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）：Kingella kingae是一种侵袭性革兰氏阴性病原体，最近被认为是幼儿脓毒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，在美国儿童中每年发生超过15，000例脓毒性关节炎和骨髓炎，发病率在生命的前3年达到高峰。儿童脓毒性关节炎和骨髓炎的并发症包括骨生长异常、关节活动受限、关节不稳定和慢性关节脱位，导致10-25%的病例出现残余骨骼功能障碍。根据流行病学资料，对克雷伯氏菌的致病机理进行了探讨。Kingae病被认为开始于上呼吸道的定植 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型皮利是K.呼吸道上皮细胞粘附 和滑膜细胞，表明在上呼吸道定植和关节播种中起关键作用。进一步的分析表明，全水平菌毛介导的粘附依赖于一种称为Knh的三聚体自转运蛋白。进一步的研究表明K. kingae产生多糖荚膜，提示K.在血液中存活。等基因包囊和非包囊菌株的比较表明，多糖胶囊干扰Khn介导的粘附。在目前的建议中，我们将阐明IV型皮利，Knh蛋白， 多糖胶囊作为K的决定因素。粘附于呼吸道上皮细胞和滑膜细胞。此外，我们将阐明K的遗传决定因素。kingae包囊在我们的原型菌株，扩展初步数据表明，K。Kingae胶囊基因以新的遗传构型组织。我们还将阐明不同菌株的多糖胶囊的异质性K。并检查胶囊类型是否与分离部位相关。这些研究将有助于我们更好地了解克雷伯氏菌引起的疾病的发病机制。并将为开发一种基于胶囊的疫苗来预防K。金氏病此外，他们将提供一般的见解封装的病原体和宿主细胞之间的相互作用机制，并将扩大我们的知识细菌多糖胶囊。