Targeting Pneumococcal Transmission

针对肺炎球菌传播

• 批准号: 10324567
• 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/10324567
• 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; 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; rational design; success; transmission process; transmission-blocking vaccine; transposon sequencing; unvaccinated; 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 - 针对肺炎球菌传播 该项目的长期目标是更全面地预防由以下疾病引起的疾病： 肺炎链球菌（Spn，肺炎球菌）。我们解决当前问题的方法 肺炎球菌疫苗的研发基于 19 年广泛儿童免疫接种的经验教训， 指出如果要降低 Spn 疾病的发病率，就必须中断宿主间的传播 进一步减少。然而，Spn 生命周期中的这一关键步骤并不是之前的重点 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易于驯服的动物，人们对此知之甚少 模型。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 产品是潜在的新预防目标。我们最近开发了一种幼年小鼠模型 窝内传播，可以详细研究 Spn 传播的生物学。这个模型是 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，以识别来自突变体的完整“传递”基因集 单一隔离。许多“命中”编码的酶可以结合和降解粘蛋白 糖蛋白。这些在 Aim#1 中进行表征的产品可能允许 Spn 退出定植宿主 利用粘液流，然后将自身从粘液捕获中释放出来，在新的宿主中建立。目标#2将采取 一种单独的方法，通过识别影响循环菌株之间自然传播的 Spn 基因 在一个社区内。第 3085 章 从约 600 名婴儿每月的鼻拭子中获得的公开可用的全基因组序列（Maela 队列）。然后，候选遗传元件将在婴儿小鼠模型中进行测试/确认 传播。我们使用婴儿小鼠模型的初步数据概括了来自 肺炎球菌免疫对 Spn 的体液免疫可阻止传播。目标#3 的焦点 是早期疫苗测试。我们将使用婴儿小鼠模型来确定其潜力 保守的表面因子，包括那些在 Tn-seq 和 GWAS 筛选中确定的因子，以诱导 无需主机内保护即可中断主机间传播的免疫力。在 项目结束后，我们将了解 Spn 如何促进其传播以及是否 可以有针对性地控制传播，以减轻肺炎球菌疾病持续的高负担。