The Structural and Functional Determination of Streptococcus mutans Adherence

变形链球菌粘附的结构和功能测定

• 批准号: 10112889
• 负责人: Champion Christdoss Selvakumar Deivanayagam
• 金额: $ 42.24万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112889
• 关键词: Acids; Address; Adherence; Adhesions; Adopted; Affect; Affinity; Animal Model; Bacterial Adhesins; Binding; Candida albicans; Child; Collagen; Complex; Comprehension; Coupled; Crystallization; Dental Models; Dental caries; Development; Dextrans; Ecology; Ensure; Etiology; Future; Gene Mutation; Genes; Glucans; Glucosyltransferases; Goals; Human; I-antigen; Individual; Investigation; Knowledge; Ligands; Maps; Mediating; Membrane Proteins; Methods; Microbe; Microbial Biofilms; Modeling; Molecular; Mutagenesis; Oral; Oral cavity; Outcome; Outcome Study; Pathogenesis; Pathogenicity; Peptides; Play; Population; Predisposition; Production; Protein C; Proteins; Rattus; Resolution; Rodent Model; Role; Salivary; Scavenger Receptor Cysteine-Rich Domain; Site; Streptococcus Viridans Group; Streptococcus adhesin; Streptococcus gordonii; Streptococcus mutans; Structure; Study models; Surface; Therapeutic; Virulence; combinatorial; comparative; dental biofilm; design; dysbiosis; early childhood; genetic manipulation; glucan-binding protein; glycoprotein 340; microbial; microbial colonization; microorganism; microorganism interaction; mutant; nanomolar; oral streptococci; pathogen; polymicrobial disease; prevent; sortase; tooth surface

Dental caries is a polymicrobial disease that affects much of the human population worldwide, where the harmony of a cooperative eco-organization shifts towards a dysbiotic framework with overrepresentation of pathogenic microorganisms, particularly by Streptococcus mutans (SM). For planktonic SM, adhesion to tooth surface and/or dental biofilms is a crucial step in the pathogenesis of dental caries, and SM has evolved (i) SM- host and (ii) SM-microbial interactions, which are mediated through its surface proteins (adhesins). SM’s adhesion mediated interactions include: (A) The recent discovery of redundant high affinity binding of SM’s adhesins to the scavenger receptor cysteine rich domains (SRCR) of the salivary glycoprotein 340 (Gp340), which promotes caries susceptibility in the SM-host interface; and (B) The revelation of SM’s adhesin required for the SM-Candida albicans (CA) biofilm formation and acid production, which enhances cariogenicity in early childhood caries in the SM-microbial interface. Together these have revealed previously unknown interactions by once thought to be well-known and well-characterized adhesins on SM. Yet the key unanswered question remains, “how does SM mediate such redundant, but specific binding to host proteins and to other microbes?” The goal of this application is to determine the specific motif(s) and/or molecular mechanism(s) that drive SM’s adherence, particularly how they enable binding to multiple ligands. Our structural and functional studies show that SM’s surface adhesins mediate these attachments primarily via two major structural domains, the V- and C-fold. We hypothesize that “the V- and C-fold present on the surface adhesins of SM mediate specific interactions through common binding motif(s) that are crucial for biofilm formation and microbial colonization”. We will address our hypothesis through three specific aims (SAs) by (a) mapping the adherence motif(s) on the V-fold (SA1) and (b) C-fold (SA2) of oral streptococcal adhesins, and (c) investigating the role of SM’s adhesins in the SM-Candida albicans (CA) interface (SA3). The results from this multi-PD/PI study will (i) Determine the binding-motif(s)/mechanisms globally adopted by the V- and C-fold among SM’s adhesins; (ii) Determine the presence of distinct and/or overlapping adherence sites for various ligands; (iii) Provide a comparative analysis of the V- and C-fold of various adhesins from mutans and viridans streptococci, revealing species-specific differences in their binding-motifs/mechanisms; (iv) Characterize the role of SM adhesins at the SM-CA interface; and (v) Elucidate alternations in the microbial ecology modulated by SM’s V- and C-folds, particularly as they relate to dental caries. Our proposed structural analyses, genetic manipulation of key adhesion motif(s) and animal model studies will determine the adherence mechanisms and address the knowledge gap on SM’s V- and C-fold, particularly their crucial role in promoting colonization and virulence. The results will enable future development of selective combinatorial therapeutics to prevent SM’s adherence to host and microbes.

龋齿是一种多微生物疾病，影响着全世界大部分人口