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.

Kingella kingae 是一种侵入性革兰氏阴性病原体，最近被认为是主要原因 幼儿骨和关节感染的发生率高达 88% <4 岁儿童骨关节感染 此外，K. kingae 是幼儿侵袭性血流感染的重要原因。 儿童骨关节感染的并发症包括骨骼生长异常、关节受限 活动能力、不稳定的关节关节和慢性关节脱位，导致 10 岁以下患者残留骨骼功能障碍 25% 的病例发生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 K. kingae 分离株具有 β-内酰胺酶活性，并且其中许多分离株具有 对其他抗生素也产生耐药性，引起人们对目前治疗方法的担忧。 没有有效的策略来预防金氏克雷伯氏菌病和相关发病率。 K. kingae 疾病始于口咽部定植，随后侵入血流并 我们已经确定 K. kingae 的分离株会产生一种病毒。 由 pamABCDE 位点编码的胞外多糖，是呋喃半乳糖的均聚物，被分泌 来自生物体，并且是完全毒力所必需的关键毒力因子。我们发现有 2 个。 独特的胞外多糖结构，通过呋喃半乳糖重复亚基的连接来区分 并称为 1 型和 2 型。重要的是，胞外多糖可促进对血清- 介导杀伤和中性粒细胞吞噬作用并促进 K. kingae 在血液中存活， 初步结果表明至少一些胞外多糖固定在细菌表面。 表明来自健康成人的混合血清和来自患有侵袭性克雷伯氏菌的儿童的恢复期血清样本。 kingae病含有针对胞外多糖的抗体。在本提案中，我们将阐明该抗体。 1 型和 2 型胞外多糖合成并固定在细菌上的机制 此外，我们还将阐明 1 型和 2 型胞外多糖的致病特性。 我们还将阐明所提出的胞外多糖的免疫原性和保护功效。 研究将为金氏 K. kingae 致病性和细菌的基本方面提供基本见解 这些研究还将促进 K. kingae 疫苗和抗体的开发。 针对具有含呋喃半乳糖表面结构的其他病原体的疗法。