Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human mononuclear cells after treatment with suppressor carbohydrates produced by CD8+ gd T cells in response to Mycobacterium tuberculosis

ABSTRACT: Mycobacterium tuberculosis (M.tb) infects 8 million and kills 2.2 million people each year worldwide. M.tb modulates the immune response of the infected individual. Empirically, suppressor carbohydrates (SC) produced by CD8+ gd T cells in response to M.tb were found to induce a T helper 2 response rather than a protective T helper 1 response in human mononuclear (MN) cells. This study 1) identifies the genes that modulate the T helper response, 2) describes their function, and 3) postulates a detailed model for the M.tb infection mechanism. MN cells from five healthy donors were pulsed with SC and gene expression profiles of 18,861 genes were assessed in a microarray experiment. Twenty-eight genes were found to be increased and 60 genes were decreased (FDR = 1%, Fold Change > 1.4) in response to SC. MIP-3a, chemotactic for dendritic, T and B cells, but not for monocytes, as well as platelet factor 4 (v1), inhibitor of angiogenesis are both significantly enriched (p <= 0.001) in the GO category "chemokine activity". Repressed genes were significantly (p <= 0.001) overrepresented in the GO terms "response to pathogenic bacteria", "inflammatory response", "apoptosis" and "coagulation", implying a key role for NF-kB. We have identified 88 differentially expressed genes, which lead us to postulate that SC produced by CD8+ gd T cells fine-tune the types of infiltrating cells, decrease apoptosis and decrease proliferation of CD4+ T helper cells at the site of M.tb infection. This will allow development of new therapeutic interventions to restore the desired T helper 1 response.

ORGANISM(S): Homo sapiens

SUBMITTER: Robert Rader

PROVIDER: E-MARS-7 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Gene expression profiling of suppressor mechanisms in tuberculosis.

Smit van Dixhoorn Mieneke G A MG Munir Riffat R Sussman Garth G Stad Robert R de Haan Muus M van der Hoeven Tessa T Rauwerda Han H Breit Timo M TM Thallinger Gerhard G GG Wadee Ahmed A AA

Molecular immunology 20080301 6

Mycobacterium tuberculosis (M.tb) infects 8 million and kills 2.2 million people each year worldwide. M.tb modulates the immune response of the infected individual. Empirically, suppressor carbohydrates (SC) produced by CD8+ T cells in response to M.tb were found to induce a T helper 2 response rather than a protective T helper 1 response in human mononuclear (MN) cells. This study (1) identifies the genes that modulate the T helper response, (2) describes their function, and (3) postulates a de ...[more]

PMID: 18068800

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Project description:Human alveolar macrophages (HAM) are primary bacterial niche and immune response cells during Mycobacterium tuberculosis (M.tb) infection, and human blood monocyte-derived macrophages (MDM) are a model for investigating M.tb-macrophage interactions. Here, we use a targeted RNA-Seq method to measure transcriptome-wide changes in RNA expression patterns of freshly obtained HAM (used within 6 h) and 6 day cultured MDM upon M.tb infection over time (2, 24 and 72 h), in both uninfected and infected cells from three donors each. The Ion AmpliSeq™ Transcriptome Human Gene Expression Kit (AmpliSeq) uses primers targeting 18,574 mRNAs and 2,228 non-coding RNAs (ncRNAs) for a total of 20,802 transcripts. AmpliSeqTM yields highly precise and reproducible gene expression profiles (R2 >0.99). Taking advantage of AmpliSeq’s reproducibility, we establish well-defined quantitative RNA expression patterns of HAM versus MDM, including significant M.tb-inducible genes, in networks and pathways that differ in part between MDM and HAM. A similar number of expressed genes are detected at all time-points between uninfected MDM and HAM, in common pathways including inflammatory and immune functions, but canonical pathway differences also exist. In particular, at 2 h, multiple genes relevant to the immune response are preferentially expressed in either uninfected HAM or MDM, while the HAM RNA profiles approximate MDM profiles over time in culture, highlighting the unique RNA expression profile of freshly obtained HAM. MDM demonstrate a greater transcriptional response than HAM upon M.tb infection, with 2 to >10 times more genes up- or down-regulated. The results identify key genes involved in cellular responses to M.tb in two different human macrophage types. Follow-up bioinformatics analysis indicates that approximately 30% of response genes have expression quantitative trait loci (eQTLs in GTEx), common DNA variants that can influence host gene expression susceptibility or resistance to M.tb, illustrated with the TREM1 gene cluster and IL-10.

Dataset Information

Transcription profiling of human mononuclear cells after treatment with suppressor carbohydrates produced by CD8+ gd T cells in response to Mycobacterium tuberculosis

Publications

Gene expression profiling of suppressor mechanisms in tuberculosis.

Similar Datasets

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