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.

金黄色葡萄球菌是一种侵袭性的革兰氏阴性病原菌，最近被认为是主要致病因素。 儿童骨关节感染，占儿童骨关节病的88% 很多年了。此外，国王克雷伯氏菌是幼儿侵袭性血液感染的重要原因。 儿童骨关节感染的并发症包括骨生长异常、关节受限 活动度、关节不稳定和慢性关节脱位，导致10-10岁的残留性骨骼功能障碍 25%的病例。侵袭性血流感染的并发症包括多器官损伤和死亡。 大约25%的国王克雷伯菌分离株具有β-内酰胺酶活性，其中许多分离株 对其他抗生素也有耐药性，这引发了人们对未来治疗方法的担忧。目前 没有有效的战略来预防国王克雷伯氏菌病及其相关的发病率。发病机制 国王克雷伯氏菌病的发病始于口咽的定植，然后是血液的侵入和 扩散到骨骼、关节和其他部位。我们已经确定K.kingae的分离株产生一种 胞外多糖是由PamABCDE基因编码的，是半乳呋喃糖的均聚物，是一种分泌的 来自有机体，是一种对完全毒力必不可少的关键毒力因子。我们发现有2个 独特的胞外多糖结构，通过半乳呋喃糖重复亚单位的连接来区分 被称为1型和2型。重要的是，胞外多糖提高了对血清的抵抗力- 介导性杀伤和中性粒细胞吞噬，从而促进Kingae在血液中的存活， 这表明至少部分胞外多糖被锚定在细菌表面。初步结果 提示来自健康成人的混合血清和来自侵袭性K。 帝王病含有抗胞外多糖的抗体。在这项建议中，我们将澄清 合成1型和2型胞外多糖并将其固定在细菌上的机制 浮出水面。此外，我们还将阐明1型和2型胞外多糖的致病特性。 我们还将阐明胞外多糖的免疫原性和保护作用。建议数 研究将提供对国王克雷伯氏菌致病性和细菌基本方面的基本见解。 胞外多糖。这些研究还将促进国王克雷伯氏菌疫苗和基于抗体的开发。 具有含半乳呋喃糖表面结构的其他病原体的治疗。