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了重要器官的感染，从而有助于其 依从性，定殖和生物膜形成。在口腔中，S。Mutans使用其表面粘附于Agi/II和 GBPC遵守GP340以遵守初始粘附，葡聚糖以促进生物膜发展，在某些情况下 掺入生物膜中的其他微生物。链球菌种的许多成员更普遍 表达一个类似AGI/II的同源物，它们用于遵守共享和规格特定的目标，隐含 它们有助于涉及这些链球菌的感染状态。在身体伤害的部位 对于牙龈或牙龈疾病，链球菌物种会渗入血液并成为系统性的机会主义 病原体。 该建议的重点是表征宿主微杆和微生物的分子机制 相互作用涉及蛋白质的AGI/II家庭。在SSPB的结构研究中，Deivanayagam实验室发现了 V区域内的肽结合裂缝，共享钙离子的共享裂缝。该肽具有纳摩尔 遵守SSPB，AGI/II和GBPC的V区；肽抑制了V区的粘附于SRCR GP340区域并减少生物膜的形成。在使用GBPC的研究中，此裂缝也参与了 V区遵守Dextran。我们的初步研究不仅表明共同的依从性目标，而且还表明 也保留了依从性的地区。 AGI/II-家庭蛋白的顶端V区和细胞壁锚定的C末端区域都显示为 参与依从性宿主表面。在此提案中，我们计划调查以下假设 AGI/II-家庭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 这有助于口腔以外的感染的倡议或进展。具体目的是AIM1： 表征AGI/II家庭蛋白质与ECM之间的相互作用。目标2：确定AGI/II蛋白的能力 与其他致病性微生物相互作用。拟议的研究将阐明依从性共享领域 确定设计抑制剂以防止相互作用的潜力，这将降低 这些链球菌有助于感染和疾病。