Elucidating the role of sialic acids and sialidase in the pathogenesis of Porphyromonas ginigvalis

阐明唾液酸和唾液酸酶在牙龈卟啉单胞菌发病机制中的作用

• 批准号: 10398165
• 负责人: Christopher Khoa Pham
• 金额: $ 4.23万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-25 至 2023-06-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398165
• 关键词: Affect; Alzheimer' s Disease; Amino Acids; Anabolism; Analytical Chemistry; Arthritis; Award; Bacteria; Binding; Biochemical; Biochemistry; Biological Process; C-terminal; Carbon; Cardiovascular Diseases; Cell Communication; Cell surface; Cells; Chronic; Complement; Complex; Dental Research; Development; Diabetes Mellitus; Disease; Doctor of Philosophy; Embryonic Development; Enrollment; Enzymes; Etiology; Excision; Fellowship; Forsythia; Foundations; Functional disorder; Genetic; Genome; Glycobiology; Glycoconjugates; Goals; Human; Immune; Immune Evasion; Immune response; Immune system; Immunology; Infection; Inflammation; Interdisciplinary Study; Invaded; Knowledge; Lead; Lipopolysaccharides; Mammalian Cell; Mediating; Microbial Biofilms; Modification; Molecular; Molecular Biology; Mucous Membrane; N-terminal; Neuraminidase; Neurologic; Oral cavity; Oral health; Pathogenesis; Pathogenicity; Pathway interactions; Peptidoglycan; Periodontal Diseases; Periodontitis; Play; Polysaccharides; Polysialic Acid; Porphyromonas; Porphyromonas gingivalis; Positioning Attribute; Protein Biochemistry; Protein Chemistry; Protein Secretion; Proteins; Reporting; Research; Research Project Grants; Resistance; Role; School Dentistry; Sequence Analysis; Series; Serum; Sialic Acids; Solid; Sugar Acids; Surface; System; Technical Expertise; Testing; Training; Universities; Virginia; Virulence; Virulence Factors; bacterial genetics; base; capsule; career; chronic infection; complement system; doctoral student; dysbiosis; extracellular; genetic approach; inhibitor; insight; interdisciplinary approach; macromolecule; mutant; nano; novel; novel strategies; oral bacteria; oral pathogen; pathogen; pathogenic bacteria; periodontopathogen; prevent; programs; protein protein interaction; sialic acid permease; symporter; uptake

Project Summary Sialic acids (SA) describe a complex class of nine-carbon sugar acids that exist primarily as terminal moieties on a variety of surface molecules on mammalian cells. SA serve as a critical self-recognition molecule in the never-ending warfare with invading pathogens. Many pathogens exploit this feature by scavenging host SA using sialidases, a group of enzymes that catalyze the removal terminal SA from host glycoconjugates. Porphyromonas gingivalis (Pg) is one of the etiological agents of periodontal disease due to its exquisite manipulation of the host immune system to cause chronic inflammation and dysbiosis in the oral cavity. Interestingly, all the genome-sequenced Pg strains have a highly conserved sialidase. Recent studies have shown that sialidase (PG0352) plays a critical role in the pathophysiology of Pg, such as capsule formation, biofilms, and serum complement resistance; however, its underlying molecular mechanism remains largely unknown. The goal of this application is to fill this knowledge gap by focusing on the following aims: Aim 1 seeks to understand the biochemical features of PG0352; Aim 2 is to elucidate the mechanism by which PG0352 protects Pg from the serum complement killing; and Aim 3 is to investigate how Pg acquires SA through studies of a putative novel SA transporter. The findings from this application will provide new insights into understanding the role of SA and sialidase in the pathogenesis of periodontitis. In addition, this multidisciplinary research project will enhance the applicant's knowledge and technical skills in bacterial genetics, protein biochemistry, host-pathogen interactions, immunology and glycobiology.

项目摘要 唾液酸（SA）描述了一类复杂的九碳糖酸，主要以末端形式存在 哺乳动物细胞上的各种表面分子上的部分。SA作为一种批判性的自我认知 在与入侵病原体的无休止的战争中。许多病原体利用这一特点， 使用唾液酸酶清除宿主SA，唾液酸酶是一组催化从宿主中除去末端SA的酶。 宿主糖缀合物。牙龈卟啉单胞菌（Porphyromonas gingivalis，Pg）是牙周炎的病原菌之一 疾病，由于其精湛的操纵宿主免疫系统，造成慢性炎症， 口腔内的微生态失调。有趣的是，所有基因组测序的Pg菌株都具有高度保守的 唾液酸酶。近年来的研究表明，唾液酸酶（PG 0352）在肿瘤的病理生理过程中起着重要的作用 Pg，如胶囊形成，生物膜和血清补体抵抗;然而，其潜在的 分子机制仍然是未知的。本应用程序的目标是填补这一知识空白 通过关注以下目标：目标1旨在了解PG 0352的生化特征;目标2 目的：探讨PG 0352保护Pg免受血清补体杀伤的机制 3是通过对一种新的SA转运蛋白的研究来探讨Pg是如何获得SA的。这些发现 从这个应用程序将提供新的见解，了解SA和唾液酸酶的作用， 牙周炎的发病机制此外，这项多学科研究项目将加强 申请人在细菌遗传学、蛋白质生物化学、宿主-病原体 相互作用，免疫学和糖生物学。

项目成果

Functional and structural analyses reveal that a dual domain sialidase protects bacteria from complement killing through desialylation of complement factors.

• DOI: 10.1371/journal.ppat.1011674
• 发表时间: 2023-09
• 期刊: PLoS pathogens
• 影响因子: 6.7