Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium

ABSTRACT Type I fimbriae in Salmonella enterica serovar Typhimurium are surface appendages that facilitate binding to eukaryotic cells. Expression of the fim gene cluster is known to be regulated by three proteins—FimW, FimY, and FimZ—and a tRNA encoded by fimU. In this work, we investigated how these proteins and tRNA coordinately regulate fim gene expression. Our results indicate that FimY and FimZ independently activate the P fimA promoter which controls the expression of the fim structural genes. FimY and FimZ were also found to strongly activate each other's expression and weakly activate their own expression. FimW was found to negatively regulate fim gene expression by repressing transcription from the P fimY promoter, independent of FimY or FimZ. Moreover, FimW and FimY interact within a negative feedback loop, as FimY was found to activate the P fimW promoter. In the case of fimU, the expression of this gene was not found to be regulated by FimW, FimY, or FimZ. We also explored the effect of fim gene expression on Salmonella pathogenicity island 1 (SPI1). Our results indicate that FimZ alone is able to enhance the expression of hilE, a known repressor of SPI1 gene expression. Based on our results, we were able to propose an integrated model for the fim gene circuit. As this model involves a combination of positive and negative feedback, we hypothesized that the response of this circuit may be bistable and thus a possible mechanism for phase variation. However, we found that the response was continuous and not bistable.

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Coordinate Regulation of Salmonella Pathogenicity Island 1 (SPI1) and SPI4 in Salmonella enterica Serovar Typhimurium

Infection and Immunity ◽

10.1128/iai.01224-07 ◽

2007 ◽

Vol 76 (3) ◽

pp. 1024-1035 ◽

Cited By ~ 59

Author(s):

Kara L. Main-Hester ◽

Katherine M. Colpitts ◽

Gracie A. Thomas ◽

Ferric C. Fang ◽

Stephen J. Libby

Keyword(s):

Mutant Strain ◽

Salmonella Enterica ◽

Salmonella Enterica Serovar Typhimurium ◽

Pathogenicity Island ◽

Open Reading Frames ◽

Type I ◽

Coordinate Regulation ◽

Serovar Typhimurium ◽

Epithelial Invasion ◽

Secretory System

ABSTRACT Salmonella enterica serovar Typhimurium harbors five pathogenicity islands (SPI) required for infection in vertebrate hosts. Although the role of SPI1 in promoting epithelial invasion and proinflammatory cell death has been amply documented, SPI4 has only more recently been implicated in Salmonella virulence. SPI4 is a 24-kb pathogenicity island containing six open reading frames, siiA to siiF. Secretion of the 595-kDa SiiE protein requires a type I secretory system encoded by siiC, siiD, and siiF. An operon polarity suppressor (ops) sequence within the 5′ untranslated region upstream of siiA is required for optimal SPI4 expression and predicted to bind the antiterminator RfaH. SiiE concentrations are decreased in a SPI1 mutant strain, suggesting that SPI1 and SPI4 may have common regulatory inputs. SPI1 gene expression is positively regulated by the transcriptional activators HilA, HilC, and HilD, encoded within SPI1, and negatively regulated by the regulators HilE and PhoP. Here, we show that mutations in hilA, hilC, or hilD similarly reduce expression of siiE, and mutations in hilE or phoP enhance siiE expression. Individual overexpression of HilA, HilC, or HilD in the absence of SPI1 cannot activate siiE expression, suggesting that these transcriptional regulators act in concert or in combination with additional SPI1-encoded regulatory loci to activate SPI4. HilA is no longer required for siiE expression in an hns mutant strain, suggesting that HilA promotes SPI4 expression by antagonizing the global transcriptional silencer H-NS. Coordinate regulation suggests that SPI1 and SPI4 play complementary roles in the interaction of S. enterica serovar Typhimurium with the host intestinal mucosa.

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SiiE Is Secreted by the Salmonella enterica Serovar Typhimurium Pathogenicity Island 4-Encoded Secretion System and Contributes to Intestinal Colonization in Cattle

Infection and Immunity ◽

10.1128/iai.01438-06 ◽

2007 ◽

Vol 75 (3) ◽

pp. 1524-1533 ◽

Cited By ~ 64

Author(s):

Eirwen Morgan ◽

Alison J. Bowen ◽

Sonya C. Carnell ◽

Timothy S. Wallis ◽

Mark P. Stevens

Keyword(s):

Salmonella Enterica ◽

Salmonella Enterica Serovar Typhimurium ◽

Pathogenicity Island ◽

Secretion System ◽

Type I ◽

Intestinal Colonization ◽

Serovar Typhimurium

ABSTRACT Here we report that Salmonella enterica serovar Typhimurium pathogenicity island 4 carries a type I secretion system (siiCDF) which secretes an ∼600-kDa protein (encoded by siiE). SiiE is surface expressed, and its production is regulated by HilA. SiiE and SiiF influence colonization in cattle and the invasion of bovine enterocytes.

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Type I interferon enhances necroptosis of Salmonella Typhimurium–infected macrophages by impairing antioxidative stress responses

The Journal of Cell Biology ◽

10.1083/jcb.201701107 ◽

2017 ◽

Vol 216 (12) ◽

pp. 4107-4121 ◽

Cited By ~ 17

Author(s):

Nina Judith Hos ◽

Raja Ganesan ◽

Saray Gutiérrez ◽

Deniz Hos ◽

Jennifer Klimek ◽

...

Keyword(s):

Cell Death ◽

Stress Responses ◽

Salmonella Enterica Serovar Typhimurium ◽

Type I Interferon ◽

Redox Homeostasis ◽

Type I ◽

Interacting Protein ◽

Serovar Typhimurium ◽

Autophagic Degradation ◽

Antioxidative Stress

Salmonella enterica serovar Typhimurium exploits the host’s type I interferon (IFN-I) response to induce receptor-interacting protein (RIP) kinase–mediated necroptosis in macrophages. However, the events that drive necroptosis execution downstream of IFN-I and RIP signaling remain elusive. In this study, we demonstrate that S. Typhimurium infection causes IFN-I–mediated up-regulation of the mitochondrial phosphatase Pgam5 through RIP3. Pgam5 subsequently interacts with Nrf2, which sequesters Nrf2 in the cytosol, thereby repressing the transcription of Nrf2-dependent antioxidative genes. The impaired ability to respond to S. Typhimurium–induced oxidative stress results in reactive oxygen species–mediated mitochondrial damage, energy depletion, transient induction of autophagy, and autophagic degradation of p62. Reduced p62 levels impair interaction of p62 with Keap1, which further decreases Nrf2 function and antioxidative responses to S. Typhimurium infection, eventually leading to cell death. Collectively, we identify impaired Nrf2-dependent redox homeostasis as an important mechanism that promotes cell death downstream of IFN-I and RIP3 signaling in S. Typhimurium–infected macrophages.

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