Targeting Pneumococcal Transmission

针对肺炎球菌传播

• 批准号: 10091397
• 负责人: Jeffrey Neal Weiser
• 金额: $ 66.47万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10091397
• 关键词: Affect; Animal Model; Bacterial Genes; Bacterial Genome; Binding; Biology; Candidate Disease Gene; Child; Childhood; Communities; Data; Disease; Enzymes; Event; Frequencies; Funding; Genes; Genetic; Genetic Screening; Genome; Genomic Library; Glycoproteins; Goals; Herd Immunity; Human; Humoral Immunities; Immunity; Immunization; Incidence; Infant; Infection; Inflammation; Interruption; Investigation; Maps; Modeling; Molecular; Mucins; Mucosal Immunity; Mucositis; Mucous body substance; Mus; Nose; Organism; Pathogenesis; Pneumococcal Infections; Pneumococcal conjugate vaccine; Polysaccharides; Population; Prevalence; Prevention; Respiratory System; Role; Serotyping; Streptococcus pneumoniae; Streptococcus pneumoniae plY protein; Surface; Testing; Toxin; Vaccinated; Vaccine Antigen; base; cohort; contagion; density; design; disorder prevention; experience; gene product; genetic element; genome wide association study; genomic locus; genomic variation; host colonization; immunogenic; improved; infant monitoring; insight; microbial; mouse model; mutant; nasal swab; novel; novel vaccines; pathogen; success; transmission process; transmission-blocking vaccine; transposon sequencing; vaccine discovery; vaccine evaluation; vaccine-induced immunity; whole genome

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.

描述 - 靶向肺炎球菌传播 该项目的长期目标是对由 肺炎链球菌（SPN，肺炎球菌）。我们解决正在进行的问题的方法 肺炎球菌是基于19年来普遍的童年免疫的教训， 指出如果SPN疾病的发生率是 进一步减少。但是，SPN生命周期中的这一关键步骤并不是以前的重点 调查或疫苗发现。这是因为导致SPN传染的细菌因素是 由于研究自然传播的复杂性和缺乏可牵引动物的复杂性，因此理解不佳 型号。我们的总体前提是特定的SPN基因有助于其传播和其基因 产品是预防的潜在新目标。我们最近开发了一个婴儿的小鼠模型 静物内传播，允许对SPN传播的生物学进行详细研究。这个模型是 用于确定毒素，肺炎肺炎在粘膜炎症中的作用，从而增加分泌物 这促进了SPN脱落并促进其传播。最近，该模型已用于 筛选TN-Seq突变体的基因组库，以识别从A的完整“传播”基因集 单分离物。许多“命中”编码可能在结合和降解粘蛋白的酶 糖蛋白。这些在AIM＃1中表征的产品可以使SPN退出殖民主机 使用粘液流，然后从粘液夹带中释放自身以在新宿主中建立。 AIM＃2将占据 通过识别影响循环菌株自然传播的SPN基因的单独方法 在社区内。这将通过3085的全基因组协会研究（GWAS）进行 从约600名婴儿的每月鼻拭子获得的公共可用的整个基因组序列（Maela 队列）。然后，将在婴儿小鼠模型中测试/确认候选遗传因素 传播。我们使用婴儿鼠标模型的初步数据概括了 肺炎球菌免疫对SPN的体液免疫阻滞了传播。目标＃3的重点 是早期疫苗测试。我们将使用婴儿鼠标模型来确定 保守的表面因素，包括在TN-Seq和GWAS屏幕中鉴定的表面因素，以诱导 无需进行主机内保护而无需中断宿主到主机的免疫力。在 该项目的结论，我们将了解SPN如何促进其传输以及是否是否 可以针对传播来减轻肺炎球菌疾病的持续高负担。