Novel carbohydrate binding functions of the CR3 I-domain modulate gonococcal-cervical cell interactions
CR3 I 结构域的新型碳水化合物结合功能调节淋球菌-宫颈细胞相互作用
基本信息
- 批准号:10318111
- 负责人:
- 金额:$ 38.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-01-16 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAffectAgonistBacteriaBacterial ProteinsBehaviorBindingBinding SitesBiologicalC3biCalorimetryCarbohydratesCell CommunicationCellsCenters for Disease Control and Prevention (U.S.)CervicalCervicitisCervix UteriCessation of lifeCoculture TechniquesComplementDataDevelopmentDiagnosisDiseaseEnsureEpithelialEpithelial CellsEventFemaleFimbriae ProteinsFoundationsFrequenciesFutureGoalsGonorrheaHIV InfectionsHealthHumanImmuneImmune responseImmune systemImmunityImmunologic ReceptorsIn VitroInfectionInfertilityInnate Immune ResponseLectinLigandsLinkLiteratureMacrophage-1 AntigenMass Spectrum AnalysisMediatingMediator of activation proteinMedical Care CostsMolecularMorbidity - disease rateMucosal ImmunityMucous MembraneMulti-Drug ResistanceNatural ImmunityNatureNeisseria gonorrhoeaeOutcomePathogenesisPathway interactionsPattern recognition receptorPelvic Inflammatory DiseasePeptidesPhagocytesPhasePilumPlayPolysaccharidesPost-Translational Protein ProcessingPrevalencePreventionPreventive measureProcessProteinsPublic HealthRecombinantsReportingRoleSeminalSignal TransductionStructureSurfaceSurface Plasmon ResonanceTestingTherapeuticUnited StatesUrsidae FamilyVariantWomanWorkappendagebaseexperienceglycosylationhuman diseasehuman pathogenimprovedinnate immune functioninnovationinsightmacrophagemicrobialneutrophilnovelnovel strategiesnovel therapeuticspathogenpathogenic bacteriapreventreceptorreproductive tractresponsesugartraffickingvaccine development
项目摘要
PROJECT SUMMARY
The prevalence of Neisseria gonorrhoeae (Ng), its associated morbidity, and the emergence of untreatable
strains, support a critical need for new preventative and therapeutic strategies for this important human-
pathogen. Such developments require a complete understanding of the pathobiology of this archetypal, host-
adapted pathogen. We show that phase-variable, glycan post-translational modifications on Ng surface
appendages, pili (fimbriae), play a vital role in human infection. Complement receptor 3 (CR3) is an important
pattern recognition receptor that is the key receptor mediating Ng colonization of human cervical mucosa. CR3
contains an “I-domain” region, which is known as a binding site for protein ligands. However, we found that
Ng binding to the I-domain is mediated by the pilin-linked glycan (PLG). This is a seminal finding in innate
immunity, as all previous literature ascribe CR3 carbohydrate binding to a separate, so called "lectin" domain.
This was also the first demonstration that post-translational modifications made to a bacterial protein
modulate pathogenesis. These findings will impact our understanding of microbial pathogenesis and innate
immune responses. The goals of the present application are to define the specific contribution of the six,
naturally occurring, PLG structures in mediating the Ng-CR3 I-domain interaction and to determine the
biological relevance of each of these interactions to infection in females. Guided by strong preliminary data, we
hypothesize that variable PLG structures initiate key, but highly divergent, outcomes with CR3 I-domain
engagement. We will resolve our hypothesis through two specific aims: Aim 1) Define the effect of variation in
pilin glycan structure on direct PLG-I-domain interactions; we will define the specific molecular interactions
occurring with the CR3 I-domain for the six natural Ng PLG structures. Aim 2) Define the effect of PLG-I-
domain interactions on Ng pathogenesis and CR3 function; we will define targeted epithelial cell responses to
CR3 I-domain engagement by Ng that bear different PLG structures and their effect on Ng pathogenesis. Our
approach is innovative in using biologically relevant human primary cervical cells, both alone and in co-culture
with phagocytes, combined with low passage Ng isolates. This ensures that data obtained are relevant to
human processes. By defining the effector functions controlled by I-domain lectin activity on primary human
epithelial cells, we will provide critical new information regarding Ng pathogenesis, CR3 function, and the
fundamental mechanisms that govern human cervical mucosal immunity. Moreover, we will define the utility
of targeting the PLG-CR3 I-domain interaction as a new, and improved, host-targeted approach to treat and/or
prevent Ng disease in women. Our studies will very likely impact work on other human pathogens and on
innate immunity, broadening the significance of our outcomes. We have extensive experience in defining the
molecular mechanisms of Ng pathogenesis. We are ideally placed to do this work in having discovered CR3 as
the key receptor for Ng cervical infection and the biosynthetic pathways for pili glycosylation.
项目总结
淋病奈瑟菌(Ng)的流行、相关发病率和无法治疗的出现
菌株,支持对这种重要的人类-新的预防和治疗策略的迫切需要-
病原体。这样的发展需要对这种原型宿主的病理生物学有一个完整的了解。
适应病原体。我们证明了Ng表面上的相变、糖链的平移后修饰
附属物,菌毛(菌毛),在人类感染中起着至关重要的作用。补体受体3(CR3)是一种重要的
模式识别受体是介导Ng在人宫颈黏膜定植的关键受体。CR3
含有一个“I-结构域”区域,它被称为蛋白质配体的结合部位。但是我们发现,
NG与I-结构域的结合是由菌毛素连接的多糖(PLG)介导的。这是《天生》杂志的一个开创性发现
免疫,正如所有以前的文献将CR3碳水化合物结合到一个单独的,所谓的凝集素结构域。
这也是第一次证明了细菌蛋白质的翻译后修饰。
调节病机。这些发现将影响我们对微生物发病机制和先天遗传的理解。
免疫反应。本申请的目的是定义这六个人的具体贡献,
自然发生的PLG结构在介导Ng-CR3 I结构域相互作用中的作用
这些相互作用中的每一个与女性感染的生物学相关性。在强劲的初步数据指引下,我们
假设可变PLG结构启动CR3I-结构域的关键但高度不同的结果
订婚。我们将通过两个具体目标来解决我们的假设:目标1)定义变化的影响
PLG-I结构域直接相互作用上的菌胶多聚糖结构;我们将定义特定的分子相互作用
与六个天然Ng PLG结构的CR3I-结构域一起发生。目的2)定义PLG-I的作用-
结构域相互作用在Ng发病机制和CR3功能中的作用;我们将定义靶向上皮细胞对
具有不同PLG结构的Ng对CR3I结构域的参与及其在Ng发病中的作用。我们的
该方法在使用生物相关的人类原代宫颈细胞方面具有创新性,无论是单独培养还是共同培养
吞噬细胞,与低传代Ng分离株结合。这确保了所获得的数据与
人类的过程。通过定义原始人I-结构域凝集素活性控制的效应器功能
上皮细胞,我们将提供关于Ng发病机制、CR3功能和
控制人类宫颈粘膜免疫的基本机制。此外,我们还将定义效用
将PLG-CR3 I结构域相互作用作为一种新的、改进的宿主靶向治疗和/或
预防女性Ng病。我们的研究很可能会影响对其他人类病原体的研究
与生俱来的免疫力,扩大了我们结果的意义。我们有丰富的经验来定义
Ng发病的分子机制。我们发现CR3是完成这项工作的理想位置
Ng宫颈感染的关键受体和菌毛糖基化的生物合成途径。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Complement Receptor 3 Mediates HIV-1 Transcytosis across an Intact Cervical Epithelial Cell Barrier: New Insight into HIV Transmission in Women.
- DOI:10.1128/mbio.02177-21
- 发表时间:2022-02-22
- 期刊:
- 影响因子:6.4
- 作者:Day CJ;Hardison RL;Spillings BL;Poole J;Jurcisek JA;Mak J;Jennings MP;Edwards JL
- 通讯作者:Edwards JL
Complete Genome Sequence of Serogroup B Neisseria meningitidis Strain C311.
- DOI:10.1128/mra.00788-21
- 发表时间:2021-10-21
- 期刊:
- 影响因子:0.8
- 作者:Jen FE;Atack JM;Zhang Y;Edwards JL;Jennings MP
- 通讯作者:Jennings MP
Analysis of Bacterial Phosphorylcholine-Related Genes Reveals an Association between Type-Specific Biosynthesis Pathways and Biomolecules Targeted for Phosphorylcholine Modification.
- DOI:10.1128/spectrum.01583-23
- 发表时间:2023-08-17
- 期刊:
- 影响因子:3.7
- 作者:Zhang, Yuan;Jen, Freda E. -C.;Edwards, Jennifer L. L.;Jennings, Michael P. P.
- 通讯作者:Jennings, Michael P. P.
Complete Genome Sequences of Seven Neisseria gonorrhoeae Clinical Isolates from Mucosal and Disseminated Gonococcal Infections.
- DOI:10.1128/mra.00734-21
- 发表时间:2021-10-28
- 期刊:
- 影响因子:0.8
- 作者:Jen FE;Atack JM;Edwards JL;Jennings MP
- 通讯作者:Jennings MP
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jennifer L Edwards其他文献
Jennifer L Edwards的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jennifer L Edwards', 18)}}的其他基金
Acquisition of gonococcal denitrification apparatus in the Neisseria meningitidis urethritis clade
脑膜炎奈瑟菌尿道炎分支中淋菌反硝化装置的获得
- 批准号:
10317302 - 财政年份:2021
- 资助金额:
$ 38.75万 - 项目类别:
Acquisition of gonococcal denitrification apparatus in the Neisseria meningitidis urethritis clade
脑膜炎奈瑟菌尿道炎分支中淋菌反硝化装置的获得
- 批准号:
10448441 - 财政年份:2021
- 资助金额:
$ 38.75万 - 项目类别:
Novel carbohydrate binding functions of the CR3 I-domain modulate gonococcal-cervical cell interactions
CR3 I 结构域的新型碳水化合物结合功能调节淋球菌-宫颈细胞相互作用
- 批准号:
10078936 - 财政年份:2018
- 资助金额:
$ 38.75万 - 项目类别:
Complement and hormone receptor modulation during gonococcal cervical infection
淋球菌宫颈感染期间的补体和激素受体调节
- 批准号:
7849963 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
The affect of hormones and oxygen-limitation on gonococcal pathophysiology
激素和限氧对淋球菌病理生理学的影响
- 批准号:
7903399 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
The affect of hormones and oxygen-limitation on gonococcal pathophysiology
激素和限氧对淋球菌病理生理学的影响
- 批准号:
8305999 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
The affect of hormones and oxygen-limitation on gonococcal pathophysiology
激素和限氧对淋球菌病理生理学的影响
- 批准号:
8102137 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
The affect of hormones and oxygen-limitation on gonococcal pathophysiology
激素和限氧对淋球菌病理生理学的影响
- 批准号:
7737528 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
Complement and hormone receptor modulation during gonococcal cervical infection
淋球菌宫颈感染期间的补体和激素受体调节
- 批准号:
7640370 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 38.75万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 38.75万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 38.75万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 38.75万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 38.75万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 38.75万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 38.75万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 38.75万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 38.75万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 38.75万 - 项目类别:
Grant-in-Aid for Early-Career Scientists