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Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β [RNA-Seq]

ABSTRACT: Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense against Salmonella remains unclear. Here, we show that IL-1b production is detrimental during Salmonella infection. Mice lacking IL-1b (IL-1b -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1b -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1b induces expression of complement anaphylatoxins and suppresses the complement-inactivator Carboxypeptidase N (CPN1). Disrupting this process via IL-1b loss prevented mortality in Salmonella-infected IL-1b -/- mice. Finally, we found that IL-1b expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1b signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1b signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE252069 | GEO | 2024/01/08

REPOSITORIES: GEO

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Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β [16S]

Project description:Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense against Salmonella remains unclear. Here, we show that IL-1b production is detrimental during Salmonella infection. Mice lacking IL-1b (IL-1b -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1b -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1b induces expression of complement anaphylatoxins and suppresses the complement-inactivator Carboxypeptidase N (CPN1). Disrupting this process via IL-1b loss prevented mortality in Salmonella-infected IL-1b -/- mice. Finally, we found that IL-1b expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1b signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1b signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

2024-01-08 | GSE252070 | GEO

Pdx1 overexpression sensitizes to IL-1b-induced apoptosis

Project description:Cytokines have been shown to play a key role in the destruction of beta cells. In the rat insulinoma cell line (INS-1ab) overexpressing pancreatic duodenum homeobox 1 (Pdx1) increases sensitivity to Interleukin 1b (IL-1b). To elucidate mechanisms of action underlying Pdx1 driven potentiation of beta-cell sensitivity to IL-1β, we performed a microarray analysis of INS-1ab cells with and without Pdx1 overexpression exposed to IL-1β between 2h and 24h. INS-1ab cells were cultured with or without 500 ng/ml doxycycline (+/- DOX). After 24 h, 40 ng/ml IL-1b was either added or not (+/- IL-1b). Cells were harvested either 2h, 4h, 6h, 12h or 24h after addition of IL-1b. Four biological replicates for each of the eight groups.

2012-09-20 | E-GEOD-40642 | biostudies-arrayexpress

Transcriptome of human ILC2s; primary vs IL-1b-primed

Project description:ILC2s regulate type2 immune responses and protect against helminth infection. We found that ILC2s can be expanded in the presence of a combination of cytokines IL-2 and IL-1b. To better understand the functional and phenotypic consequence of IL-1β activation of ILC2s, we utilized whole transcriptome sequencing (RNA-seq) of freshly isolated ILC2s and IL-1β-primed ILC2s. Differential expression analysis revealed a substantial number of genes underwent significant change between the two conditions (total 4,744 gene, FDR<0.01, Fold change >2), among which 3,871 genes were upregulated in IL-1β –primed ILC2s.

2016-04-25 | GSE72460 | GEO

Hemochromatosis drives acute lethal intestinal responses to hyper-yersiniabactin-producing Yersinia pseudotuberculosis

Project description:Hemachromatosis (iron-overload) increases host susceptibility to siderophilic bacterial infections that cause serious complications, but the underlying mechanisms remain elusive. The present study demonstrates that oral infection with hyper-yersiniabactin (Ybt) producing Yersinia pseudotuberculosis Δfur mutant (termed Δfur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δfur infected intestine revealed upregulation in cytokine-cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and downregulation in cell adhesion molecules and TLR signaling pathways. Further studies indicate that dysregulated IL-1b signaling triggered in hemachromatotic mice infected with Δfur damages the intestinal barrier by activation of myosin light chain kinases (MLCK) and excessive neutrophilia. Inhibiting MLCK activity or depleting neutrophil infiltration reduces barrier disruption, largely ameliorates immunopathology, and substantially rescues hemochromatotic mice from lethal Δfur infection. Moreover, early intervention of IL-1b overproduction can completely rescue hemochromatotic mice from the lethal infection.

2021-12-15 | GSE180888 | GEO

Pdx1 overexpression sensitizes to IL-1b-induced apoptosis

2012-09-20 | GSE40642 | GEO

Gene expression kinetics in Murine Gut wall tissue: Reference (Total RNA Mixture of all samples) vs. Probiotics/Salmonella treated mice

Project description:Transcriptional profiling of mouse gut wall tissue following infection with Salmonella or treatment with Probiotics to see the role of probiotics in preventing salmonella infection through gut mucosal route of mouse.

2018-06-18 | GSE98353 | GEO

Genome-wide characterization of a novel necrotic granuloma model of latent tuberculosis infection and reactivation in mice

Project description:We sought to develop and characterize a novel paucibacillary model in mice, which develop necrotic lung granulomas following infection with Mycobacterium tuberculosis. Paucibacillary infection was established, recapitulating the sterilizing activities of human LTBI regimens. TNF neutralization led to increased lung bacillary load, disrupted granuloma architecture with expanded necrotic foci and reduced tissue hypoxia, and accelerated animal mortality. TNF-neutralized mouse lungs and sera showed significant upregulation of IFNγ, IL-1β, IL-6, IL-10, CCL2, CCL3, and matrix metalloproteinase genes

2014-02-20 | GSE55183 | GEO

Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges

Project description:Bacterial flagellin is a dominant innate immune activator of the intestine. Therefore, we examined the role of the intracellular flagellin receptor, NLRC4, in protecting the gut and/or driving inflammation. In accord with NLRC4 acting via transcription-independent pathways, loss of NLRC4 did not reduce the rapid robust changes in intestinal gene expression induced by flagellin administration. Loss of NLRC4 did not alter basal intestinal homeostasis nor predispose mice to development of colitis upon administration of an anti-IL-10R monoclonal antibody. However, in response to epithelial injury induced by dextran sulfate sodium (DSS), loss of NLRC4 resulted in more severe disease indicating a role for NLRC4 in protecting the gut. Moreover, loss of NLRC4 resulted in increased mortality in response to flagellate, but not aflagellate Salmonella infection. Thus, despite not being involved in rapid intestinal gene remodeling upon detection of flagellin, NLRC4-mediated inflammasome activation protects mice from mucosal and systemic challenges Flagellin (FliC) from WT Salmonella enterica serovar Typhimurium (SL3201, fljB–) was purified through sequential cation and anion-exchange chromatography and purity was verified as previously described 4. WT, T5KO, N4KO and T5/N4-DKO mice (n=6) were given either 0.2 mL PBS or flagellin (10μg/mouse in 0.2 mL PBS) intraperitoneally. After 1h, mice were euthanized and colon was taken and stored in RNAlater (Invitrogen) for 1 day. Total mRNA was isolated from colonic tissues using TRIzol (Invitrogen) and purified using the RNeasy® Plus Mini kit (Qiagen) according to the manufacturer’s instructions

2012-01-01 | E-GEOD-34492 | biostudies-arrayexpress

Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment

Project description:SARS-CoV-2 infection may result in a severe pneumonia associated to elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients, however the mechanisms by which SARS-CoV2 virus trigger such an extensive inflammation remain unexplained. A pivotal cytokine driving inflammatory phenotypes is IL-1β, whose maturation and secretion is regulated by NLRP3 inflammasome. In the present report we provide a mechanistic explanation for the strong inflammatory manifestations associated to COVID-19 and further evidence that NLRP3 and IL-1β targeting could be an effective strategy in this disease.

2022-12-23 | GSE163317 | GEO

Butyrate protects pancreatic beta cells from cytokine induced dysfunction

Project description:Beta cell dysfunction, caused by metabolic and inflammatory stress, contributes to the development of type 2 diabetes. Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on IL-1β-induced β cell dysfunction. We showed that long-term exposure of mouse islets to non-cytotoxic concentrations of IL-1β impaired insulin secretion and content and reduced proliferation. This dysfunction was prevented when the islets were exposed to butyrate and butyrate alone also boosted insulin secretion. In contrast, butyrate further downregulated the proliferation. To get a better indication of mechanisms of actions we investigated the global mRNA expression profiles using RNA sequencing. Our results indicated that the protective effects of butyrate are associated with upregulation of secretion/transport-related genes and downregulation of inflammatory genes induced by IL-1β. In addition, several cell cycle related genes were strongly inhibited by butyrate. In conclusion, butyrate plays an essential role in supporting beta cell function under inflammatory conditions, suggesting a potential for therapeutic use in treatment and prevention of T2D.

2021-09-27 | GSE180317 | GEO

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