Multifunctional Roles of AgI/II Family Proteins

AgI/II 家族蛋白的多功能作用

• 批准号: 10750344
• 负责人: Joshua Lee Mieher
• 金额: $ 7.71万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10750344
• 关键词: Abscess; Address; Adherence; Adhesions; Affinity; Agglutinins; Antibiotics; Antigens; Apical; Area; Bacteria; Bacterial Adhesins; Binding; Binding Sites; Biological; Biological Assay; Blood; Brain; C-terminal; Calcium ion; Calorimetry; Candida albicans; Cardiovascular system; Cell Wall; Characteristics; Clinical; Co-Immunoprecipitations; Collagen; Dental Care; Dental caries; Development; Dextrans; Dimensions; Disease; Dose; Etiology; Extracellular Matrix; Extracellular Matrix Proteins; Family; Fellowship; Fibrinogen; Fibronectins; Goals; Growth; Heart; Heart Valves; Homologous Gene; Housing; Human; Immunofluorescence Microscopy; Immunoglobulin Domain; In Vitro; Infection; Infection prevention; Infective endocarditis; Infiltration; Inflammation; Interruption; Invaded; Knock-out; Length; Liver; Lung; Membrane Proteins; Meta-Analysis; Microbe; Microbial Biofilms; Minor; Modeling; Molecular; Oral cavity; Organ; Pathogenicity; Peptides; Periodontal Diseases; Periodontitis; Play; Protein Family; Proteins; Pseudomonas aeruginosa; Pulmonary Cystic Fibrosis; Reporting; Role; Salivary; Scavenger Receptor Cysteine-Rich Domain; Site; Spleen; Stream; Streptococcus; Streptococcus gordonii; Streptococcus intermedius; Streptococcus mutans; Structure; Surface; Surface Plasmon Resonance; Therapeutic; Tissues; Titrations; Variant; cystic fibrosis infection; dental agent; design; glycoprotein 340; host-microbe interactions; inhibitor; member; microbial; microorganism; mutant; nanomolar; opportunistic pathogen; oral commensal; oral infection; oral streptococci; prevent; treatment fees

Project Summary Streptococcal bacteria contribute to infections of vital organs through their surface proteins which facilitate their adherence, colonization, and biofilm formation. In the oral cavity, S. mutans use its surface adhesins AgI/II and GbpC to adhere to Gp340 for initial adherence, dextran to promote biofilm development, and in some cases other microbes which are incorporated into biofilms. More generally many members of the streptococcal species express an AgI/II-like homolog which they use to adhere to both shared and species-specific targets, implicating them in contributing to the disease state of infections involving these streptococci. At sites of physical damage to gums or gum disease, streptococcal species can infiltrate the blood stream and become systemic opportunistic pathogens. This proposal focuses on characterizing the molecular mechanisms of host-microbe and microbe-microbe interactions involving the AgI/II-family of proteins. In structural studies of SspB the Deivanayagam lab discovered a peptide-binding cleft within the V-region, a shared cleft housing a calcium ion. This peptide has nanomolar adherence with the V-regions of SspB, AgI/II and GbpC; the peptide inhibits the V-regions adherence to SRCR region of Gp340 and reduces biofilm formation. In studies with GbpC, this cleft was shown to also be involved in the V-regions adherence to dextran. Our preliminary studies have shown not only shared adherence targets, but also conserved areas of adherence. Both the apical V-region and cell-wall anchored C-terminal regions of AgI/II-family proteins have been shown to be involved in adherence host surfaces. In this proposal we plan to investigate the hypothesis that the Extracellular matrix (ECM) protein interactions among AgI/II-family proteins would share similar but distinct motifs that contribute to the initiation or progression of infections outside the oral cavity. The specific aims are Aim1: Characterize the interactions between AgI/II-family proteins and ECMs. Aim 2: Determine AgI/II proteins’ ability to interact with other pathogenic microorganisms. The proposed studies will elucidate shared areas of adherence to determine the potential for designing inhibitors to prevent the interaction which would reduce the ability of these streptococci to contribute to infection and disease.

项目摘要 链球菌细菌通过其表面蛋白促进重要器官的感染， 粘附、定殖和生物膜形成。在口腔中，S.变形杆菌利用其表面粘附素AgI/II， GbpC粘附于Gp 340用于初始粘附，葡聚糖促进生物膜发育，并且在某些情况下， 其他微生物也被纳入生物膜中。更普遍的是，链球菌属的许多成员 表达一种AgI/II样同源物，它们用来粘附共同的和物种特异性的靶标，这意味着 它们在促成涉及这些链球菌的感染的疾病状态中起作用。在物理损坏的地方 对于牙龈或牙龈疾病，链球菌可以渗透到血液中，成为全身性的机会性感染。 病原体 本研究的重点是研究宿主-微生物和微生物-微生物的分子机制 涉及AgI/II-蛋白质家族的相互作用。在SspB的结构研究中，Deivanayagam实验室发现 V区内的肽结合裂缝，一个容纳钙离子的共享裂缝。这种肽具有纳摩尔 与SspB、AgI/II和GbpC的V区粘附;该肽抑制V区与SRCR的粘附 Gp 340区域并减少生物膜形成。在对GbpC的研究中，这种裂缝也被证明参与了 V区对葡聚糖的粘附。我们的初步研究表明，不仅有共同的坚持目标， 还保留了粘附区域。 AgI/II家族蛋白质的顶端V区和细胞壁锚定的C端区都被证明是 参与粘附宿主表面。在本提案中，我们计划调查的假设， AgI/II家族蛋白之间的细胞外基质（ECM）蛋白相互作用将共享相似但不同的基序 导致口腔外感染的开始或进展。具体目标是： 表征AgI/II家族蛋白与ECM之间的相互作用。目的2：确定AgI/II蛋白的能力 与其他病原微生物相互作用。拟议的研究将阐明共同遵守的领域 以确定设计抑制剂以防止相互作用的潜力，这种相互作用会降低 这些链球菌有助于感染和疾病。