Molecular basis of virulence in the emerging pathogen Kingella kingae

新发病原体 Kingella kingae 毒力的分子基础

• 批准号: 8731463
• 负责人: Joseph W. St. Geme
• 金额: $ 39.36万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2015-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731463
• 关键词: 4 year old; ATP phosphohydrolase; Accounting; Acetylgalactosamine; Acute suppurative arthritis due to bacteria; Address; Adherence; Alcian Blue; Anabolism; Bacteria; Bacterial Polysaccharides; Blood Circulation; Bone Growth; Cell surface; Cells; Child; Chromosomes; Chronic; Clinical; Data; Development; Disease; Encapsulated; Epithelial Cells; Foundations; Functional disorder; Galactose; Genes; Genetic; Genetic Determinism; Goals; Heterogeneity; Incidence; Joint Dislocation; Joints; Kingella kingae; Knowledge; Life; Location; Mediating; Molecular; Organism; Osteomyelitis; Outcome; Pathogenesis; Pathogenicity; Patients; Pattern; Pilum; Polysaccharides; Population; Process; Production; Proteins; Receptor Cell; Research; Residual state; Ribose; Role; Site; Staining method; Stains; Structure; Surface; Synovial Cell; Upper respiratory tract; Vaccine Antigen; Vaccines; Virulence; Virulence Factors; Work; base; bone; capsule; early childhood; epidemiologic data; improved; insight; novel; pathogen; prevent; programs; prototype; public health relevance; research study; respiratory; skeletal

DESCRIPTION (provided by applicant): Kingella kingae is an invasive gram-negative pathogen that has been recognized recently as a leading cause of septic arthritis and osteomyelitis in young children, accounting for up to 78% of cases in children <4 years old. Estimates indicate that over 15,000 cases of septic arthritis and osteomyelitis occur annually among children in the US, with the peak incidence in the first 3 years of life. Complications of septic arthritis and osteomyelitis in children include abnormalities in bone growth, limitation of joint mobility, unstable joint articulation, and chronic joint dislocation, resulting in residual skeletal dysfunction in 10-25% of cases. Based on epidemiologic data, the pathogenesis of K. kingae disease is believed to begin with colonization of the upper respiratory tract and to involve invasion of the bloodstream and spread to joints and bones. In recent work, we have established that type IV pili are essential for K. kingae adherence to respiratory epithelial cells and synovial cells, suggesting a critical role in colonization of the upper respiratory tract and seeding of joints. Further analysis has demonstrated that full-level pilus-mediated adherence is dependent on a trimeric autotransporter protein called Knh. Additional studies revealed that K. kingae produces a polysaccharide capsule, suggesting a mechanism for K. kingae survival in the bloodstream. Comparison of isogenic encapsulated and non-encapsulated strains demonstrated that the polysaccharide capsule interferes with Khn- mediated adherence. In the present proposal we will elucidate the interrelationship between type IV pili, the Knh protein, and the polysaccharide capsule as determinants of K. kingae adherence to respiratory epithelial cells and synovial cells. In addition, we will elucidate the genetic determinants of K. kingae encapsulation in our prototype strain, extending preliminary data suggesting that the K. kingae capsule genes are organized in a novel genetic configuration. We will also elucidate the heterogeneity of the polysaccharide capsule among diverse isolates of K. kingae and examine whether capsule type correlates with site of isolation. The proposed studies will yield an improved understanding of the pathogenesis of disease due to K. kingae and will lay the foundation for developing a capsule-based vaccine to prevent K. kingae disease. In addition, they will provide general insights into the mechanism of interaction between encapsulated pathogens and host cells and will expand our knowledge of bacterial polysaccharide capsules.

描述（由申请人提供）：金氏菌是一种侵袭性革兰氏阴性病原体，最近被认为是幼儿化脓性关节炎和骨髓炎的主要原因，占 4 岁以下儿童病例的 78%。据估计，美国儿童每年发生超过 15,000 例化脓性关节炎和骨髓炎病例，其中出生后 3 年内发病率最高。儿童化脓性关节炎和骨髓炎的并发症包括骨骼生长异常、关节活动受限、关节不稳定和慢性关节脱位，导致 10-25% 的病例残留骨骼功能障碍。根据流行病学数据，K. kingae 病的发病机制被认为始于上呼吸道定植并涉及 侵入血液并扩散到关节和骨骼。在最近的工作中，我们已经确定 IV 型菌毛对于 K. kingae 粘附呼吸道上皮细胞至关重要 和滑膜细胞，表明在上呼吸道定植和关节播种中发挥着关键作用。进一步的分析表明，菌毛介导的全水平粘附依赖于一种名为 Knh 的三聚体自转运蛋白。其他研究表明，K. kingae 会产生多糖胶囊，这表明 K. kingae 在血液中存活的机制。同基因包封和非包封菌株的比较表明，多糖胶囊干扰 Khn 介导的粘附。在本提案中，我们将阐明 IV 型菌毛、Knh 蛋白和 多糖胶囊作为 K. kingae 粘附于呼吸道上皮细胞和滑膜细胞的决定因素。此外，我们将阐明原型菌株中 K. kingae 包囊的遗传决定因素，扩展表明 K. kingae 胶囊基因以一种新的遗传结构组织的初步数据。我们还将阐明 K. kingae 不同分离株之间多糖荚膜的异质性，并检查荚膜类型是否与分离位点相关。拟议的研究将加深对 K. kingae 疾病发病机制的了解，并为开发预防 K. kingae 疾病的胶囊疫苗奠定基础。此外，它们还将提供对封装病原体与宿主细胞之间相互作用机制的一般见解，并将扩展我们对细菌多糖胶囊的了解。