Bacterial CRISPR interference to define macrophage responses to group B Streptococcus proteins
细菌 CRISPR 干扰定义巨噬细胞对 B 族链球菌蛋白的反应
基本信息
- 批准号:10724607
- 负责人:
- 金额:$ 25.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:Adverse eventAffectAllelesAmniotic FluidAnimal ModelAnti-Inflammatory AgentsBacteriaBacterial GenesBindingBinding ProteinsCRISPR interferenceCandidate Disease GeneCell WallCellsClinicalClustered Regularly Interspaced Short Palindromic RepeatsComplementComplement 5aComplexConfocal MicroscopyDangerousnessDefectDetectionDiseaseEarly treatmentEtiologyFetal DevelopmentFetusGene DeletionGene ExpressionGenerationsGenesGeneticGoalsGrowthHealthHomeostasisHumanHyaluronidaseImmuneImmune EvasionImmune responseImmunologic SurveillanceImmunophenotypingIncubatedInfectionInflammatoryInflammatory ResponseInnate Immune SystemInterleukin-1 betaInvadedLeadLibrariesLifeMacrophageMacrophage ActivationMaternal-Fetal ExchangeMeasurementMediatingMicrobeModelingMolecular MimicryMothersMusNatural ImmunityNewborn InfantOutcomePathogenesisPeptide HydrolasesPhagocytesPhagocytosisPlacentaPlayPolysaccharidesPredispositionPregnancyPregnant UterusPregnant WomenPremature BirthPremature LaborPreventionProductionProtein SecretionProteinsReactive Oxygen SpeciesReceptor SignalingRoleSialic AcidsSignal TransductionSortingStreptococcal InfectionsStreptococcus CAMP proteinStreptococcus Group BSurfaceTNF geneTechniquesTestingTherapeuticTimeTissuesUnited StatesVaginaVirulenceWestern BlottingWorkadverse pregnancy outcomeantimicrobialcandidate identificationcapsuleclinically relevantcomplement 4b-binding proteincomplement systemcytokinedelivery complicationsdensityearly onsetexperimental studyfetalhigh rewardhigh riskin vivoinnovationinterestintraamniotic infectionintrauterine infectionknock-downmicrobialmouse modelmultimodalitymutantneonatal sepsisnovelnovel therapeuticsnovel vaccinespathogenpost pregnancyresponsesingle-cell RNA sequencingstillbirthtool
项目摘要
Project Summary
Group B Streptococcus (GBS) is a major cause of intrauterine infections in the United States and around the
world. These infections commonly lead to serious adverse pregnancy outcomes including stillbirth, preterm
labor, neonatal sepsis, and systemic maternal disease, which can be life-threatening. One reason that GBS is
such a common etiology of serious intrauterine infection is that—among bacterial vaginal colonizers—it has
exceptional abilities to suppress and evade fetal and maternal innate immune surveillance that is highly
effective at clearing other microbes from the intrauterine cavity. Macrophages are key effectors of maternofetal
innate immunity, and serve important roles in maintaining gestational health, yet can fail to eliminate GBS from
pregnancy tissues, setting the stage for serious complications. The goal of this proposal is to examine, in
detail, molecular interactions between macrophages and GBS cells to discover basic mechanisms of
GBS evasion and suppression of gestational macrophage signaling and bacterial killing. We will use
novel CRISPR/Cas-based bacterial gene suppression techniques to systematically test GBS strains from
knockdown libraries that are deficient in specific, highly conserved, surface trafficked proteins. These strains
with specific externalized protein defects will be coincubated with ex vivo human placental macrophages, both
maternal and fetal-derived, to examine their effects on macrophage cytokine expression, phagocytosis, and
microbial killing. We will use these screens to identify novel GBS surface trafficked proteins with significant
effects on placental macrophage immunophenotypes. Discoveries from these screens, including several
already made in preliminary experiments, will inform generation of targeted gene deletion GBS mutants. These
mutants and appropriate complemented controls will then be used to characterize effects on placental
macrophages in detail, through multiplex cytokine profiling, single-cell transcriptomics, immunofluorescent
confocal microscopy, and examination of in vivo outcomes from a clinically relevant mouse model of GBS
intrauterine infection. Our two proposed aims will use innovative, multimodal approaches to identify GBS
externalized protein targets for new vaccines or therapeutics for prevention and early treatment of dangerous
intrauterine infections.
项目摘要
B族链球菌(GBS)是美国和世界各地子宫内感染的主要原因。
世界这些感染通常会导致严重的不良妊娠结局,包括死产、早产
分娩、新生儿败血症和可能危及生命的全身性母体疾病。GBS之所以
严重子宫内感染的常见病因是,在细菌阴道定植者中,
抑制和逃避胎儿和母体先天免疫监视的特殊能力,
有效清除子宫腔内的其他微生物。巨噬细胞是母胎发育的关键效应子
先天免疫,并在维持妊娠期健康中发挥重要作用,但不能消除GBS,
妊娠组织,为严重的并发症做好准备。该提案的目的是审查,在
详细,巨噬细胞和GBS细胞之间的分子相互作用,以发现
GBS逃避和抑制妊娠巨噬细胞信号传导和细菌杀伤。我们将使用
基于CRISPR/Cas的新型细菌基因抑制技术,用于系统地测试来自
缺乏特异性、高度保守、表面运输蛋白质的敲除库。这些菌株
将与离体人胎盘巨噬细胞共孵育,
母体和胎儿来源的,以检查它们对巨噬细胞细胞因子表达、吞噬作用和
微生物杀灭我们将使用这些筛选来鉴定新的GBS表面运输蛋白,
对胎盘巨噬细胞免疫表型的影响。从这些屏幕上的发现,包括几个
已经在初步实验中,将告知靶基因缺失GBS突变体的产生。这些
然后将使用突变体和适当的补充对照来表征对胎盘的影响。
巨噬细胞详细,通过多重细胞因子谱,单细胞转录组学,免疫荧光
共聚焦显微镜检查和临床相关GBS小鼠模型的体内结果检查
宫内感染我们提出的两个目标将使用创新的多模式方法来识别GBS
用于预防和早期治疗危险性疾病的新疫苗或治疗剂的外部化蛋白质靶点
子宫内感染
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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David M Aronoff其他文献
Infections caused by emClostridium perfringens/em and emPaeniclostridium sordellii/em after unsafe abortion
不安全流产后由产气荚膜梭菌和索氏梭菌引起的感染
- DOI:
10.1016/s1473-3099(22)00590-4 - 发表时间:
2023-02-01 - 期刊:
- 影响因子:31.000
- 作者:
David M Aronoff;Jeanne M Marrazzo - 通讯作者:
Jeanne M Marrazzo
David M Aronoff的其他文献
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{{ truncateString('David M Aronoff', 18)}}的其他基金
The Role of macrophages in chorioamnionitis and group B streptococcal infections
巨噬细胞在绒毛膜羊膜炎和 B 族链球菌感染中的作用
- 批准号:
10576123 - 财政年份:2017
- 资助金额:
$ 25.29万 - 项目类别:
Determining the contribution of zinc deficiency to perinatal Group B Streptococcus infections
确定锌缺乏对围产期 B 族链球菌感染的影响
- 批准号:
10163224 - 财政年份:2017
- 资助金额:
$ 25.29万 - 项目类别:
The Role of macrophages in chorioamnionitis and group B streptococcal infections
巨噬细胞在绒毛膜羊膜炎和 B 族链球菌感染中的作用
- 批准号:
9978691 - 财政年份:2017
- 资助金额:
$ 25.29万 - 项目类别:
The Role of macrophages in chorioamnionitis and group B streptococcal infections
巨噬细胞在绒毛膜羊膜炎和 B 族链球菌感染中的作用
- 批准号:
10211123 - 财政年份:2017
- 资助金额:
$ 25.29万 - 项目类别:
Determining the contribution of zinc deficiency to perinatal Group B Streptococcus infections
确定锌缺乏对围产期 B 族链球菌感染的影响
- 批准号:
9381886 - 财政年份:2017
- 资助金额:
$ 25.29万 - 项目类别:
The Role of macrophages in chorioamnionitis and group B streptococcal infections
巨噬细胞在绒毛膜羊膜炎和 B 族链球菌感染中的作用
- 批准号:
9403144 - 财政年份:2017
- 资助金额:
$ 25.29万 - 项目类别:
Prostaglandins as protective mediators in Clostridium difficile infection
前列腺素作为艰难梭菌感染的保护介质
- 批准号:
9316517 - 财政年份:2016
- 资助金额:
$ 25.29万 - 项目类别:
Repurposing misoprostol for Clostridium difficile colitis as identified by PheWAS
PheWAS 确定米索前列醇重新用于治疗艰难梭菌结肠炎
- 批准号:
9336367 - 财政年份:2016
- 资助金额:
$ 25.29万 - 项目类别:
Mechanisms of group B streptococcal interactions with extraplacental membranes
B 族链球菌与胎盘外膜相互作用的机制
- 批准号:
8507835 - 财政年份:2012
- 资助金额:
$ 25.29万 - 项目类别:
Epidemiology and Genomics of Clostridium difficile
艰难梭菌的流行病学和基因组学
- 批准号:
8026742 - 财政年份:2010
- 资助金额:
$ 25.29万 - 项目类别:
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