Leveraging a transcription regulatory network to understand Salmonella invasion of host epithelial cells
Leveraging a transcription regulatory network to understand Salmonella invasion of host epithelial cells
批准号:
10374120
负责人:
Nicholas J. Mantis
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
项目状态:
未结题
起止时间:
2021-04-01 至 2025-03-31
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
中文摘要
总结
英文摘要
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.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3389/fimmu.2023.1193855
发表时间:
2023
期刊:
Frontiers in immunology
影响因子:
7.3
作者:
[]
通讯作者:
Leveraging a transcription regulatory network to understand Salmonella invasion of host epithelial cells
-
批准号:10154895
-
项目类别:
-
资助金额:$18.1万
-
财政年份:2021
-
负责人:Nicholas J. Mantis
-
依托单位:
Lyme Disease: B cell epitope discovery and mechanisms of antibody protection
-
批准号:10677521
-
项目类别:
-
资助金额:$188.72万
-
财政年份:2020
-
负责人:Nicholas J. Mantis
-
依托单位:
High-Throughput Dried Blood Spot (HT-DBS) Technologies in SARS COV-2 Serology and Vaccinology
-
批准号:10855042
-
项目类别:
-
资助金额:$82.46万
-
财政年份:2020
-
负责人:Nicholas J. Mantis
-
依托单位:
Lyme Disease: B cell epitope discovery and mechanisms of antibody protection
-
批准号:10246232
-
项目类别:
-
资助金额:$190.14万
-
财政年份:2020
-
负责人:Nicholas J. Mantis
-
依托单位:
High-Throughput Dried Blood Spot (HT-DBS) Technologies in SARS COV-2 Serology and Vaccinology
-
批准号:10222023
-
项目类别:
-
资助金额:$115.32万
-
财政年份:2020
-
负责人:Nicholas J. Mantis
-
依托单位:
Tickborne Disease: B cell epitope discovery and mechanisms of antibody Protection
-
批准号:10678249
-
项目类别:
-
资助金额:$112.33万
-
财政年份:2020
-
负责人:Nicholas J. Mantis
-
依托单位:
High-Throughput Dried Blood Spot (HT-DBS) Technologies in SARS COV-2 Serology and Vaccinology
-
批准号:10688352
-
项目类别:
-
资助金额:$59.23万
-
财政年份:2020
-
负责人:Nicholas J. Mantis
-
依托单位:
Lyme Disease: B cell epitope discovery and mechanisms of antibody protection
-
批准号:10021076
-
项目类别:
-
资助金额:$166.08万
-
财政年份:2019
-
负责人:Nicholas J. Mantis
-
依托单位:
Lyme Disease: B cell epitope discovery and mechanisms of antibody protection
-
批准号:10912412
-
项目类别:
-
资助金额:$186.52万
-
财政年份:2019
-
负责人:Nicholas J. Mantis
-
依托单位:
Mechanisms of IgA - mediated immunity to Vibrio cholerae
-
批准号:9438996
-
项目类别:
-
资助金额:$4.68万
-
财政年份:2017
-
负责人:Nicholas J. Mantis
-
依托单位:
Development of a Preclinical Assay to Predict Efficacy of Ricin Toxin Subunit Vaccines
-
批准号:9913443
-
项目类别:
-
资助金额:$51.98万
-
财政年份:2016
-
负责人:Nicholas J. Mantis
-
依托单位:
Development of a Preclinical Assay to Predict Efficacy of Ricin Toxin Subunit Vaccines
-
批准号:9152465
-
项目类别:
-
资助金额:$96.24万
-
财政年份:2016
-
负责人:Nicholas J. Mantis
-
依托单位:
Mechanisms of IgA - mediated immunity to Vibrio cholerae
-
批准号:9054307
-
项目类别:
-
资助金额:$22.03万
-
财政年份:2016
-
负责人:Nicholas J. Mantis
-
依托单位:
Development of a Preclinical Assay to Predict Efficacy of Ricin Toxin Subunit Vaccines
-
批准号:9264977
-
项目类别:
-
资助金额:$105.74万
-
财政年份:2016
-
负责人:Nicholas J. Mantis
-
依托单位:
Mechanisms of IgA-mediated immunity to Salmonella
-
批准号:9089877
-
项目类别:
-
资助金额:$7.31万
-
财政年份:2015
-
负责人:Nicholas J. Mantis
-
依托单位:
Ricin toxin: Neutralizing antibodies and vaccine design
-
批准号:8432003
-
项目类别:
-
资助金额:$6.78万
-
财政年份:2012
-
负责人:Nicholas J. Mantis
-
依托单位:
Ricin toxin: Neutralizing antibodies and vaccine design
-
批准号:8301906
-
项目类别:
-
资助金额:$6.78万
-
财政年份:2012
-
负责人:Nicholas J. Mantis
-
依托单位:
MECHANISMS OF SECRETORY IGA MEDIATED IMMUNITY TO ENTERIC PATHOGENS
-
批准号:8172284
-
项目类别:
-
资助金额:$1.62万
-
财政年份:2010
-
负责人:Nicholas J. Mantis
-
依托单位:
MECHANISMS OF SECRETORY IGA MEDIATED IMMUNITY TO ENTERIC PATHOGENS
-
批准号:7954588
-
项目类别:
-
资助金额:$2.23万
-
财政年份:2009
-
负责人:Nicholas J. Mantis
-
依托单位:
Mannose Receptor in Ricin Pathogenesis
-
批准号:7876804
-
项目类别:
-
资助金额:$17.88万
-
财政年份:2009
-
负责人:Nicholas J. Mantis
-
依托单位:
海外基金