Leveraging a transcription regulatory network to understand Salmonella invasion of host epithelial cells
利用转录调控网络了解沙门氏菌对宿主上皮细胞的侵袭
基本信息
- 批准号:10374120
- 负责人:
- 金额:$ 20.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:Africa South of the SaharaAnimal ModelBiological ModelsCellsChildComplexDNA BindingDataDiseaseDissectionEpithelial CellsFutureGene ExpressionGenesGenetic TranscriptionGenomic SegmentGrowthImmunocompromised HostIn VitroIndividualInfectionInjectionsIntestinal MucosaInvadedLeadLinkLiquid substanceMapsModelingMulti-Drug ResistanceMutagenesisNaturePathogenesisPathogenicity IslandPeyer&aposs PatchesPlayProcessProteinsPublishingRegulationRegulonRoleSalmonellaSalmonella entericaSignal TransductionSystemTestingTimeTissuesTranscriptional ActivationVirulenceWorkbasegene regulatory networkgenome-widehigh riskin vivomembernon-typhoidal Salmonellanovelpathogenic bacteriaresistant straintranscription factortranscription regulatory networkvaccine development
项目摘要
SUMMARY
Non-typhoidal Salmonella enterica strains, including serovar Typhimurium (STm), are an emerging cause of
invasive disease among children and the immunocompromised. While vaccine development efforts are ongoing,
the emergence of multidrug resistant strains of STm affirms the need to seek alternative strategies to protect
high-risk individuals from infection. STm invades the intestinal mucosa before disseminating systemically.
Invasion requires injection of specific effector proteins into host cells through a Type Three Secretion System
(T3SS). Most of the structural components of the invasion-associated T3SS and its secreted effector proteins
are encoded in a genomic region known as Salmonella Pathogenicity Island 1 (SPI-1). Regulation of SPI-1 genes
represents a model system for how pathogenic bacteria respond to environmental signals to induce expression
of virulence genes. The master regulator of SPI-1 gene transcription is a DNA-binding transcription factor, HilD,
which is itself encoded within SPI-1. Five of the HilD-activated genes encode regulators, HilC, RtsA, InvF, SprB
and HilA, which we postulate are involved in temporal regulation of SPI-1 gene expression. However, very little
is known about how the different regulators contribute to the timing of expression of target genes during infection.
We comprehensively mapped the regulatory targets of HilD, HilC, RtsA, InvF, SprB and HilA, defining the
invasion “super-regulon”. Remarkably, the large majority of the >100 direct regulatory interactions we identified
were novel. By analyzing published data, we identified 12 members of the invasion super-regulon whose in vitro
expression profiles correlate with those of known invasion genes. We refer to these as “Invasion-Co-Regulated
Genes” (ICGs). A large-scale transposon mutagenesis study performed by another group suggests that most or
all of the ICGs are required for efficient infection of multiple animal models. We will dissect the function of ICGs
at different stages of infection using in vitro and in vivo infection models, and we will determine the expression
profiles of invasion super-regulon genes upon activation and inactivation in liquid growth and during infection of
epithelial cells in vitro, thereby defining the relationship between regulator and expression timing. The work
proposed here will represent the first step in establishing the role of uncharacterized genes that have strong ties
to the invasion process. We also expect to show that expression timing for invasion super-regulon genes is
determined by the associated transcription factors, which would represent an important advance in our
understanding of how regulatory networks contribute to bacterial pathogenesis.
摘要
非伤寒沙门氏菌菌株,包括鼠伤寒沙门氏菌(STM),是一种新的致病因素
儿童中的侵袭性疾病和免疫功能受损。虽然疫苗开发工作仍在进行中,
STM多药耐药菌株的出现表明有必要寻求替代策略来保护
高危人群不受感染。STM先侵袭肠粘膜,然后全身传播。
侵袭需要通过3型分泌系统将特定的效应蛋白注入宿主细胞
(T3SS)。侵袭相关T3SS及其分泌的效应蛋白的大部分结构成分
编码在称为沙门氏菌致病岛1(SPI-1)的基因组区域。SPI-1基因的调控
代表了病原菌如何响应环境信号以诱导表达的模型系统
毒力基因。SPI-1基因转录的主要调控因子是DNA结合转录因子HILD,
其本身在SPI-1中编码。其中5个由Hild激活的基因编码调节子:HilC、RTSA、InvF、SprB
和Hila,我们推测它们参与了SPI-1基因表达的时间调控。然而,几乎没有
已知不同的调控因子如何在感染过程中对靶基因的表达时间做出贡献。
我们全面绘制了Hild、HilC、RTSA、InvF、SprB和Hila的监管目标,定义了
入侵的“超级规则”。值得注意的是,我们发现的大多数>;100直接监管互动
都是新奇的。通过分析已发表的数据,我们在体外鉴定了12个侵袭超调节基因的成员
表达谱与已知入侵基因的表达谱相关联。我们把这些称为“入侵--共同调控”
基因“(ICGS)。另一个小组进行的一项大规模转座子突变研究表明,大多数或
所有ICGS都是有效感染多种动物模型所必需的。我们将剖析ICGS的功能
在感染的不同阶段,使用体外和体内感染模型,我们将确定表达
侵袭超调节基因在液体生长和感染过程中的激活和失活
在体外培养上皮细胞,从而确定调控因子和表达时机之间的关系。这项工作
这里提出的将是确定具有强烈联系的未表征基因的作用的第一步
在入侵过程中。我们还希望表明侵袭性超调节基因的表达时机是
由相关的转录因子决定,这将是我们的
了解调控网络如何促进细菌发病。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Flagellar-based motility accelerates IgA-mediated agglutination of Salmonella Typhimurium at high bacterial cell densities.
- DOI:10.3389/fimmu.2023.1193855
- 发表时间:2023
- 期刊:
- 影响因子:7.3
- 作者:
- 通讯作者:
{{
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 }}
Nicholas J. Mantis其他文献
Collaboration of epithelial cells with organized mucosal lymphoid tissues
上皮细胞与有组织的黏膜淋巴样组织的协作
- DOI:
10.1038/ni1101-1004 - 发表时间:
2001-11-01 - 期刊:
- 影响因子:27.600
- 作者:
Marian R. Neutra;Nicholas J. Mantis;Jean-Pierre Kraehenbuhl - 通讯作者:
Jean-Pierre Kraehenbuhl
Inter-laboratory harmonization of microsphere immunoassays for SARS-CoV-2 antibody detection in contrived dried blood spots and oral fluids
用于在人为干血斑和口腔液中检测 SARS-CoV-2 抗体的微球免疫测定的实验室间协调
- DOI:
10.1128/spectrum.02690-24 - 发表时间:
2025-03-31 - 期刊:
- 影响因子:3.800
- 作者:
Kate L. DeRosa;Nora Pisanic;Kate Kruczynski;Christopher D. Heaney;Linda M. Styer;Nicholas J. Mantis - 通讯作者:
Nicholas J. Mantis
A type-specific B-cell epitope at the apex of outer surface protein C (OspC) of the Lyme disease spirochete, emBorreliella burgdorferi/em
莱姆病螺旋体伯氏疏螺旋体外表面蛋白 C(OspC)顶点的一种特定类型 B 细胞表位
- DOI:
10.1128/spectrum.02883-24 - 发表时间:
2025-02-14 - 期刊:
- 影响因子:3.800
- 作者:
David J. Vance;Grace Freeman-Gallant;Kathleen McCarthy;Carol Lyn Piazza;Yang Chen;Clint Vorauer;Beatrice Muriuki;Michael J. Rudolph;Lisa Cavacini;Miklos Guttman;Nicholas J. Mantis - 通讯作者:
Nicholas J. Mantis
Antibody signatures elicited by potent and subpotent whole-cell pertussis vaccines in mice
强效和次强效全细胞百日咳疫苗在小鼠中引发的抗体特征
- DOI:
10.1128/spectrum.03253-24 - 发表时间:
2025-03-31 - 期刊:
- 影响因子:3.800
- 作者:
Yetunde Adewunmi;Jennifer Doering;Prashant Kumar;Jozelyn V. Pablo;Andy A. Teng;Vu Huynh;Kathryn Secrist;David B. Volkin;Sangeeta B. Joshi;Joseph J. Campo;Nicholas J. Mantis - 通讯作者:
Nicholas J. Mantis
Nicholas J. Mantis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('Nicholas J. Mantis', 18)}}的其他基金
Leveraging a transcription regulatory network to understand Salmonella invasion of host epithelial cells
利用转录调控网络了解沙门氏菌对宿主上皮细胞的侵袭
- 批准号:
10154895 - 财政年份:2021
- 资助金额:
$ 20.91万 - 项目类别:
Lyme Disease: B cell epitope discovery and mechanisms of antibody protection
莱姆病:B 细胞表位发现和抗体保护机制
- 批准号:
10677521 - 财政年份:2020
- 资助金额:
$ 20.91万 - 项目类别:
High-Throughput Dried Blood Spot (HT-DBS) Technologies in SARS COV-2 Serology and Vaccinology
SARS COV-2 血清学和疫苗学中的高通量干血斑 (HT-DBS) 技术
- 批准号:
10855042 - 财政年份:2020
- 资助金额:
$ 20.91万 - 项目类别:
Lyme Disease: B cell epitope discovery and mechanisms of antibody protection
莱姆病:B 细胞表位发现和抗体保护机制
- 批准号:
10246232 - 财政年份:2020
- 资助金额:
$ 20.91万 - 项目类别:
High-Throughput Dried Blood Spot (HT-DBS) Technologies in SARS COV-2 Serology and Vaccinology
SARS COV-2 血清学和疫苗学中的高通量干血斑 (HT-DBS) 技术
- 批准号:
10222023 - 财政年份:2020
- 资助金额:
$ 20.91万 - 项目类别:
Tickborne Disease: B cell epitope discovery and mechanisms of antibody Protection
蜱传疾病:B 细胞表位发现和抗体保护机制
- 批准号:
10678249 - 财政年份:2020
- 资助金额:
$ 20.91万 - 项目类别:
High-Throughput Dried Blood Spot (HT-DBS) Technologies in SARS COV-2 Serology and Vaccinology
SARS COV-2 血清学和疫苗学中的高通量干血斑 (HT-DBS) 技术
- 批准号:
10688352 - 财政年份:2020
- 资助金额:
$ 20.91万 - 项目类别:
Lyme Disease: B cell epitope discovery and mechanisms of antibody protection
莱姆病:B 细胞表位发现和抗体保护机制
- 批准号:
10021076 - 财政年份:2019
- 资助金额:
$ 20.91万 - 项目类别:
Lyme Disease: B cell epitope discovery and mechanisms of antibody protection
莱姆病:B 细胞表位发现和抗体保护机制
- 批准号:
10912412 - 财政年份:2019
- 资助金额:
$ 20.91万 - 项目类别:
Mechanisms of IgA - mediated immunity to Vibrio cholerae
IgA 介导的霍乱弧菌免疫机制
- 批准号:
9438996 - 财政年份:2017
- 资助金额:
$ 20.91万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 20.91万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 20.91万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 20.91万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 20.91万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 20.91万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 20.91万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 20.91万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 20.91万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 20.91万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 20.91万 - 项目类别:
Grant-in-Aid for Early-Career Scientists














{{item.name}}会员




