Rational identification of Corynebacterium strains for use as probiotics

项目摘要 肺炎是儿童的头号传染病杀手。细菌病原体，特别是链球菌 肺炎是引起最严重疾病和死亡的原因。接种疫苗可减少侵袭性疾病，如 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地降低 肺炎的负担，以及非疫苗肺炎链球菌的血清型继续出现，导致呼吸道和 侵袭性感染。因此，存在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，以及微生物区系 作为病原体定植和随后入侵下呼吸道的屏障。我们的研究 而其他研究表明，共生的、非致病的棒状杆菌物种与较低的 细菌呼吸道病原体，包括肺炎链球菌的定殖率。数据显示， 鼻咽微生物区系中棒状杆菌的相对丰度与 肺炎链球菌的定植风险。这些棒状杆菌可能是很有前途的生物疗法。 如果它们对细菌呼吸道病原体实施特定的机械控制，就有可能开发。 本研究的总体目标是确定棒状杆菌的致病机制。殖民人类 鼻咽和排除肺炎链球菌定植。其基本原理是定义这些的机制 种间相互作用将导致棒状杆菌的鉴定。它运用了多种机制 病原体排除，是未来预防呼吸道感染的生物疗法的候选药物。 具体目标是：1)鉴定棒状杆菌的致病机制。坚持以人为本 通过竞争性黏附抑制Sp定植，以及2)阐明非黏附 棒状杆菌的致病机制。抑制Sp的定植。这项提案将结合各种模式 细菌-宿主和细菌-细菌的相互作用，以确定棒状杆菌抑制S. 肺炎定植。我们将利用一个大型棒状杆菌菌株库的比较基因组学 确定介导呼吸道上皮附着、竞争性黏附的辅助基因候选 肺炎链球菌，通过分泌因子抑制肺炎链球菌的生长。 这项工作的影响预计来自于机械洞察力和棒状杆菌菌株鉴定 这可能会导致第一种合理设计的生物疗法来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.