Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Primary macrophage response to L. monocytogenes and bacteria-derived ligands

ABSTRACT: Transcriptional profiling of macrophages (of various genetic backgrounds) infected with L. monocytogenes or transfected with purified ligands Keywords: Timecourse, cell type comparison, bacteria strain comparison, drug comparison, ligand comparison. Timecourse experiment in different genetic backgrounds, with both WT and mutant bacteria, and with different combinations of purified ligands. Multiple biological replicates (see array names), with one replicate per array.

ORGANISM(S): Mus musculus

SUBMITTER: Jess Leber

PROVIDER: E-GEOD-8104 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen.

Leber Jess H JH Crimmins Gregory T GT Raghavan Sridharan S Meyer-Morse Nicole P NP Cox Jeffery S JS Portnoy Daniel A DA

PLoS pathogens 20080101 1

How the innate immune system tailors specific responses to diverse microbial infections is not well understood. Cells use a limited number of host receptors and signaling pathways to both discriminate among extracellular and intracellular microbes, and also to generate responses commensurate to each threat. Here, we have addressed these questions by using DNA microarrays to monitor the macrophage transcriptional response to the intracellular bacterial pathogen Listeria monocytogenes. By utilizin ...[more]

PMID: 18193943

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Project description:The intracellular bacterial pathogen Legionella pneumophila causes an inflammatory pneumonia called Legionnaires’ Disease. For virulence, L. pneumophila requires a Dot/Icm type IV secretion system that translocates bacterial effectors to the host cytosol. L. pneumophila lacking the Dot/Icm system is recognized by Toll-like receptors (TLRs), leading to a canonical NF-κB-dependent transcriptional response. In addition, L. pneumophila expressing a functional Dot/Icm system potently induces unique transcriptional targets, including proinflammatory genes such as Il23a and Csf2. Here we demonstrate that this Dot/Icm-dependent response, which we term the effector-triggered response (ETR), requires five translocated bacterial effectors that inhibit host protein synthesis. Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor. Thus, macrophages infected with wildtype L. pneumophila exhibited prolonged activation of NF-κB, which was associated with transcription of ETR target genes such as Il23a and Csf2. L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR. L. pneumophila mutants expressing enzymatically inactive effectors were also unable to fully induce the ETR, whereas multiple compounds or bacterial toxins that inhibit host protein synthesis via distinct mechanisms recapitulated the ETR when administered with TLR ligands. Previous studies have demonstrated that the host response to bacterial infection is induced primarily by specific microbial molecules that activate TLRs or cytosolic pattern recognition receptors. Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis. Three-condition experiment: macrophages left uninfected (negative control), or infected with wildtype Legionella pneumophila, or the mutant Δ5, which lacks five bacterial effectors involved in inhibition of host protein synthesis (lgt1, lgt2, lgt3, sidI, sidL) (two experimental conditions). Biological replicates: two, independently infected, harvested, and hybridized to arrays. One technical replicate per array.

Project description:The intracellular bacterial pathogen Legionella pneumophila causes an inflammatory pneumonia called Legionnaires’ Disease. For virulence, L. pneumophila requires a Dot/Icm type IV secretion system that translocates bacterial effectors to the host cytosol. L. pneumophila lacking the Dot/Icm system is recognized by Toll-like receptors (TLRs), leading to a canonical NF-κB-dependent transcriptional response. In addition, L. pneumophila expressing a functional Dot/Icm system potently induces unique transcriptional targets, including proinflammatory genes such as Il23a and Csf2. Here we demonstrate that this Dot/Icm-dependent response, which we term the effector-triggered response (ETR), requires five translocated bacterial effectors that inhibit host protein synthesis. Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor. Thus, macrophages infected with wildtype L. pneumophila exhibited prolonged activation of NF-κB, which was associated with transcription of ETR target genes such as Il23a and Csf2. L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR. L. pneumophila mutants expressing enzymatically inactive effectors were also unable to fully induce the ETR, whereas multiple compounds or bacterial toxins that inhibit host protein synthesis via distinct mechanisms recapitulated the ETR when administered with TLR ligands. Previous studies have demonstrated that the host response to bacterial infection is induced primarily by specific microbial molecules that activate TLRs or cytosolic pattern recognition receptors. Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis. Four-condition experiment: macrophages left uninfected (negative control), or infected with wildtype Legionella pneumophila, the flagellin-deficient mutant ΔflaA, or the secretion-deficient mutant ΔdotA (three experimental conditions). Biological replicates: two, independently infected, harvested, and hybridized to arrays. One to two technical replicates per array, as indicated in file titles.

Dataset Information

Primary macrophage response to L. monocytogenes and bacteria-derived ligands

Publications

Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen.

Similar Datasets

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