Targeting Pneumococcal Transmission

描述-针对肺炎球菌传播 该项目的长期目标是更全面地预防由 肺炎链球菌（Spn，肺炎球菌）。我们对持续存在的 肺炎球菌是基于19年来广泛的儿童免疫接种的教训， 指出，如果要降低Spn病的发病率， 进一步减少。然而，Spn生命周期中的这一关键步骤并不是以前的重点。 研究或疫苗发现。这是因为有助于Spn传染的细菌因素是 由于研究自然传播的复杂性和缺乏易于驾驭的动物， 模型我们的总体前提是，特定的Spn基因有助于其传播， 产品是潜在的新预防目标。我们最近开发了一个婴儿小鼠模型， 窝内传播，使详细研究的生物学的SPN传播。该模型 用于确定毒素肺炎球菌溶血素在增加分泌物的粘膜炎症中的作用 促进SPN脱落并促进其传播。最近，该模型已被用于 筛选Tn-seq突变体的基因组文库，以从一个 单个分离株。许多“命中”编码的酶可以结合和降解粘蛋白 糖蛋白在目标#1中表征的这些产物可允许Spn离开定殖宿主 利用粘液流动，然后从粘液捕获中释放出来，在新的宿主中建立。目标#2将 通过鉴定影响菌株间自然传播的Spn基因， 在一个社区内。这将通过3085的全基因组关联研究（GWAS）进行。 从约600名婴儿的每月鼻拭子中获得的公开可用的全基因组序列（Maela 群组）。然后将在哺乳动物的幼鼠模型中测试/确认候选遗传元件。 传输我们使用幼鼠模型的初步数据概括了 在对Spn体液免疫中的肺炎球菌免疫阻断了传播。目标#3 是早期的疫苗测试我们将使用幼鼠模型来确定 保守的表面因子，包括在Tn-seq和GWAS筛选中鉴定的那些，以诱导 不需要主机内保护即可中断主机到主机传播的抗扰性。在 项目结束后，我们将了解SPN如何促进其传播，以及是否 可以有针对性地减少肺炎球菌疾病的持续高负担。

Description- Targeting Pneumococcal Transmission The long-term goal of this project is a more comprehensive prevention of disease caused by Streptococcus pneumoniae (Spn, the pneumococcus). Our approach to the ongoing problem of the pneumococcus is based on the lessons from 19 years of widespread childhood immunization, which point to the critical need to interrupt host-to-host transmission if the incidence of Spn disease is to be reduced further. This key step in the Spn lifecycle, however, has not been the focus of previous investigation or vaccine discovery. This is because bacterial factors contributing to Spn contagion are poorly understood due to the complexities of studying natural transmission and a lack of tractable animal models. Our overall premise is that specific Spn genes contribute to its transmission and that their gene products are potential novel targets for prevention. We recently developed an infant mouse model of intra-litter spread that allows for the detailed study of the biology of Spn transmission. This model was used to establish the role of the toxin, pneumolysin, in mucosal inflammation that increases secretions that promote Spn shedding and facilitate its transmission. More recently, this model has been used to screen a genomic library of Tn-seq mutants to identify the complete set of `transmission' genes from a single isolate. Many of the `hits' encode enzymes that could function in binding to and degrading mucin glycoproteins. These products to be characterized in Aim#1 could allow Spn to exit the colonized host using mucus flow, then release itself from mucus entrapment to establish in a new host. Aim#2 will take a separate approach by identifying Spn genes affecting natural transmission among strains circulating within a community. This will be carried out with a genome-wide association study (GWAS) on 3085 publicly-available whole genome sequences obtained from monthly nasal swabs of ~600 infants (Maela cohort). Candidate genetic elements will then be tested/confirmed in the infant mouse model of transmission. Our preliminary data using the infant mouse model recapitulates the experience from pneumococcal immunization in that humoral immunity to Spn blocks transmission. The focus of Aim#3 is early-stage vaccine testing. We will use the infant mouse model to determine the potential for conserved surface factors, including those identified in the Tn-seq and GWAS screens, to induce immunity that interrupts host-to-host spread without the requirement for within-host protection. At the conclusion of the project, we will understand how Spn promotes its transmission and whether transmission can be targeted to mitigate the continued high burden of pneumococcal disease.