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

粘质沙雷氏菌荚膜多糖位点的遗传变异及其对血流感染的影响

• 批准号: 10116278
• 负责人: MARK T. ANDERSON
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116278
• 关键词: Address; Anabolism; Antibiotic Resistance; Antibiotic-resistant organism; Antibiotics; Bacteremia; Bacterial Capsules; Blood Circulation; Cessation of life; Clinical; Data; Data Set; Elements; Environment; Exhibits; Foundations; Frequencies; Future; Generations; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; High Prevalence; Human; Human Activities; Individual; Infection; Investigation; Knowledge; Life; Mining; Modeling; Mus; Mutation; Organism; Pathogenesis; Patients; Phenotype; Physiology; Polysaccharides; Production; Public Health; Recombinants; Resistance; Resources; Risk Factors; Role; Sepsis; Septicemia; Sequence Analysis; Serratia marcescens; Serum; Severities; Structure; Surface; United States; Variant; Virulence; Virulence Factors; Work; bactericide; base; capsule; combat; experimental study; fitness; gene product; genetic approach; health care settings; insight; microbial; mortality; novel; opportunistic pathogen; pathogen; pathogenic bacteria; tool

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.

项目摘要 血流感染（BSI）是一个主要的公共卫生负担，并与高发病率相关。 mortality.这些感染对于在医疗保健环境中的个体尤其成问题，在医疗保健环境中， 感染增加且经常遇到抗生素抗性生物体。革兰氏阴性 细菌病原体粘质沙雷氏菌是所有血流感染的十种最常见原因之一， 但是驱动S.粘质杆菌感染在很大程度上没有特征。我们最近 确定了S.哺乳动物血液中的粘质酶依赖于 多糖胶囊S.小鼠菌血症模型中的粘质杆菌是胶囊依赖性的， 对人血清杀菌活性的抗性。尽管S.粘质软胶囊 尚未对该微生物进行胶囊生产的全面遗传评估。的 大多数负责胶囊生产的基因聚集在一个单一的染色体位点，包括 保守基因的混合物，编码多糖转运等功能，以及辅助基因 是特定类型的。尽管在荚膜生物合成位点内存在着大量的物种水平的变异， 已经确定在S.粘质菌血症 分离株此外，BSI相关的荚膜类型含有其他荚膜类型不存在的辅助荚膜基因。 分离株该建议的首要目标是确定S. 从BSI患者中分离的粘质杆菌菌株，并确定可变荚膜基因在 感染本研究的主要目的有两个：1）明确猪的遗传变异性;粘质 荚膜生物合成位点，并鉴定与BSI相关的荚膜类型。2)确定的贡献 可变的BSI相关荚膜基因与S.粘质虫毒力在完成这些目标后，我们将有 分离并测序S. marcescens菌株来源于BSI，确定了多糖结构 BSI相关的荚膜类型，并确定了可变的荚膜辅助基因对 血液感染这项工作将对目前关于S. marcescens发病机制，并有可能告知未来的抗胶囊为基础的治疗，以打击BSI。