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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jul 05, 2013 |
| Title |
A TLR- and non-TLR-mediated innate response to lentiviruses restricts hepatocyte entry and can be ameliorated by pharmacological blockade |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Lentiviral vector (LV)-mediated gene transfer is a promising method of gene therapy. We previously reported that systemic injection of LV triggers a transient inflammatory response. Here, we carried out studies to better characterize this response, and to develop a strategy to overcome the effects of interferon (IFN) on LV-mediated gene transfer. We profiled gene expression in the liver after LV administration using deep-sequencing, and identified several innate response pathways. We examined the response to LV in MyD88-TRIF knock-out mice, which are incapable of toll-like receptor (TLR) signaling. The IFN response to LV was not reduced in the liver, indicating that a non-TLR pathway can recognize LV in this tissue. Indeed, blocking reverse-transcription with AZT reduced the IFN response only in the liver, suggesting that proviral DNA can be a trigger. To block the inflammatory response, we pre-treated mice with a short-course of dexamethasone. At 4 hours post-treatment, all of the IFN-induced genes were normalized. By blocking the inflammatory response, hepatocyte transduction was dramatically increased, which doubled the level of human factor-IX produced by a hepatocyte-specific LV. Our studies uncover new insights into LV-induced immune responses in the liver, and provide a means to increase the safety and efficiency of LV-mediated gene transfer.
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| Overall design |
mRNA profiles from livers of untreated and LV-treated mice were generated by deep-sequencing in Illumina HiSeq 2000.
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| Contributor(s) |
Brown BD, Agudo J |
| Citation(s) |
22871668 |
| Submission date |
Jul 05, 2012 |
| Last update date |
May 15, 2019 |
| Contact name |
Brian Brown |
| E-mail(s) |
bdblab@gmail.com
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| Organization name |
Icahn School of Medicine at Mount Sinai
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| Department |
Genetics and Genomic Sciences
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| Street address |
1470 Madison Avenue
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA170059 |
| SRA |
SRP014029 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE39129_Liver+LV_consolidated.txt.gz |
74.7 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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