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.
总结
非伤寒性肠道沙门氏菌菌株,包括鼠伤寒血清型(STm),是引起肠伤寒的新原因。
儿童的侵袭性疾病和免疫功能低下。虽然疫苗开发工作正在进行中,
STm多药耐药菌株的出现证实了寻求替代策略以保护
高危人群感染。STm在全身传播之前侵入肠粘膜。
入侵需要通过第三型分泌系统将特定的效应蛋白注入宿主细胞
(T3SS)。侵袭相关的T3 SS及其分泌的效应蛋白的大部分结构组分
在称为沙门氏菌致病岛1(SPI-1)的基因组区域中编码。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基因转录的主要调节因子是DNA结合转录因子HilD,
其本身编码在SPI-1中。HilD激活的基因中有5个编码调控因子,即HilC、RtsA、InvF、SprB
和HilA,我们推测它们参与SPI-1基因表达的时间调节。然而,
关于不同的调节因子如何在感染过程中对靶基因表达的时机做出贡献,
我们全面绘制了HilD、HilC、RtsA、InvF、SprB和HilA的调控靶点,
入侵“超级调节子”。值得注意的是,在我们确定的100多个直接监管相互作用中,
是新奇的。通过分析已发表的数据,我们鉴定了12个侵袭超调节子成员,其在体外
表达谱与已知的侵袭基因的表达谱相关。我们称之为“入侵共同管制
基因”(ICG)。另一个小组进行的大规模转座子诱变研究表明,大多数或
所有ICG都是有效感染多种动物模型所必需的。我们将剖析ICG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
在液体生长中和感染期间激活和失活的入侵超调节子基因的概况
上皮细胞在体外,从而确定调节和表达时机之间的关系。工作
这里提出的将代表建立具有强联系的未表征基因的作用的第一步,
入侵的过程。我们还希望表明,侵袭性超调节子基因的表达时间是
这是由相关的转录因子决定的,这将代表我们在研究中的一个重要进展。
了解调控网络如何促进细菌发病机制。
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:
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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
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{{ 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:
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