Serine-rich repeat proteins in evolution of Lactobacillus-host specificity

乳酸菌宿主特异性进化中富含丝氨酸的重复蛋白

• 批准号: 10573683
• 负责人: William Basil Ludington
• 金额: $ 24.23万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573683
• 关键词: Adhesions; Animals; Bacteria; Bacterial Adhesins; Binding; Bioinformatics; Biological Assay; Biological Models; Cell Adhesion Molecules; Cell Wall; Cell surface; Cells; Colon Carcinoma; Communities; Competitive Binding; Data; Digestion; Digestive System Disorders; Drosophila genus; Drosophila melanogaster; Engineering; Enzymes; Evolution; Fermentation; Food; Future; Gastrointestinal tract structure; Gene Proteins; Genes; Genetic; Genus staphylococcus; Goals; Grant; Growth; Health; Homologous Gene; Human; Image; In Vitro; Incidence; Infection prevention; Island; Knock-out; Knowledge; Lactobacillaceae; Lactobacillus; Lactobacillus plantarum; Lead; Ligand Binding; Ligands; Malignant neoplasm of gastrointestinal tract; Measures; Membrane Proteins; Metabolic syndrome; Metabolism; Microbe; Microbial Biofilms; Modeling; Molecular; Mucous Membrane; Mucous body substance; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Polysaccharides; Population; Postdoctoral Fellow; Probiotics; Property; Proteins; Resolution; Resources; Risk; Role; Serine; Site; Specificity; Streptococcus; Structure; Surface; Testing; Therapeutic; Time; Tissues; Training; Visualization; Work; activation-induced cytidine deaminase; cancer risk; combat; commensal microbes; cost; fitness; fly; gene discovery; genetic resource; glycosylation; gut colonization; gut microbiome; gut microbiota; host microbiome; immunoregulation; improved; in vivo; microbial; microbiome; microbiome composition; mutant; pathogen; physical property; pressure; receptor; recruit; spatiotemporal; success; sugar; unpublished works

Abstract Probiotic lactobacilli colonize mucosae and benefit human health by preventing infections, reducing cancer risk, and improving metabolism. Among the lactobacilli, Lactobacillus plantarum is one of the most widely studied probiotics. Lactobacilli use surface molecules called adhesins to form physical associations with host tissues, and serine-rich repeat proteins (SRRPs) are one specific class of adhesin used by probiotics and pathogens alike within in the Lactobacillaceae. A key gap in our knowledge is how these proteins evolve specificity for their colonization site within the host. This proposal investigates the hypothesis that cell-cell competition inside the host creates an evolutionary selection pressure on SRRP genes to maximize bacterial cell fitness inside the host. We investigate the first SRRP genes discovered in L. plantarum, which we found to be necessary for colonization of a specific physical niche in the host digestive tract. The proposal will examine evolution and specialization of the SRRP genes as well as the functions of specific subdomains of the protein for their role in binding host mucus vs forming a biofilm, vs promoting bacterial growth within the niche by enzymatically liberating host glycans. We will use in vivo assays to connect the molecular properties of the SRRPs to cellular fitness in the host. These assays include imaging the bacteria at single cell resolution inside the guts of living animals to visualize the cell-cell competition directly. Success in this work could develop an unparalleled model system to study the evolution of colonization specificity. Due to the wide conservation of SRRPs in binding host mucus, this model may reveal conserved genetic mechanisms that can be applied to develop better probiotics for humans and combat mucosal pathogens.

摘要 益生菌乳酸杆菌定殖于粘膜并通过预防感染而有益于人类健康， 降低癌症风险，改善新陈代谢。在乳杆菌中，植物乳杆菌 是研究最广泛的益生菌之一。乳酸杆菌利用表面分子粘附素 与宿主组织形成物理联系，富含丝氨酸的重复蛋白（SRRP）是其中之一 乳酸杆菌科中益生菌和病原体所使用的一类特殊粘附素。 我们知识中的一个关键空白是这些蛋白质如何进化出它们的定殖位点的特异性 在主机内。该提案调查了细胞内细胞竞争的假设， 宿主对SRRP基因产生进化选择压力， 健身在主机内。我们研究了在L.植物， 我们发现对于宿主消化道中特定物理生态位的定殖是必要的。 该提案将研究SRRP基因的进化和特化，以及 蛋白质的特定亚结构域的功能，因为它们在结合宿主粘液与形成 生物膜，相对于通过酶促释放宿主聚糖来促进微生态位内的细菌生长。 我们将使用体内试验来连接SRRP的分子特性与细胞适应性 在主机中。这些试验包括在肠道内以单细胞分辨率对细菌进行成像， 活的动物来直接观察细胞间的竞争。这项工作的成功可以发展 一个无与伦比的模型系统来研究殖民特异性的演变。由于广泛 SRRP在结合宿主粘液中的保守性，该模型可能揭示了保守的遗传 这些机制可用于开发更好的人类益生菌， 病原体