A metabolomics analysis of Salmonella infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE21720 | GEO | 2011/02/08
SECONDARY ACCESSION(S): PRJNA127359
REPOSITORIES: GEO
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Project description:The interplay between pathogens and hosts has been studied for decades using targeted approaches such as the analysis of mutants and host immunological responses. Although much has been learned from such studies, they focus on individual pathways and fail to reveal the global effects of infection on the host. To alleviate this issue, high-throughput methods such as transcriptomics and proteomics have been used to study host-pathogen interactions. Recently, metabolomics was established as a new method to study changes in the biochemical composition of host tissues. We report a metabolomics study of Salmonella enterica serovar Typhimurium infection. We used Fourier Transform Ion Cyclotron Resonance Mass Spectrometry with Direct Infusion to reveal that dozens of host metabolic pathways are affected by Salmonella in a murine infection model. In particular, multiple host hormone pathways are disrupted. Our results identify unappreciated effects of infection on host metabolism and shed light on mechanisms used by Salmonella to cause disease, and by the host to counter infection. Female C57BL/6 mice were infected with Salmonella enterica serovar Typhimurium SL1344 cells by oral gavage. Feces and livers were collected and metabolites extracted using acetonitrile. For experiments with feces, samples were collected from 4 mice before and after infection. For liver experiments, 11 uninfected and 11 infected mice were used. Samples were combined into 3 groups of 3-4 mice each, resulting in the analysis of 3 group samples of uninfected and 3 of infected mice. Extracts were infused into a 12-T Apex-Qe hybrid quadrupole-FT-ICR mass spectrometer equipped with an Apollo II electrospray ionization source, a quadrupole mass filter and a hexapole collision cell. Raw mass spectrometry data were processed as described elsewhere (Han et al. 2008. Metabolomics. 4:128-140 [PMID 19081807]). To identify differences in metabolite composition between uninfected and infected samples, we filtered the list of masses for metabolites which were present on one set of samples but not the other. Additionally, we calculated the ratios between averaged intensities of metabolites from uninfected and infected mice. To assign possible metabolite identities, monoisotopic neutral masses of interest were queried against MassTrix (http://masstrix.org). Masses were searched against the Mus musculus database within a mass error of 3 ppm. Data were analyzed by unpaired t tests with 95% confidence intervals.
2011-02-08 | E-GEOD-21720 | biostudies-arrayexpress
Project description:To cause disease, Salmonella enterica serovar Typhimurium requires two type-III secretion systems, encoded on Salmonella Pathogenicity Islands 1 and 2 (SPI-1 and -2). These secretion systems serve to deliver virulence proteins, termed effectors, into the host cell cytosol. While the importance of these effector proteins to promote colonization and replication within the host has been established, the specific roles of individual secreted effectors in the disease process are not well understood. In this study, we used an in vivo gallbladder epithelial cell infection model to study the function of the SPI-2-encoded effector, SseL. Deletion of the sseL gene resulted in bacterial filamentation and elongation and unusual localization of Salmonella within infected epithelial cells. Infection with the ?sseL strain also caused dramatic changes in lipid metabolism and led to massive accumulation of lipid droplets in infected cells. Some of these changes were investigated through metabolomics of gallbladder tissue. This phenotype was directly attributed to the deubiquitinase activity of SseL, as a Salmonella strain carrying a single point mutation in the catalytic cysteine resulted in the same phenotype as the deletion mutant. Excessive buildup of lipids due to the absence of a functional sseL gene was also observed in S. Typhimurium-infected livers. These results demonstrate that SseL alters host lipid metabolism in infected epithelial cells by modifying ubiquitination patterns of cellular targets. Female C57BL/6 mice were infected with the indicated strain of Salmonella enterica serovar Typhimurium by oral gavage. Four gallbladders were collected and pooled per sample group and metabolites extracted using a mixture of methanol and chloroform. Extracts were infused into a 12-T Apex-Qe hybrid quadrupole-FT-ICR mass spectrometer equipped with an Apollo II electrospray ionization source, a quadrupole mass filter and a hexapole collision cell. Raw mass spectrometry data were processed as described elsewhere (Han et al. 2008. Metabolomics. 4:128-140). To identify differences in metabolite composition between different groups of samples, we filtered the list of masses for metabolites which were present on one set of samples but not the other. Additionally, we calculated the ratios between averaged intensities of metabolites from each group of mice. To assign possible metabolite identities, monoisotopic neutral masses of interest were queried against MassTrix (http://masstrix.org). Masses were searched against the Mus musculus database within a mass error of 3 ppm.
2011-08-22 | E-GEOD-27604 | biostudies-arrayexpress
Project description:To cause disease, Salmonella enterica serovar Typhimurium requires two type-III secretion systems, encoded on Salmonella Pathogenicity Islands 1 and 2 (SPI-1 and -2). These secretion systems serve to deliver virulence proteins, termed effectors, into the host cell cytosol. While the importance of these effector proteins to promote colonization and replication within the host has been established, the specific roles of individual secreted effectors in the disease process are not well understood. In this study, we used an in vivo gallbladder epithelial cell infection model to study the function of the SPI-2-encoded effector, SseL. Deletion of the sseL gene resulted in bacterial filamentation and elongation and unusual localization of Salmonella within infected epithelial cells. Infection with the ΔsseL strain also caused dramatic changes in lipid metabolism and led to massive accumulation of lipid droplets in infected cells. Some of these changes were investigated through metabolomics of gallbladder tissue. This phenotype was directly attributed to the deubiquitinase activity of SseL, as a Salmonella strain carrying a single point mutation in the catalytic cysteine resulted in the same phenotype as the deletion mutant. Excessive buildup of lipids due to the absence of a functional sseL gene was also observed in S. Typhimurium-infected livers. These results demonstrate that SseL alters host lipid metabolism in infected epithelial cells by modifying ubiquitination patterns of cellular targets.
2011-08-23 | GSE27604 | GEO
Project description:During the colonization of hosts, bacterial pathogens are presented with many challenges that must be overcome for colonization to successfully occur. This requires bacterial sensing of the surroundings and adaptation to the conditions encountered. One of the major impediments to pathogen colonization of the mammalian gastrointestinal tract is the antibacterial action of bile. Salmonella enterica serovar Typhimurium has specific mechanisms involved in resistance to bile. Besides being resistant to it, Salmonella can also successfully multiply in bile, using it as a source of nutrients. This accomplishment is highly relevant to pathogenesis, as Salmonella colonizes the gallbladder of hosts, where it can be carried asymptomatically and promote further host spread and transmission. In order to gain insights into the mechanisms used by Salmonella to grow in bile, we studied the changes elicited by Salmonella in the chemical composition of bile during growth in vitro and in vivo through a metabolomics approach. Our data suggest that phospholipids are an important source of carbon and energy for Salmonella during growth in the laboratory as well as during gallbladder infections of mice. Further studies in this area will generate a better understanding of how Salmonella exploits this generally hostile environment for its own benefit. For in vitro studies, bile was extracted from C57BL/6 mice and used immediately. An overnight culture of Salmonella enterica serovar Typhimurium SL1344 was used to inoculate 10 ?L of bile at an approximate density of 5x10^6 cells/mL. The experiment was performed in duplicate, and a total of 2 uninfected and 2 infected bile samples were studied. Samples were incubated for 24 hours at 37 oC with shaking. After incubation, samples were centrifuged to remove bacteria and the supernatant was saved for metabolomic analyses. For in vivo studies, C57BL/6 mice were infected with approximately 10^8 bacterial cells by oral gavage. Four groups of three to four mice each were either infected with Salmonella or kept uninfected (total of 11 mice per treatment group). Five days after infection, all mice were sacrificed and bile was collected. Samples were centrifuged and supernatants saved for metabolomic analyses. Samples were prepared by mixing equal volumes of bile from three to four mice, generating three samples per treatment (uninfected and infected), which were used in the subsequent steps. Seven microliters of each sample was evaporated and the residue resuspended in 50% acetonitrine. Extracts were infused into a 12-T Apex-Qe hybrid quadrupole-FT-ICR mass spectrometer equipped with an Apollo II electrospray ionization source, a quadrupole mass filter and a hexapole collision cell. Raw mass spectrometry data were processed as described elsewhere (Han et al. 2008. Metabolomics. 4:128-140). To identify differences in metabolite composition between different groups of samples, we filtered the list of masses for metabolites which were present on one set of samples but not the other. Additionally, we calculated the ratios between averaged intensities of metabolites from each group of mice. To assign possible metabolite identities to the masses selected as described above, the monoisotopic neutral masses of interest were queried against the Human Metabolome Database (HMDB, http://www.hmdb.ca), with a tolerance of 0.001 Da.
2011-07-06 | E-GEOD-30404 | biostudies-arrayexpress
Project description:During the colonization of hosts, bacterial pathogens are presented with many challenges that must be overcome for colonization to successfully occur. This requires bacterial sensing of the surroundings and adaptation to the conditions encountered. One of the major impediments to pathogen colonization of the mammalian gastrointestinal tract is the antibacterial action of bile. Salmonella enterica serovar Typhimurium has specific mechanisms involved in resistance to bile. Besides being resistant to it, Salmonella can also successfully multiply in bile, using it as a source of nutrients. This accomplishment is highly relevant to pathogenesis, as Salmonella colonizes the gallbladder of hosts, where it can be carried asymptomatically and promote further host spread and transmission. In order to gain insights into the mechanisms used by Salmonella to grow in bile, we studied the changes elicited by Salmonella in the chemical composition of bile during growth in vitro and in vivo through a metabolomics approach. Our data suggest that phospholipids are an important source of carbon and energy for Salmonella during growth in the laboratory as well as during gallbladder infections of mice. Further studies in this area will generate a better understanding of how Salmonella exploits this generally hostile environment for its own benefit.
2011-07-07 | GSE30404 | GEO
Project description:Raghunathan2009 - Genome-scale metabolic
network of Salmonella typhimurium (iRR1083)
This model is described in the article:
Constraint-based analysis of
metabolic capacity of Salmonella typhimurium during
host-pathogen interaction.
Raghunathan A, Reed J, Shin S,
Palsson B, Daefler S.
BMC Syst Biol 2009; 3: 38
Abstract:
BACKGROUND: Infections with Salmonella cause significant
morbidity and mortality worldwide. Replication of Salmonella
typhimurium inside its host cell is a model system for studying
the pathogenesis of intracellular bacterial infections.
Genome-scale modeling of bacterial metabolic networks provides
a powerful tool to identify and analyze pathways required for
successful intracellular replication during host-pathogen
interaction. RESULTS: We have developed and validated a
genome-scale metabolic network of Salmonella typhimurium LT2
(iRR1083). This model accounts for 1,083 genes that encode
proteins catalyzing 1,087 unique metabolic and transport
reactions in the bacterium. We employed flux balance analysis
and in silico gene essentiality analysis to investigate growth
under a wide range of conditions that mimic in vitro and host
cell environments. Gene expression profiling of S. typhimurium
isolated from macrophage cell lines was used to constrain the
model to predict metabolic pathways that are likely to be
operational during infection. CONCLUSION: Our analysis suggests
that there is a robust minimal set of metabolic pathways that
is required for successful replication of Salmonella inside the
host cell. This model also serves as platform for the
integration of high-throughput data. Its computational power
allows identification of networked metabolic pathways and
generation of hypotheses about metabolism during infection,
which might be used for the rational design of novel
antibiotics or vaccine strains.
This model is hosted on
BioModels Database
and identified by:
MODEL1507180058.
To cite BioModels Database, please use:
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To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2015-07-30 | MODEL1507180058 | BioModels
Project description:The rise of antibiotic-resistant strains of Salmonella has demand the development of alternative therapeutic strategies. Recent studies have shown that targeting host factors may provide an alternative approach for the treatment of intracellular pathogens. Host-directed therapy (HDT) modulates host cellular factors that are essential to support the replication of the intracellular pathogens. In the current study, we identified Gefitinib as a potential host directed therapeutic drug against Salmonella. Further, using the proteome analysis of Salmonella-infected macrophages, we identified EGFR, a host factor, promoting intracellular survival of Salmonella via mTOR-HIF-1α axis. Blocking of EGFR, mTOR or HIF-1α inhibits the intracellular survival of Salmonella within the macrophages and in mice. Global proteo-metabolomics profiling indicated the upregulation of host factors predominantly associated with ATP turn over, glycolysis, urea cycle, which ultimately promote the activation of EGFR-HIF1α signalling upon infection. Importantly, inhibition of EGFR and HIF1α restored both proteomics and metabolomics changes caused by Salmonella infection. Taken together, this study identifies Gefitinib as a host directed drug that holds potential translational values against Salmonella infection and might be useful for the treatment of other intracellular infections.
2021-03-26 | PXD024771 | Pride
Project description:Anaplasma phagocytophilum is an emerging zoonotic pathogen that causes human granulocytic anaplasmosis. These intracellular bacteria establish infection by affecting cell function in both the vertebrate host and the tick vector, Ixodes scapularis. Previous studies have characterized the tick transcriptome and proteome in response to A. phagocytophilum infection. However, in the post-genomic era, the integration of omics datasets through a systems biology approach allows network-based analyses to describe the complexity and functionality of biological systems such as host-pathogen interactions and the discovery of new targets for prevention and control of infectious diseases. This study reports for the first time a systems biology integration of metabolomics, transcriptomics and proteomics data to characterize essential metabolic pathways involved in the response of tick cells to A. phagocytophilum infection. The results showed that infection affected protein processing in endoplasmic reticulum and glucose metabolic pathways in tick cells. These results supported tick-Anaplasma co-evolution by providing new evidence of how tick cells limit pathogen infection, while the pathogen benefits from the tick cell response to establish infection. The results suggested that A. phagocytophilum induces protein misfolding to limit the tick cell response and facilitate infection, but requires protein degradation to prevent ER stress and cell apoptosis to survive in infected cells. Additionally, A. phagocytophilum may benefit from the tick cellâs ability to limit bacterial infection through PEPCK inhibition leading to decreased glucose metabolism, which also results in the inhibition of cell apoptosis that increases infection of tick cells. These results support the use of this experimental approach to systematically identify tick cell pathways and molecular mechanisms involved in tick-pathogen interactions Two samples with two replicates each were analyzed. Samples included Ixodes scapularis ISE6 cells uninfected (control) and infected with Anaplasma phagocytophilum human NY18 isolate.
2016-01-06 | E-GEOD-68881 | biostudies-arrayexpress
Project description:Metabolomics and Transcriptomics Reveal Key Metabolism Pathways of Giant Embryo Development in Rice
| PRJNA725152 | ENA
Project description:Anaplasma phagocytophilum is an emerging zoonotic pathogen that causes human granulocytic anaplasmosis. These intracellular bacteria establish infection by affecting cell function in both the vertebrate host and the tick vector, Ixodes scapularis. Previous studies have characterized the tick transcriptome and proteome in response to A. phagocytophilum infection. However, in the post-genomic era, the integration of omics datasets through a systems biology approach allows network-based analyses to describe the complexity and functionality of biological systems such as host-pathogen interactions and the discovery of new targets for prevention and control of infectious diseases. This study reports for the first time a systems biology integration of metabolomics, transcriptomics and proteomics data to characterize essential metabolic pathways involved in the response of tick cells to A. phagocytophilum infection. The results showed that infection affected protein processing in endoplasmic reticulum and glucose metabolic pathways in tick cells. These results supported tick-Anaplasma co-evolution by providing new evidence of how tick cells limit pathogen infection, while the pathogen benefits from the tick cell response to establish infection. The results suggested that A. phagocytophilum induces protein misfolding to limit the tick cell response and facilitate infection, but requires protein degradation to prevent ER stress and cell apoptosis to survive in infected cells. Additionally, A. phagocytophilum may benefit from the tick cell’s ability to limit bacterial infection through PEPCK inhibition leading to decreased glucose metabolism, which also results in the inhibition of cell apoptosis that increases infection of tick cells. These results support the use of this experimental approach to systematically identify tick cell pathways and molecular mechanisms involved in tick-pathogen interactions
2016-01-06 | GSE68881 | GEO