease outcomes. In this project, we will evaluate the function of a subset of toxin-antitoxin systems that have been identified as one of the bacterial switches that sense stress and activate a persistence phenotype. We will determine their association with bacterial persistence both in vitro and in vivo. Our central hypothesis is that selective toxins are upregulated in vivo in response to specific conditions, and loss of their function results in reduced host-associated persistence. It is important to point out that current antibiotics used against B. pseudomallei generate persister frequencies of up to 50%. Because current treatments last months due to the propensity of B. pseudomallei to generate latent infections, the study of toxin-antitoxin systems can help identify new drug targets and therefore improve antibiotic efficacy. Our proposed experimental approach will focus on two specific aims: first, we will evaluate the role of selected toxins in survival and induction of a persistent stage during B. pseudomallei infection of macrophages because this cell type likely facilitates latent infections; secondly, we will evaluate the contribution of the toxins in B. pseudomallei's ability to persist during host-associated in vivo conditions. Our proposal is significant because it is expected to elucidate the role of the specific toxins that have a strong association with the persistence phenotype, and this might result in the development of alternative therapeutic approaches to prevent latent infections caused by B. pseudomallei, a CDC Category B Tier 1 Select Biothreat Agent and an understudied emerging pathogen.