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.

项目概要 链球菌通过其表面蛋白促进重要器官的感染，从而促进其 粘附、定植和生物膜形成。在口腔中，变形链球菌使用其表面粘附素 AgI/II 和 GbpC 粘附 Gp340 以实现初始粘附，葡聚糖促进生物膜形成，在某些情况下 融入生物膜的其他微生物。更普遍的是链球菌属的许多成员 表达类似 AgI/II 的同系物，它们用来粘附共享的和物种特异性的目标，这意味着 它们导致涉及这些链球菌的感染的疾病状态。在物理损坏的地方 对于牙龈或牙龈疾病，链球菌种类可以渗入血流并成为全身性机会主义细菌 病原体。 该提案的重点是表征宿主-微生物和微生物-微生物的分子机制 涉及 AgI/II 蛋白家族的相互作用。 Deivanayagam 实验室在 SspB 结构研究中发现 V 区内的肽结合裂隙，是容纳钙离子的共享裂隙。该肽具有纳摩尔 与 SspB、AgI/II 和 GbpC 的 V 区结合；该肽抑制 V 区与 SRCR 的粘附 Gp340 区域并减少生物膜形成。在 GbpC 的研究中，该裂缝也被证明与 V 区对葡聚糖的粘附。我们的初步研究不仅表明了共同的遵守​​目标，而且 还保留了粘附区域。 AgI/II 家族蛋白的顶端 V 区和细胞壁锚定的 C 端区已被证明 参与粘附宿主表面。在本提案中，我们计划研究以下假设： 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 导致口腔外感染的发生或进展。具体目标是Aim1： 表征 AgI/II 家族蛋白与 ECM 之间的相互作用。目标 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的遵守​​领域 确定设计抑制剂以防止相互作用的可能性，这种相互作用会降低 这些链球菌有助于感染和疾病。