Rational identification of Corynebacterium strains for use as probiotics

益生菌用棒状杆菌菌株的合理鉴定

• 批准号: 10622610
• 负责人: Matthew Scott Kelly
• 金额: $ 19.43万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622610
• 关键词: Accounting; Adherence; Bacteremia; Bacteria; Bacterial Pneumonia; Biological Response Modifier Therapy; Candidate Disease Gene; Cells; Cessation of life; Child; Child Mortality; Childhood; Comparative Genomic Analysis; Competitive Binding; Corynebacterium; Data; Defensins; Development; Disease; Epithelial Attachment; Epithelium; Exclusion; Exhibits; Future; Genes; Genetic; Genomics; Genotype; Goals; Growth; Human; In Vitro; Infection; Infection prevention; Intervention; Invaded; Knowledge; Low Prevalence; Lower respiratory tract structure; Mediating; Meningitis; Modeling; Nasopharynx; Pathogenicity; Peptides; Phenotype; Pneumococcal Infections; Pneumonia; Prevention; Probiotics; Proteomics; Research; Respiratory System; Respiratory Tract Infections; Risk; Serotyping; Skin; Streptococcus pneumoniae; Surface; Testing; Tissue Model; Upper respiratory tract; Vaccination; Vaccines; Work; airway epithelium; antimicrobial; antimicrobial peptide; bacterial resistance; biobank; colonization resistance; comparative; comparative genomics; experimental study; genome annotation; genome sequencing; infection risk; insight; microbiota; mortality; novel; pan-genome; pathogen; pathogenic bacteria; patient population; prevent; rational design; repository; respiratory; respiratory colonization; respiratory pathogen; therapeutic candidate; whole genome

Project Summary Pneumonia is the leading infectious killer of children. Bacterial pathogens, particularly Streptococcus pneumoniae, cause the most serious disease and mortality. Vaccination reduces invasive diseases such as bacteremia and meningitis caused by vaccine serotypes. However, vaccination does not equally lower the burden of pneumonia, and non-vaccine S. pneumoniae serotypes continue to emerge to cause respiratory and invasive infections. Thus, an opportunity exists for new ways to prevent these infections. Nasopharyngeal colonization precedes bacterial pneumonia and other respiratory infections, and the microbiota serves as a barrier to pathogen colonization and subsequent invasion of the lower respiratory tract. Our studies and others demonstrate that commensal, non-pathogenic Corynebacterium species are associated with a lower prevalence of colonization by bacterial respiratory pathogens, including S. pneumoniae. The data show an inverse correlation between the relative abundance of Corynebacterium in the nasopharyngeal microbiota and the risk of colonization by S. pneumoniae. These Corynebacterium species may be promising biotherapeutic candidates for development if they exert specific mechanistic control of bacterial respiratory pathogens. The overall objective herein is to identify the mechanisms by which Corynebacterium spp. colonize the human nasopharynx and exclude S. pneumoniae colonization. The rationale is that defining the mechanisms of these interspecies interactions will lead to identifying Corynebacterium spp. that exert multiple mechanisms of pathogen exclusion and are candidates for future biotherapeutics to prevent respiratory infections. The Specific Aims are: 1) Identify mechanisms by which Corynebacterium spp. adhere to the respiratory epithelium and inhibit Sp colonization through competitive adherence, and 2) Elucidate non-adherence mechanisms by which Corynebacterium spp. inhibit Sp colonization. This proposal will combine models of bacteria-host and bacteria-bacteria interactions to define mechanisms through which Corynebacterium inhibit S. pneumoniae colonization. We will leverage comparative genomics of a large Corynebacterium strain repository to identify accessory gene candidates that mediate respiratory epithelium attachment, competitive adherence with S. pneumoniae, and pneumococcal growth inhibition through secreted factors. The impact of this work is expected from the mechanistic insights and Corynebacterium strain identification that may lead to the first rationally-designed biotherapeutics to prevent pneumonia and other respiratory infections.

项目摘要 肺炎是儿童的主要传染病杀手。细菌病原体，特别是链球菌 肺炎，导致最严重的疾病和死亡率。疫苗接种减少了侵入性疾病，例如 疫苗血清型引起的菌血症和脑膜炎。但是，疫苗接种并不能同样降低 肺炎的负担和非疫苗S.肺炎血清型继续出现，引起呼吸道和 侵入性感染。因此，存在一个新方法来防止这些感染的机会。 鼻咽定植先于细菌性肺炎和其他呼吸道感染，以及微生物群 作为病原体定植的障碍，随后入侵下呼吸道。我们的研究 其他人则表明，共同的非致病性Corynebacterium种类与较低的 包括肺炎链球菌在内的细菌呼吸道病原体定植的患病率。数据显示 鼻咽微生物群中cory菌的相对丰度和相对的相关性 肺炎链球菌定植的风险。这些corynebacterium物种可能是有希望的生物治疗 如果候选者对细菌呼吸道病原体的特定机械控制，则发育。 本文的总体目的是确定Corynebacterium spp的机制。殖民人类 鼻咽并排除肺炎链球菌定殖。理由是定义这些机制 种间相互作用将导致识别corynebacterium spp。这施加了多种机制 病原体排除，是未来生物治疗剂预防呼吸道感染的候选者。 具体目的是：1）确定corynebacterium spp的机制。坚持呼吸道 上皮和通过竞争性遵守抑制SP定植，2）阐明不遵守 Corynebacterium spp的机制。抑制SP定植。该建议将结合 细菌宿主和细菌 - 细菌相互作用以定义机制，通过该机制抑制S. 肺炎定植。我们将利用大型Corynebacterium菌株存储库的比较基因组学 确定介导呼吸上皮附着的辅助基因候选者，竞争性依从性 肺炎链球菌和通过分泌因素抑制肺炎球菌的生长抑制。 这项工作的影响是从机械洞察力和Corynebacterium菌株识别中的影响 这可能会导致第一个合理设计的生物疗法，以防止肺炎和其他呼吸道 感染。