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
基本信息
- 批准号:9978691
- 负责人:
- 金额:$ 47.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-18 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AntibioticsBacteriaBacterial GenesBacterial InfectionsBacterial ModelBiomedical EngineeringDataDevelopmentDiagnosisDiseaseElementsEpithelial CellsEquilibriumFetal MembranesFetusGenesGenotypeGleanGravidHost DefenseHumanImmuneImmune EvasionImmune ToleranceImmunologyInfectionInflammationInflammatoryInflammatory ResponseInterventionInvadedKnowledgeLightMaternal-Fetal ExchangeMatrix MetalloproteinasesMembraneMetalloproteasesMicrobeMicrofluidicsModelingMolecularMorbidity - disease rateMothersMutagenesisMutationNADH peroxidaseNatural HistoryNatural ImmunityOxidative StressPathogenesisPlacentationPregnancyPregnancy OutcomePremature BirthPremature LaborPrevention therapyProblem SolvingProcessReproductive ImmunologyRoleRuptureSeriesShapesStreptococcal InfectionsStreptococcusStreptococcus Group BStromal CellsStructureSyndromeTechniquesTestingTherapeutic InterventionTimeTissuesUterusVaginaVariantadverse outcomeamnionbasedefense responsedisabilityfascinatefetalhealthy pregnancyhost-microbe interactionsimprovedin vivoinstrumentintraamniotic infectionmacrophagemicrobialmouse modelneonatal sepsisnovel diagnosticsparacrinepathogenpathogenic bacteriaprematurepreventprognosticresponsetooltranscriptome sequencingtrophoblast
项目摘要
Chorioamnionitis (CAM), or inflammation of the fetal membranes, is often the result of ascending bacterial
infection and is a major contributor to premature birth, neonatal sepsis, and long-term disability and morbidity
in babies. Unfortunately, CAM is often asymptomatic and not easily diagnosed in time to prevent maternal and
fetal adverse outcomes. Solving this problem is hamstrung by a limited understanding of early steps in disease
pathogenesis. Despite its relatively simple structure, surprisingly little is known about how fetal membranes
participate in immune defense against potential pathogens. Defining the cellular and molecular basis of innate
immunity within the membranes promises to reveal actionable, host-based targets for diagnosis, prevention
and therapy against CAM. Our objective is to define specific contributions of macrophages to fetal membrane
immunology in the context of bacterial CAM caused by the common pathogen Group B Streptococcus (GBS).
Macrophages in the gravid uterus balance host defense activities with pregnancy-specific actions such as
promoting placental development and governing immune tolerance between mother and fetus. It is fascinating
that both maternal (decidual) and fetal (placental) macrophages are present at the maternal-fetal interface, yet
their specific roles in innate immunity are unknown. We hypothesize (1) that maternal and fetal macrophages
make unique contributions both to host defense and tissue inflammatory responses during bacterial infection
and (2) that the common CAM pathogen, GBS, evades innate immunity by resisting the oxidative stress within
these macrophages. We will test this hypothesis through three Aims. In Aim 1 we will determine the extent to
which maternal and fetal macrophages contribute to the natural history of CAM in vivo using a model of
ascending GBS infection. In Aim 2 we will identify the extent to which GBS survival within macrophages
depends upon the NADH peroxidase (npx) or other genotype-specific intracellular survival defenses.
Mutagenesis studies will be conducted to better understand the impact of npx and other GBS mutations on
survivability and disease in vivo, and to classify bacterial and host genes important for the process using RNA
sequencing. Additional genotypes will be examined for variation in the ability to survive inside decidual and
placental macrophages and persist in the presence of antibiotics commonly used to treat GBS infections.
Lastly, in Aim 3 we will define the paracrine contribution of macrophages within the human fetal membrane
during infection. For this aim, we will take a deconstructive approach, populating a microfluidic, instrumented
fetal membrane-on-chip with decidual or placental macrophages, decidual stromal cells, trophoblasts and
amnion epithelial cells. We will test the sub-hypothesis that distinct macrophage types contribute uniquely to
inflammatory quiescence within uninfected membranes and amplify proinflammatory responses upon microbial
threat in specific manners. These studies will shed new light on reproductive immunology and accelerate the
development of new diagnostic, prognostic, and therapeutic interventions that support healthy pregnancies.
绒毛膜羊膜炎(CAM),或胎膜炎症,通常是上升细菌的结果
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
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
- 批准号:
10724607 - 财政年份:2023
- 资助金额:
$ 47.26万 - 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:
10576123 - 财政年份:2017
- 资助金额:
$ 47.26万 - 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:
$ 47.26万 - 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:
$ 47.26万 - 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:
$ 47.26万 - 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:
$ 47.26万 - 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:
$ 47.26万 - 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:
$ 47.26万 - 项目类别:
Mechanisms of group B streptococcal interactions with extraplacental membranes
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- 批准号:
8507835 - 财政年份:2012
- 资助金额:
$ 47.26万 - 项目类别:
Epidemiology and Genomics of Clostridium difficile
艰难梭菌的流行病学和基因组学
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8026742 - 财政年份:2010
- 资助金额:
$ 47.26万 - 项目类别:
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