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| Status |
Public on Apr 12, 2021 |
| Title |
Transcriptome and translatome profiling of Mtb-infected human DC identifies GSK-3beta as a molecular switch of rapamycin-driven immune stimulation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
In human primary dendritic cells (DC) rapamycin - an autophagy inducer and protein synthesis inhibitor - overcomes the autophagy block induced by Mycobacterium tuberculosis (Mtb) and promotes Th1 response via IL-12 secretion. Here, the immunostimulatory activity of rapamycin in Mtb-infected DC was investigated by analyzing the transcriptome and the translatome profiles.
Several differentially expressed genes (DEGs) were found in transcriptome and translatome of Mtb-infected DC, showing an additional increase in presence of rapamycin, which was instead ineffective in uninfected cells. The majority of DEGs identified in the translatome resulted also present in the transcriptome-modulated genes, suggesting that both RNAs are actively translated mRNAs. The DEG in silico analysis showed significant changes in intracellular cascades related to cytokine production, cytokine-induced signaling and immune response to pathogens. In particular, rapamycin treatment of Mtb-infected DC caused a significant enrichment of IFN-beta, IFN-lambda and IFN-stimulated genes in the polysome-associated RNA fraction. In addition, IL-12, IL-23, IL-1B, IL-6, and TNF-A were induced at RNA and protein level by rapamycin in Mtb-infected DC, while IL-10 was reduced. Interestingly, upon siRNA or pharmacologically GSK-3beta inhibition, rapamycin-driven modulation of the pro- and anti-inflammatory cytokine balance was lost, thus indicating that in Mtb-infected DC GSK-3beta functions as molecular switch for the regulation of cytokine milieu.
In conclusion, our study sheds light on the molecular mechanism by which autophagy contributes to DC activation during Mtb infection and highlights that rapamycin and its analogs as well as GSK-3beta modulators are promising compounds for host-directed therapy in the control of Mtb infection.
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| Overall design |
Matched transcriptome and translatome profiles of human primary Dendrtitic cells infected with Mtb and treated with rapamycin, four biological replicates for each condition.
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| Contributor(s) |
Etna MP, Licursi V, Palumbo O, Stallone R, Carella M, Negri R, Coccia EM |
| Citation(s) |
33936070 |
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| Submission date |
Dec 18, 2020 |
| Last update date |
Jul 13, 2021 |
| Contact name |
Valerio Licursi |
| E-mail(s) |
valerio.licursi@uniroma1.it
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| Organization name |
Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR)
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| Department |
c/o Dept. Biology and Biotechnologies "C. Darwin", Sapienza University of Rome
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| Street address |
via degli Apuli, 4
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| City |
Rome |
| ZIP/Postal code |
00185 |
| Country |
Italy |
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| Platforms (1) |
| GPL20265 |
[HTA-2_0] Affymetrix Human Transcriptome Array 2.0 [transcript (gene) version] |
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| Samples (32)
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| GSM4981002 |
Untreated, polysome, biological replicate 1 |
| GSM4981003 |
Untreated, total, biological replicate 1 |
| GSM4981004 |
Mtb, 16h, polysome, biological replicate 1 |
| GSM4981005 |
Mtb, 16h, total, biological replicate 1 |
| GSM4981006 |
Mtb + Rapa, 16h, polysome, biological replicate 1 |
| GSM4981007 |
Mtb + Rapa, 16h, total, biological replicate 1 |
| GSM4981008 |
Rapamycin, 12h, polysome, biological replicate 1 |
| GSM4981009 |
Rapamycin, 12h, total, biological replicate 1 |
| GSM4981010 |
Untreated, polysome, biological replicate 2 |
| GSM4981011 |
Untreated, total, biological replicate 2 |
| GSM4981012 |
Mtb, 16h, polysome, biological replicate 2 |
| GSM4981013 |
Mtb, 16h, total, biological replicate 2 |
| GSM4981014 |
Mtb + Rapa, 16h, polysome, biological replicate 2 |
| GSM4981015 |
Mtb + Rapa, 16h, total, biological replicate 2 |
| GSM4981016 |
Rapamycin, 12h, polysome, biological replicate 2 |
| GSM4981017 |
Rapamycin, 12h, total, biological replicate 2 |
| GSM4981018 |
Untreated, polysome, biological replicate 3 |
| GSM4981019 |
Untreated, total, biological replicate 3 |
| GSM4981020 |
Mtb, 16h, polysome, biological replicate 3 |
| GSM4981021 |
Mtb, 16h, total, biological replicate 3 |
| GSM4981022 |
Mtb + Rapa, 16h, polysome, biological replicate 3 |
| GSM4981023 |
Mtb + Rapa, 16h, total, biological replicate 3 |
| GSM4981024 |
Rapamycin, 12h, polysome, biological replicate 3 |
| GSM4981025 |
Rapamycin, 12h, total, biological replicate 3 |
| GSM4981026 |
Untreated, polysome, biological replicate 4 |
| GSM4981027 |
Untreated, total, biological replicate 4 |
| GSM4981028 |
Mtb, 16h, polysome, biological replicate 4 |
| GSM4981029 |
Mtb, 16h, total, biological replicate 4 |
| GSM4981030 |
Mtb + Rapa, 16h, polysome, biological replicate 4 |
| GSM4981031 |
Mtb + Rapa, 16h, total, biological replicate 4 |
| GSM4981032 |
Rapamycin, 12h, polysome, biological replicate 4 |
| GSM4981033 |
Rapamycin, 12h, total, biological replicate 4 |
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| Relations |
| BioProject |
PRJNA686434 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE163531_RAW.tar |
722.9 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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