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)。我们对正在进行的问题的方法 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Spn病的发病率是 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 调查或疫苗发现。这是因为导致Spn感染的细菌因素是 由于研究自然传播的复杂性和缺乏易驯养的动物，人们对此知之甚少 模特们。我们的总体前提是，特定的Spn基因有助于其传播，并且它们的基因 产品是潜在的预防新目标。我们最近开发了一种幼鼠模型 窝内传播，允许详细研究Spn传播的生物学。这个模型是 用来确定毒素，肺溶素，在增加分泌物的粘膜炎症中的作用 促进Spn的脱落并促进其传播。最近，这种模式已被用于 筛选Tn-seq突变体的基因组文库，以鉴定来自 单一隔离。许多Hit编码的酶可以与粘蛋白结合并降解粘蛋白 糖蛋白。这些将在AIM#1中表征的产品可以使Spn离开被殖民的宿主 利用粘液流动，然后将自身从粘液中释放出来，建立在新的宿主中。目标2将采取 一种识别影响循环菌株间自然传播的Spn基因的单独方法 在一个社区内。这将与3085的全基因组关联研究(GWAS)一起进行 从每月约600名婴儿的鼻拭子中获得的公开可用全基因组序列(Maela 队列)。候选遗传因素随后将在幼鼠模型中进行测试/确认 变速箱。我们使用幼鼠模型的初步数据概括了来自 肺炎球菌免疫在对Spn的体液免疫中阻止传播。目标3的重点 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筛查中确定的那些，以诱导 无需主机内部保护即可中断主机到主机传播的免疫力。在 项目结束后，我们将了解Spn是如何促进其传播的，以及 可以有针对性地进行传播，以减轻肺炎球菌病持续高企的负担。

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.