Rational identification of Corynebacterium strains for use as probiotics

项目摘要 肺炎是儿童的主要传染性杀手。细菌病原体，特别是链球菌 肺炎，引起最严重的疾病和死亡率。接种疫苗可减少侵袭性疾病， 由疫苗血清型引起的菌血症和脑膜炎。然而，接种疫苗并不能同样降低 肺炎的负担，以及非疫苗S.肺炎血清型继续出现，引起呼吸道和 侵入性感染因此，存在一个预防这些感染的新方法的机会。 鼻咽定植先于细菌性肺炎和其他呼吸道感染， 作为病原体定植和随后侵入下呼吸道的屏障。我们的研究 和其他人证明，非致病性棒状杆菌属物种与较低的 细菌性呼吸道病原体的定植率，包括S.肺炎。数据显示， 鼻咽微生物群中棒状杆菌的相对丰度与 S.肺炎。这些棒状杆菌属物种可能是有前途的生物菌种 如果它们对细菌性呼吸道病原体发挥特定的机械控制作用，则是开发的候选物。 本文的总体目标是鉴定棒状杆菌属物种（Corynebacterium spp.）殖民人类 鼻咽部，排除S.肺炎菌定植。基本原理是，定义这些机制 种间相互作用将导致鉴定棒状杆菌属。发挥多种机制， 病原体排除，并且是未来预防呼吸道感染的生物治疗剂的候选者。 具体的目的是：1）确定棒状杆菌属的机制。坚持呼吸道 通过竞争性粘附抑制Sp定植，和2）阐明非粘附 Corynebacterium spp.抑制Sp定殖。该提案将联合收割机模型 细菌-宿主和细菌-细菌相互作用，以确定棒状杆菌抑制S. 肺炎菌定植。我们将利用大型棒状杆菌菌株库的比较基因组学 为了鉴定介导呼吸上皮附着、竞争性粘附的辅助基因候选物， 链球菌肺炎，和通过分泌因子抑制肺炎球菌生长。 这项工作的影响，预计从机制的见解和棒状杆菌菌株鉴定 这可能会导致第一个合理设计的生物治疗药物，以预防肺炎和其他呼吸道疾病。 感染.

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.