Genetic variation of the Serratia marcescens capsule polysaccharide locus and its contribution to bloodstream infection

项目总结 血液感染(BSI)是一个主要的公共卫生负担，并与高发病率有关 死亡率。这些感染对医疗保健环境中的个人来说尤其成问题，在那里，风险因素为 感染增加，经常遇到具有抗生素耐药性的生物体。革兰氏阴性杆菌 粘质沙雷氏菌是所有血液感染的十大最常见原因之一， 但是，导致粘质葡萄球菌感染的毒力因素在很大程度上还没有定论。我们最近做了 确定粘质链球菌在哺乳动物血液中的适合性取决于产生一种 多糖胶囊。粘质链球菌在小鼠菌血症模型中的存活是包膜依赖的 对人血清杀菌活性的抗药性。尽管粘质链球菌胶囊很重要，但一种 还没有对这种生物的胶囊生产进行全面的遗传评估。这个 大多数负责胶囊生产的基因聚集在一个单一的染色体上，该基因包括 一种保守基因的混合物，编码诸如多糖运输等功能，以及辅助基因 是特定于类型的。尽管胶囊生物合成位点在物种水平上存在很大差异，但我们 已经确定在粘质链球菌菌血症中有两种特殊的胶囊类型的高流行率 分离株。此外，与BSI相关的包膜类型含有其他类型所没有的副包膜基因。 分离株。这项建议的首要目标是确定S。 从BSI患者中分离出粘质菌株并确定可变被膜基因在BSI中的作用 感染。本次调查将集中于两个具体目标：1)确定粘质链霉菌的遗传变异性 与BSI相关的包膜生物合成位点和鉴定包膜类型。2)确定以下项目的贡献 粘质链霉菌毒力的BSI相关基因变异。在完成这些目标后，我们将拥有 分离和测序了来源于BSI的粘质链霉菌，测定了其多糖结构 BSI相关的包膜类型，并确定了不同的包膜辅助基因对 血液感染。这项工作将对目前关于S。 Marcescens的发病机制，并有可能为未来基于抗囊的治疗提供信息，以对抗BSI。

PROJECT SUMMARY Bloodstream infections (BSI) represent a major public health burden and are associated with high rates of mortality. These infections are especially problematic for individuals in healthcare settings where risk factors for infection are increased and antibiotic resistant organisms are frequently encountered. The Gram-negative bacterial pathogen Serratia marcescens is among the ten most common causes of all bloodstream infections, but the virulence factors that drive S. marcescens infection are largely uncharacterized. We have recently determined that fitness of S. marcescens in the mammalian bloodstream is dependent on the production of a polysaccharide capsule. Survival of S. marcescens in a murine bacteremia model is capsule-dependent as is resistance to the bactericidal activity of human serum. Despite the importance of S. marcescens capsule, a comprehensive genetic assessment of capsule production has not been performed for this organism. The majority of genes responsible for capsule production are clustered in a single chromosomal locus that includes a mixture of conserved genes, encoding functions such as polysaccharide transport, as well as accessory genes that are type-specific. Despite the substantial species-level variation within the capsule biosynthetic locus, we have determined that there is a high prevalence of two specific capsule types among S. marcescens bacteremia isolates. Furthermore, BSI-associated capsule types harbor accessory capsule genes that are absent from other isolates. The overarching goal of this proposal is to define the genetic variability of the capsule locus for S. marcescens strains isolated from patients with BSI and determine the role of variable capsule genes during infection. This investigation will focus on two specific aims: 1) Define the genetic variability of the S. marcescens capsule biosynthesis locus and identify capsule types associated with BSI. 2) Determine the contribution of variable BSI-associated capsule genes to S. marcescens virulence. Upon completion of these aims, we will have isolated and sequenced S. marcescens strains originating from BSI, determined the polysaccharide structure of BSI-associated capsule types, and determined the contribution of variable capsule accessory genes to bloodstream infection. This work will have a substantial impact on the current state of knowledge regarding S. marcescens pathogenesis and has the potential to inform future anti-capsule-based therapies to combat BSI.