Molecular basis of virulence in the emerging pathogen Kingella kingae

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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.