Molecular basis of virulence in the emerging pathogen Kingella kingae

描述（由申请人提供）：Kingella kingae是一种侵袭性革兰氏阴性病原体，最近被认为是幼儿感染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，每年有超过15000例脓毒性关节炎和骨髓炎在儿童中发生，在生命的前3年发病率最高。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、关节关节不稳定和慢性关节脱位，10-25%的病例导致残留的骨骼功能障碍。根据流行病学资料，金氏K. kinae病的发病机制被认为始于上呼吸道的定植，并涉及

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.