Unravelling the mysteries of virulence gene regulation in <i>Salmonella typhimurium</i>

Lucas, Robin L.; Lee, Catherine A.

doi:10.1046/j.1365-2958.2000.01961.x

Cited by 122 publications

(122 citation statements)

References 47 publications

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“…Analysis of hilA-lacZ transcriptional fusions by Lee and colleagues (30)(31)(32)42), among others, led to a model proposing that hilA transcription is repressed by a negative factor acting within the promoter region between positions Ϫ300 and Ϫ100. The HilD and perhaps the HilC proteins play central roles in controlling hilA transcription and may counteract this repressor activity.…”

Section: Discussionmentioning

confidence: 99%

“…Many regulatory proteins influence invasion gene expression (31,32), but the key regulator is the SPI1-encoded HilA protein, which can activate their transcription directly (1,4,28) or by increasing expression of the activator InvF (9). The N-terminal region of HilA carries a DNA-binding and transcription-activating helix-loop-helix motif typical of OmpR/ToxR family members (4).…”

mentioning

confidence: 99%

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DNA-Binding Activities of the HilC and HilD Virulence Regulatory Proteins ofSalmonella entericaSerovar Typhimurium

2002

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The HilC and HilD proteins of Salmonella enterica serovar Typhimurium are members of the AraC/XylS family of transcription regulators. They are encoded on Salmonella pathogenicity island 1 (SPI1) and control expression of the hilA gene, which encodes the major transcriptional activator for many genes encoded on SPI1 and elsewhere that contribute to invasion of host cells. Gel electrophoretic shift and DNase footprinting assays revealed that purified HilC and HilD proteins can bind to multiple regions in the hilA and hilC promoters and to a single region in the hilD promoter. Although both HilC and -D proteins can bind to the same DNA regions, they showed different dependencies on the sequence and lengths of their DNA targets. To identify the binding-sequence specificity of HilC and HilD, a series of single base substitutions changing each position in a DNA fragment corresponding to positions ؊92 to ؊52 of the hilC promoter was tested for binding to HilC and HilD in a gel shift DNA-binding assay. This mutational analysis in combination with sequence alignments allowed deduction of consensus sequences for binding of both proteins. The consensus sequences overlap but differ so that HilC can bind to both types of sites but HilD only to one. The hilA and hilC promoters contain multiple binding sites of each type, whereas the hilD promoter contains a site that binds HilC but not HilD without additional binding elements. The HilC and HilD proteins had no major effect on transcription from the hilA or hilD promoters using purified proteins in vitro but changed the choice of promoter at hilC. These results are consistent with a model derived from analysis of lacZ fusions stating that HilC and HilD enhance hilA expression by counteracting a repressing activity.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

DNA-Binding Activities of the HilC and HilD Virulence Regulatory Proteins ofSalmonella entericaSerovar Typhimurium

2002

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“…Alternative pathways of dissemination have also been identified (4), possibly occurring as dendritic cells (DC) 3 sample the gut lumen directly (5). To survive and replicate in the diverse host environments encountered during infection, Salmonella have the ability to regulate the expression of numerous genes in response to specific environmental conditions (6). For example, the two-component regulatory system PhoP/PhoQ activates or represses expression of over 40 genes in response to the environment encountered in the phagosomes of host cells (7,8) and is essential for virulence (9,10).…”

Section: T He Pathogen Salmonella Enterica Serovar Typhimurium (Smentioning

confidence: 99%

“…Salmonella replication, either extracellularly or inside host cells, requires coordinate regulation of many genes (6). We hypothesized that alteration of gene expression in response to changing environments during infection would impact production of bacterial Ags, and influence the antigenic specificity of responding CD4 ϩ T cell populations.…”

Section: Differential Stimulation Of Ag-specific Cd4 ϩ T Cells By Extmentioning

confidence: 99%

FliC-Specific CD4+ T Cell Responses Are Restricted by Bacterial Regulation of Antigen Expression

Cummings¹,

Barrett²,

Wilkerson³

et al. 2005

The Journal of Immunology

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Salmonella typhimurium, a facultatively intracellular pathogen, regulates expression of virulence factors in response to distinct environments encountered during the course of infection. We tested the hypothesis that the transition from extra- to intracellular environments during Salmonella infection triggers changes in Ag expression that impose both temporal and spatial limitations on the host T cell response. CD4+ T cells recovered from Salmonella immune mice were propagated in vitro using Ag derived from bacteria grown in conditions designed to emulate extra- or intracellular environments in vivo. Extracellular phase bacteria supported a dominant T cell response to the flagellar subunit protein FliC, whereas intracellular phase bacteria were unable to support expansion of FliC-specific T cells from populations known to contain T cells with reactivity to this Ag. This result was attributed to bacterial regulation of FliC expression: transcription and protein levels were repressed in bacteria growing in the spleens of infected mice. Furthermore, Salmonella-infected splenocytes taken directly ex vivo stimulated FliC-specific T cell clones only when intracellular FliC expression was artificially up-regulated. Although it has been suggested that a microanatomical separation of immune T cells and infected APC exists in vivo, we demonstrate that intracellular Salmonella can repress FliC expression below the T cell activation threshold. This potentially provides a mechanism for intracellular Salmonella at systemic sites to avoid detection by Ag-specific T cells primed at intestinal sites early in infection.

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“…One (Inv /Spa ) is located in Salmonella pathogenicity island ( SPI )-1 and controls bacterial invasion of epithelial cells. 12,13 The other is located in SPI -2 where it plays a crucial role in systemic growth in its host and is required for survival within macrophages. 14 -18 Thus, in an attempt to better understand the bacterial antitumor phenotype, we analyzed the effects of mutations in SPI -1 and SPI -2 virulence genes on bacterial growth suppression of B16F10 melanomas in C57B6 mice.…”

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confidence: 99%

Salmonella pathogenicity island-2 and anticancer activity in mice

et al. 2002

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Salmonella enterica servovar Typhimurium is capable of targeting, colonizing, and eliciting growth suppression of tumors in mice. We examined the effects of mutations on this anticancer phenotype in two Salmonella virulence gene clusters. Salmonella pathogenicity island ( SPI ) -1 genes promote systemic invasion from the intestine, whereas SPI -2 genes support systemic survival within macrophages and other cells. Disabling SPI -1 ( prgH À ) strongly reduced invasion in vitro, but had no effect on tumor growth suppression in vivo. However, disabling SPI -2 ( ssaT À ) ablated tumor growth suppression. In addition to ssaT À , mutations in SPI -2 genes sseA, sseB, sseC, sscA, and ssrA also eliminated antitumor activity, whereas mutations in sseF or sseG yielded partial loss of function. Impaired tumor amplification was seen in three SPI -2 mutants tested after intravenous or intratumoral injection. A SPI -2 À strain was unable to suppress tumor growth in CD18 -deficient mice with defective macrophages and neutrophils, suggesting that loss of tumor growth suppression in wild -type mice by SPI -2 mutants was not solely a function of increased susceptibility to immune attack. Thus, SPI -2 is essential for the Salmonella antitumor effects, perhaps by aiding bacterial amplification within tumors, and is the first identified genetic system for this Salmonella phenotype.

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Unravelling the mysteries of virulence gene regulation in Salmonella typhimurium

Cited by 122 publications

References 47 publications

DNA-Binding Activities of the HilC and HilD Virulence Regulatory Proteins ofSalmonella entericaSerovar Typhimurium

DNA-Binding Activities of the HilC and HilD Virulence Regulatory Proteins ofSalmonella entericaSerovar Typhimurium

FliC-Specific CD4+ T Cell Responses Are Restricted by Bacterial Regulation of Antigen Expression

Salmonella pathogenicity island-2 and anticancer activity in mice

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