Targeting Pneumococcal Transmission
Targeting Pneumococcal Transmission
批准号:
10555215
负责人:
Jeffrey Neal Weiser
金额:
$66.47万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-02-01 至 2025-01-31
关键词:
AffectAnimal ModelBacterial GenesBacterial GenomeBindingBiologyCandidate Disease GeneChildChildhoodCommunitiesDataDiseaseEnzymesEventFrequenciesFundingGenesGeneticGenetic ScreeningGenomeGenomic LibraryGlycoproteinsGoalsHerd ImmunityHumanHumoral ImmunitiesImmunityImmunizationIncidenceInfantInfectionInflammationInterruptionInvestigationLife Cycle StagesMapsModelingMolecularMucinsMucosal ImmunityMucositisMucous body substanceMusNoseOrganismPathogenesisPneumococcal InfectionsPneumococcal conjugate vaccinePolysaccharidesPopulationPrevalencePreventionRespiratory SystemRoleSerotypingStreptococcus pneumoniaeStreptococcus pneumoniae plY proteinSurfaceTestingToxinVaccinatedVaccine Antigencohortcontagiondensitydisorder preventionexperiencegene productgenetic elementgenome wide association studygenomic locusgenomic variationhost colonizationimmunogenicimprovedinfant monitoringinsightmicrobialmouse modelmutantnasal swabnovelnovel vaccinespathogenrational designsuccesstransmission blockingtransmission processtransmission-blocking vaccinetransposon sequencingunvaccinatedvaccine discoveryvaccine evaluationvaccine-induced immunitywhole genome
中文摘要
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。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Targeting Pneumococcal Colonization
-
批准号:10113534
-
项目类别:
-
资助金额:$21.19万
-
财政年份:2020
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Targeting Pneumococcal Transmission
-
批准号:10091397
-
项目类别:
-
资助金额:$66.47万
-
财政年份:2020
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Targeting Pneumococcal Transmission
-
批准号:10324567
-
项目类别:
-
资助金额:$66.47万
-
财政年份:2020
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Early Events in Pneumococcal Colonization
-
批准号:9185923
-
项目类别:
-
资助金额:$42.38万
-
财政年份:2015
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Early Events in Pneumococcal Colonization
-
批准号:8630673
-
项目类别:
-
资助金额:$39.47万
-
财政年份:2013
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Bacterial and host factors in pneumococcal competition
-
批准号:8197203
-
项目类别:
-
资助金额:$38.0万
-
财政年份:2008
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Bacterial and host factors in pneumococcal competition
-
批准号:8389668
-
项目类别:
-
资助金额:$35.72万
-
财政年份:2008
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Bacterial and host factors in pneumococcal competition
-
批准号:7991364
-
项目类别:
-
资助金额:$38.0万
-
财政年份:2008
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Bacterial and host factors in pneumococcal competition
-
批准号:7578559
-
项目类别:
-
资助金额:$38.77万
-
财政年份:2008
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Bacterial and host factors in pneumococcal competition
-
批准号:7751906
-
项目类别:
-
资助金额:$38.38万
-
财政年份:2008
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Microbial Pathogenesis and Genomics
-
批准号:8269825
-
项目类别:
-
资助金额:$24.16万
-
财政年份:2006
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Microbial Pathogenesis and Genomics
-
批准号:8147592
-
项目类别:
-
资助金额:$23.47万
-
财政年份:2006
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Training in bacteriology
-
批准号:7251892
-
项目类别:
-
资助金额:$13.92万
-
财政年份:2006
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Microbial Pathogenesis and Genomics
-
批准号:8454420
-
项目类别:
-
资助金额:$24.24万
-
财政年份:2006
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Training in bacteriology
-
批准号:7615011
-
项目类别:
-
资助金额:$17.71万
-
财政年份:2006
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Training in bacteriology
-
批准号:7778307
-
项目类别:
-
资助金额:$18.27万
-
财政年份:2006
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Training in bacteriology
-
批准号:7447911
-
项目类别:
-
资助金额:$10.92万
-
财政年份:2006
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Training in bacteriology
-
批准号:7123679
-
项目类别:
-
资助金额:$14.07万
-
财政年份:2006
-
负责人:Jeffrey Neal Weiser
-
依托单位:
Competition Among Bacterial Resiratory Pathogens
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批准号:6697065
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项目类别:
-
资助金额:$23.78万
-
财政年份:2003
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负责人:Jeffrey Neal Weiser
-
依托单位:
Competition Among Bacterial Resiratory Pathogens
-
批准号:6601912
-
项目类别:
-
资助金额:$22.46万
-
财政年份:2003
-
负责人:Jeffrey Neal Weiser
-
依托单位:
海外基金