Inclusion membrane protein (Inc) modulation of the innate immune response to Chlamydia trachomatis
包涵膜蛋白 (Inc) 调节沙眼衣原体先天免疫反应
基本信息
- 批准号:10246668
- 负责人:
- 金额:$ 80.26万
- 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:2020-09-04 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:Affinity ChromatographyAntibioticsApoptosisAreaBacteriaBindingBiochemicalBioinformaticsBiologicalCellsCellular biologyChlamydiaChlamydia InfectionsChlamydia trachomatisChronic DiseaseCoiled-Coil DomainComplexDataData SetDeveloping CountriesDiseaseEnvironmentEpitopesEventEye InfectionsFamilyGeneticGrantHealth Care CostsHumanHuman Cell LineIRF3 geneIndividualInfectionInflammasomeInnate Immune ResponseInterferonsKnowledgeLinkMammalian CellMass Spectrum AnalysisMediatingMembraneMembrane ProteinsMethodologyMicrobeMorbidity - disease ratePathogenesisPharmaceutical PreparationsPositioning AttributePrevalencePreventionProcessProductionProteinsProteomePublishingRegulationReportingReproducibilityRespiratory Tract InfectionsRoleScaffolding ProteinSignal TransductionTNF Receptor-Associated FactorsTestingTimeTransfectionType III Secretion System PathwayVaccinesWorkbasecost effectivecytokinefascinategenetic approachgenital infectionhuman diseasehuman pathogenmembernon-Nativenovelobligate intracellular parasitepathogenprotein complexprotein functionprotein protein interactionrecruittoolunpublished works
项目摘要
Project Summary/Abstract
Chlamydia infections are important causes of human disease for which no vaccine exists. Their extraordinary
prevalence, associated morbidity, health care costs, and link to various chronic disease states make them public
concerns of critical importance. Although infections can be treated with antibiotics, no drug is cost-effective
enough for widespread elimination of disease. An important gap in our knowledge is how this obligate intracellular
vacuolar bacterium establishes a privileged niche--a membrane bound compartment termed the inclusion--and
avoids the host innate immune response. Chlamydia encode a distinctive family of secreted effectors, the Incs
(Inclusion membrane proteins), which are translocated from the bacteria through the type III secretion system
and inserted into the inclusion membrane. We hypothesize that some of these effectors, by virtue of their position
at the host-pathogen interface, modulate the innate immune response. However, since tractable genetic tools
have only recently been developed for Chlamydia, the specific function of the majority of Incs remains unknown.
We pioneered using a high throughput affinity purification-mass spectroscopy (AP-MS) strategy in conjunction
with transfection to identify putative host binding partners for 2/3 of the C. trachomatis Incs. In recent unpublished
work, we have discovered unexpected roles for several of these effectors that suggests that not only can Incs
function as proteins scaffolds, but that they may establish higher order novel protein complexes at the inclusion.
Nonetheless, our “transfection” interactome is potentially limited by the non-native presentation of Incs or the
requirement that some Inc-host protein-protein interactions (PPIs) require multiple Incs. In aim 1, we propose a
high throughput strategy to overcome these limitations by adapting our AP-MS screen to rapidly identify and
validate host interacting partners in the context of infection and to identify new Inc-host PPIs that may have been
missed in our initial screen. In preliminary data, we validate this “infection” interactome approach, which has
enabled us to prioritize the further study of two fascinating effectors, CT226 and CT224, that may influence the
host innate immune response to C. trachomatis infections, an understudied area in general for intracellular
vacuolar human pathogens. We have discovered that the predicted coiled-coil domain in the C-terminus of
CT226 binds to a complex comprised of Flightless-1 and LRRFIP1 and/or LRRFIP2 (L/F complex). The function
of this complex is incompletely understood but has been reported to modulate inflammasome as well as IRF3
and NFkB signaling in mammalian cells. We have discovered that the predicted coiled-coil domain in the C-
terminus of CT224 binds to TRAF7, a unique member of the TNF receptor associated factors that modulates
NFkB signaling, cytokine production, and apoptosis. We hypothesize that the CT226:L/F and the CT224:TRAF7
interactions modulate the host cell innate immune response to C. trachomatis infection. In aims 2 and 3, we will
decode the function of CT226 and CT224, respectively, using biochemical, cell biological, and genetic strategies
to explore their role in C. trachomatis infections.
项目摘要/摘要
衣原体感染是人类疾病的重要原因,目前尚不存在疫苗。他们的非凡之处
流行率、相关发病率、医疗保健费用以及与各种慢性病州的联系使其公之于众
至关重要的关切。虽然感染可以用抗生素治疗,但没有一种药物是划算的。
足以广泛根除疾病。我们知识中的一个重要缺口是这种细胞内的义务是如何
液泡细菌建立了一个特权的生态位--一个被膜包裹的隔间,称为包涵体--以及
避免宿主的先天免疫反应。衣原体编码一个独特的分泌型效应器家族,即Incs
(包涵膜蛋白),通过III型分泌系统从细菌转移
并插入到包涵膜中。我们假设这些效应器中的一些根据它们的位置
在宿主-病原体界面,调节先天免疫反应。然而,由于易驯服的遗传工具
尽管最近才开发出针对衣原体的INC,但大多数INC的具体功能仍不清楚。
我们率先将高通量亲和纯化-质谱学(AP-MS)策略与
通过转染法鉴定2/3的沙眼衣原体可能的宿主结合伙伴。在最近未发表的文章中
工作中,我们发现其中几个效应器具有意想不到的作用,这表明Incs不仅可以
作为蛋白质支架的功能,但它们可能会在包涵体上建立更高阶的新蛋白质复合体。
然而,我们的“转基因”交互作用组可能受到incs或incs的非自然呈现的限制。
要求某些INC-宿主蛋白质-蛋白质相互作用(PPI)需要多个INC。在目标1中,我们提出了一个
高吞吐量战略,通过调整我们的AP-MS屏幕来快速识别和
在感染环境中验证主机交互合作伙伴,并确定新的Inc.主机PPI
在我们最初的屏幕上错过了。在初步数据中,我们验证了这种“感染”交互作用组方法,它具有
使我们能够优先进一步研究两个令人着迷的效应器,CT226和CT224,这可能会影响
宿主对沙眼衣原体感染的先天免疫反应,这是一个普遍研究较少的细胞内领域
空泡状的人类病原体。我们发现,预测的螺旋线圈结构域在C-末端
CT226结合到由LRRFIP1和/或LRRFIP2组成的复合体(L/F复合体)。该功能
这个复合体的作用还不完全清楚,但已有报道调节炎症体和IRF3。
和哺乳动物细胞中的NFkB信号。我们已经发现,预测的盘绕线圈结构域在C-
CT224的末端与TRAF7结合,TRAF7是肿瘤坏死因子受体相关因子中的一个独特成员
NFkB信号、细胞因子的产生和细胞凋亡。我们假设CT226:L/F和CT224:TRAF7
相互作用调节宿主细胞对沙眼衣原体感染的先天免疫反应。在目标2和目标3中,我们将
分别使用生化、细胞生物学和遗传策略破译CT226和CT224的功能
探讨它们在沙眼衣原体感染中的作用。
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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Joanne N. Engel其他文献
Inhibition of the in vitro pituitary response to luteinizing hormone-releasing hormone by melatonin, serotonin, and 5-methoxytryptamine.
褪黑激素、血清素和 5-甲氧基色胺抑制体外垂体对黄体生成素释放激素的反应。
- DOI:
10.1210/endo-100-3-675 - 发表时间:
1977 - 期刊:
- 影响因子:4.8
- 作者:
Jeanne E. Martin;Joanne N. Engel;David C. Klein - 通讯作者:
David C. Klein
Global mapping of the Chlamydia trachomatis conventional secreted effector – host interactome reveals CebN interacts with nucleoporins and Rae1 to impede STAT1 nuclear translocation
沙眼衣原体常规分泌效应子-宿主相互作用组的全局图谱揭示 CebN 与核孔蛋白和 Rae1 相互作用以阻止 STAT1 核转位
- DOI:
10.1101/2024.04.25.587017 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
B. Steiert;Shelby E Andersen;Paige N. McCaslin;C. Elwell;R. Faris;Xavier Tijerina;Parker Smith;Quinn Eldridge;Brian S. Imai;Justine V. Arrington;Peter M. Yau;Kathleen M. Mirrashidi;Jeffrey R. Johnson;Erik Verschueren;John Von Dollen;Gwendolyn M. Jang;N. Krogan;Joanne N. Engel;Mary M. Weber - 通讯作者:
Mary M. Weber
The emChlamydia/em effector Dre1 binds dynactin to reposition host organelles during infection
衣原体效应蛋白 Dre1 与动力蛋白复合物结合,在感染过程中重新定位宿主细胞器
- DOI:
10.1016/j.celrep.2025.115509 - 发表时间:
2025-04-22 - 期刊:
- 影响因子:6.900
- 作者:
Jessica Sherry;Komal Ishwar Pawar;Lee Dolat;Erin Smith;I-Chang Chang;Khavong Pha;Robyn Kaake;Danielle L. Swaney;Clara Herrera;Eleanor McMahon;Robert J. Bastidas;Jeffrey R. Johnson;Raphael H. Valdivia;Nevan J. Krogan;Cherilyn A. Elwell;Kliment Verba;Joanne N. Engel - 通讯作者:
Joanne N. Engel
Antagonistic response regulators spatially regulate receptor methylation in the emPseudomonas aeruginosa/em Pil-Chp surface sensing system
对抗性反应调节因子在铜绿假单胞菌 Pil-Chp 表面感应系统中对受体甲基化进行空间调节
- DOI:
10.1016/j.celrep.2025.115536 - 发表时间:
2025-04-22 - 期刊:
- 影响因子:6.900
- 作者:
Ramiro Patino;Marco J. Kühn;Henriette Macmillan;Yuki F. Inclan;Ivan Chavez;Alexandre Persat;Joanne N. Engel - 通讯作者:
Joanne N. Engel
Joanne N. Engel的其他文献
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{{ truncateString('Joanne N. Engel', 18)}}的其他基金
Finding the way: Sensory adaptation during bacterial mechanotransduction
寻找方法:细菌机械传导过程中的感觉适应
- 批准号:
10744926 - 财政年份:2023
- 资助金额:
$ 80.26万 - 项目类别:
Dissecting the role of the Inclusion membrane protein IncE, a master multi-tasking scaffolding protein, in the pathogenesis of Chlamydia trachomatis infections
剖析包涵膜蛋白 IncE(一种主要的多任务支架蛋白)在沙眼衣原体感染发病机制中的作用
- 批准号:
10453533 - 财政年份:2022
- 资助金额:
$ 80.26万 - 项目类别:
Dissecting the role of the Inclusion membrane protein IncE, a master multi-tasking scaffolding protein, in the pathogenesis of Chlamydia trachomatis infections
剖析包涵膜蛋白 IncE(一种主要的多任务支架蛋白)在沙眼衣原体感染发病机制中的作用
- 批准号:
10669588 - 财政年份:2022
- 资助金额:
$ 80.26万 - 项目类别:
Sensing living P. aeruginosa using D-alanine derived radiotracers
使用 D-丙氨酸衍生的放射性示踪剂感测活的铜绿假单胞菌
- 批准号:
10230924 - 财政年份:2021
- 资助金额:
$ 80.26万 - 项目类别:
Sensing living P. aeruginosa using D-alanine derived radiotracers
使用 D-丙氨酸衍生的放射性示踪剂感测活的铜绿假单胞菌
- 批准号:
10399593 - 财政年份:2021
- 资助金额:
$ 80.26万 - 项目类别:
Sensing living P. aeruginosa using D-alanine derived radiotracers
使用 D-丙氨酸衍生的放射性示踪剂感测活的铜绿假单胞菌
- 批准号:
10570987 - 财政年份:2021
- 资助金额:
$ 80.26万 - 项目类别:
Understanding the role of sensory adaptation in bacterial mechanochemical signaling pathways
了解感觉适应在细菌机械化学信号通路中的作用
- 批准号:
10204959 - 财政年份:2020
- 资助金额:
$ 80.26万 - 项目类别:
Adapting to a changing environment: How surface contact induces virulence factor production in Pseudomonas aeruginosa
适应不断变化的环境:表面接触如何诱导铜绿假单胞菌产生毒力因子
- 批准号:
9403170 - 财政年份:2017
- 资助金额:
$ 80.26万 - 项目类别:
Decoding the Chlamydia inclusion membrane protein-host protein interactome
解码衣原体包涵膜蛋白-宿主蛋白相互作用组
- 批准号:
9185266 - 财政年份:2015
- 资助金额:
$ 80.26万 - 项目类别:
High throughput proteomics to dissect Chlamydia-host cell interactions
高通量蛋白质组学剖析衣原体-宿主细胞相互作用
- 批准号:
8491133 - 财政年份:2013
- 资助金额:
$ 80.26万 - 项目类别:
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