Pathogenicity of the emerging pathogen Kingella kingae

新出现的病原体金氏菌的致病性

• 批准号: 10559927
• 负责人: Joseph W. St. Geme
• 金额: $ 44.5万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-04 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559927
• 关键词: 4 year old; Accounting; Acute suppurative arthritis due to bacteria; Address; Adult; Alleles; Anabolism; Animals; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Therapy; Antimicrobial Resistance; Articulation; Awareness; Bacterial Adhesins; Biological Assay; Biology; Blood Circulation; Bone Growth; Child; Chronic; Culture Techniques; Detection; Development; Diagnostic Procedure; Diphtheria Toxin; Disease; Distant; Endocardium; Family; Functional disorder; Future; Glycoconjugates; Human; Immune response; Incidence; Infant; Infection; Invaded; Joint Dislocation; Joints; Kingella kingae; Lipopolysaccharides; Mediating; Modeling; Monobactams; Morbidity - disease rate; Nature; Neisseria gonorrhoeae; Neisseriaceae; Organism; Oropharyngeal; Osteomyelitis; Pathogenesis; Pathogenicity; Phagocytosis; Pilum; Polysaccharides; Production; Property; Rattus; Reporting; Residual state; Resistance; Sampling; Sepsis; Series; Serum; Side; Site; Structure; Surface; Testing; Toxin; Vaccine Antigen; Vaccines; Virulence; Virulence Factors; Work; antimicrobial peptide; bacterial resistance; beta-Lactam Resistance; beta-Lactamase; bone; capsule; disorder prevention; emerging pathogen; gene product; immunogenic; immunogenicity; improved; insight; joint infection; joint mobilization; member; molecular diagnostics; mortality; multiorgan injury; mutant; neutrophil; pathogen; pathogenic bacteria; prevent; protective efficacy; skeletal

Kingella kingae is an invasive gram-negative pathogen that has been recognized recently as a leading cause of bone and joint infections in young children, accounting for up to 88% of osteoarticular cases in children <4 years old. In addition, K. kingae is an important cause of invasive bloodstream infections in young children. Complications of osteoarticular infections 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. Complications of invasive bloodstream infections include multi-organ injury and mortality. Approximately 25% of K. kingae isolates possess β-lactamase activity, and many of these isolates are resistant to other antibiotics as well, raising concern about approaches to treatment in the future. At present there are no effective strategies to prevent K. kingae disease and the associated morbidity. The pathogenesis of K. kingae disease begins with colonization of the oropharynx, followed by invasion of the bloodstream and spread to bones, joints, and other sites. We have established that isolates of K. kingae produce an exopolysaccharide that is encoded by the pamABCDE locus, is a homopolymer of galactofuranose, is secreted from the organism, and is a critical virulence factor essential for full virulence. We have found that there are 2 distinct exopolysaccharide structures, distinguished by the linkage of the galactofuranose repeating subunit and referred to as type 1 and type 2. Importantly, the exopolysaccharide promotes resistance to serum- mediated killing and neutrophil phagocytosis and thereby promotes K. kingae survival in the bloodstream, indicating that at least some of the exopolysaccharide is anchored to the bacterial surface. Preliminary results indicate that pooled serum from healthy adults and convalescent serum samples from children with invasive K. kingae disease contain antibodies against the exopolysaccharide. In this proposal, we will elucidate the mechanism by which the type 1 and type 2 exopolysaccharides are synthesized and anchored to the bacterial surface. In addition, we will elucidate the pathogenic properties of the type 1 and type 2 exopolysaccharides. We will also elucidate the immunogenicity and protective efficacy of the exopolysaccharides. The proposed studies will provide fundamental insight into K. kingae pathogenicity and basic aspects of bacterial exopolysaccharides. These studies will also facilitate development of a K. kingae vaccine and antibody-based therapeutics against other pathogens with galactofuranose-containing surface structures.

金氏菌是一种侵入性革兰氏阴性病原体，最近被认为是主要病因