Mechanisms of maternal Immunoglobulin A control over the neonatal microbiota and the development of Necrotizing Enterocolitis.
母体免疫球蛋白 A 控制新生儿微生物群和坏死性小肠结肠炎发展的机制。
基本信息
- 批准号:10541105
- 负责人:
- 金额:$ 44.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-15 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:16S ribosomal RNA sequencingAffectAnti-Bacterial AgentsAntibodiesAntibody RepertoireAntibody-mediated protectionAreaAsthmaB-LymphocytesBacteriaBenignBindingCause of DeathCellsChildChronic DiseaseCommunitiesDangerousnessDataDevelopmentDiseaseDropsEnterobacteriaceaeEpitheliumGenerationsGenetic TranscriptionGnotobioticHealthHeterogeneityHuman MilkIgA DeficiencyImmuneImmune responseImmune systemImmunoglobulin AIncidenceIndividualInfantInfectionInfection preventionInfiltrationInflammatoryIntestinal MucosaIntestinesInvadedKnowledgeLinkMammary glandMaternal antibodyMeasuresMediatingMilkMilk BanksMothersMucosal Immune ResponsesMucous MembraneMusMutationNecrotizing EnterocolitisNeonatalObesityPredispositionPremature InfantPremature Infant DiseasesPreventive therapyProductionPropertyRag1 MouseResearchRiskRoleSamplingSecretory Immunoglobulin ASepsisShapesSourceStructureT-LymphocyteTaxonTestingTherapeuticVariantWomanbacterial communitybacterial genome sequencingcostde novo mutationdonor milkgut microbiotaimprovedintestinal epitheliummicrobial communitymicrobiomemicrobiotamodel organismmouse modelneonatal miceneonatenovelpathogenprematurepreventprospectiveprotective effectpupresponsetranscriptome
项目摘要
Abstract
Neonates are particularly susceptible to invasion by colonizing bacteria and thus mammalian mothers protect
their children via antibodies and in particular, Immunoglobulin A (IgA), secreted into maternal milk. Necrotizing
Enterocolitis (NEC) is a disease of premature infants characterized by invasion of the neonatal intestine by the
microbiota. Studies have shown that the incidence of NEC is significantly reduced in infants fed with breast milk,
though the mechanism is unclear. Our preliminary studies show that maternal IgA (mIgA) is an important factor
in protection against NEC. Analysis of IgA-binding on fecal samples from premature infants indicated that breast
milk was the predominant source of IgA in the first month post-delivery and that a relative drop in the fraction of
bacteria bound by IgA is associated with the development of NEC. Sequencing of IgA-bound and unbound
bacteria indicated that NEC was associated with a unique increase in IgA negative Enterobacteriaceae. Further,
we confirmed that IgA is critical in preventing NEC in the murine model, where we demonstrate that pups reared
by mIgA deficient mothers are susceptible to disease, indicating that IgA in breast milk is necessary for
protection. Together these data indicate that mIgA binding is critical in preventing the development of NEC by
shaping the neonatal microbiota. In order to mediate effects on bacterial communities IgA acts on bacterial sub-
populations. Therefore, our central hypothesis is that IgA in maternal milk modifies intestinal bacteria directly,
preventing their invasion of the neonatal intestine and the induction of inflammatory immune responses. We will
test this hypothesis in three aims. In the first aim we will investigate the mechanisms of how individual sub-
populations of Enterobacteriaceae change to elude mIgA. Further we will investigate the mIgA repertoire of
different breast milk donors to test the hypothesis that variation in this repertoire is important in binding different
intestinal bacteria. In aim 2 we will investigate the mechanism of IgA binding on the neonatal microbiota at the
community level, via 16S rRNA gene sequencing and by transcriptional analysis of a model organism in
gnotobiotic mice. Our hope is to associate these data with analysis of the role of IgA on epithelial association of
intestinal bacteria and the downstream immune responses that are induced. In the third aim we will investigate
whether the production of mammary gland antibodies that protect against NEC are dependent upon maternal T
cells. These aims will lead to a better understanding of how mIgA shapes the nascent microbiome and the
neonatal immune response. In addition, our proposal may improve provide strategies to prevent NEC via the
targeted provision of breast milk containing protective antibodies to the most at-risk children.
摘要
新生儿特别容易受到殖民细菌的入侵,因此哺乳动物母亲保护
通过抗体,特别是分泌到母乳中的免疫球蛋白A(伊加),坏死性
小肠结肠炎(NEC)是早产儿的一种疾病,其特征是新生儿肠道被新生儿肠上皮细胞侵袭,
微生物群研究表明,母乳喂养的婴儿NEC的发病率显著降低,
尽管其机制尚不清楚。我们的初步研究表明,母亲伊加(mIgA)是一个重要的因素,
保护NEC。早产儿粪便样本IgA结合分析表明,
在分娩后的第一个月,牛奶是伊加的主要来源,
伊加结合的细菌与NEC的发生有关。IgA结合和未结合的测序
细菌表明NEC与伊加阴性肠杆菌科的独特增加相关。此外,本发明还
我们在小鼠模型中证实了伊加在预防NEC中的关键作用,在该模型中,我们证明了
缺乏mIgA的母亲容易患病,这表明母乳中的伊加对于
保护总之,这些数据表明,mIgA结合在预防NEC的发展中是至关重要的,
塑造新生儿的微生物群。为了调节对细菌群落的影响伊加作用于细菌亚群,
人口。因此,我们的中心假设是母乳中的伊加直接改变了肠道细菌,
防止它们侵入新生儿肠道和诱导炎性免疫应答。我们将
在三个目标中检验这个假设。在第一个目标中,我们将研究个体亚-
肠杆菌科的种群改变以逃避mIgA。进一步,我们将研究的mIgA剧目,
不同的母乳捐赠者,以测试这一假设,即在这个剧目的变化是重要的结合不同的
肠道细菌在目标2中,我们将研究伊加结合新生儿微生物群的机制,
群落水平,通过16 S rRNA基因测序和转录分析的模式生物,
无菌小鼠我们的希望是将这些数据与伊加在上皮细胞联合中的作用分析相关联,
肠道细菌和诱导的下游免疫应答。在第三个目标中,我们将研究
是否乳腺抗体的产生,防止NEC是依赖于母体T
细胞这些目标将使我们更好地了解mIgA如何塑造新生的微生物组,
新生儿免疫反应此外,我们的建议可能会改善提供战略,以防止NEC通过
有针对性地向高危儿童提供含有保护性抗体的母乳。
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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Timothy Wesley Hand其他文献
Timothy Wesley Hand的其他文献
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{{ truncateString('Timothy Wesley Hand', 18)}}的其他基金
Investigating the tissue location and protective function of oral vaccine-specific tissue resident memory CD4 T cells
研究口服疫苗特异性组织驻留记忆 CD4 T 细胞的组织定位和保护功能
- 批准号:
10646930 - 财政年份:2023
- 资助金额:
$ 44.97万 - 项目类别:
Identifying the mechanism of anti-colorectal immunity induced by mucoinvasive colonic bacteria
确定粘膜侵袭性结肠细菌诱导的抗结直肠免疫机制
- 批准号:
10585344 - 财政年份:2022
- 资助金额:
$ 44.97万 - 项目类别:
Mechanisms of maternal Immunoglobulin A control over the neonatal microbiota and the development of Necrotizing Enterocolitis.
母体免疫球蛋白 A 控制新生儿微生物群和坏死性小肠结肠炎发展的机制。
- 批准号:
10312104 - 财政年份:2020
- 资助金额:
$ 44.97万 - 项目类别:
Mechanisms of maternal Immunoglobulin A control over the neonatal microbiota and the development of Necrotizing Enterocolitis.
母体免疫球蛋白 A 控制新生儿微生物群和坏死性小肠结肠炎发展的机制。
- 批准号:
9883292 - 财政年份:2020
- 资助金额:
$ 44.97万 - 项目类别:
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