Toll-like Receptor 9 Triggers an Innate Immune Response to Helper-dependent Adenoviral Vectors
A major obstacle to the clinical application of systemic adenoviral gene replacement therapy is the host innate immune response. Although recent studies have attempted to characterize the cellular basis for this response to systemically administered helper-dependent adenoviral vector (HD-Ad), the un...
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| Veröffentlicht in: | Molecular therapy 2007-02, Vol.15 (2), p.378-385 |
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| creator | Cerullo, Vincenzo Seiler, Michael P Mane, Viraj Brunetti-Pierri, Nicola Clarke, Christian Bertin, Terry K Rodgers, John R Lee, Brendan |
| description | A major obstacle to the clinical application of systemic adenoviral gene replacement therapy is the host innate immune response. Although recent studies have attempted to characterize the cellular basis for this response to systemically administered helper-dependent adenoviral vector (HD-Ad), the underlying molecular components of the innate immune repertoire required to recognize the viral vector have yet to be identified. Here, we show that primary macrophages can sense HD-Ad vectors via the Toll-like Receptor 9 (TLR9) and respond by increasing pro-inflammatory cytokine secretion. Moreover, TLR9 sensing is involved in the rapid innate immune response to HD-Ad in vivo. TLR9 deficiency attenuates the innate immune response to HD-Ad, whereas TLR9 blockade reduces the acute inflammatory response after intravenous injection of the vector. Moreover, HD-Ad upregulates TLR9 gene expression independent of TLR9 function, suggesting that additional innate signaling pathways work cooperatively with TLR9. The identification of the components of the innate immune response to adenovirus will facilitate the development of combinatorial therapy directed at increasing the maximal tolerated dose of systemically delivered adenoviral vectors. |
| doi_str_mv | 10.1038/sj.mt.6300031 |
| format | Article |
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Although recent studies have attempted to characterize the cellular basis for this response to systemically administered helper-dependent adenoviral vector (HD-Ad), the underlying molecular components of the innate immune repertoire required to recognize the viral vector have yet to be identified. Here, we show that primary macrophages can sense HD-Ad vectors via the Toll-like Receptor 9 (TLR9) and respond by increasing pro-inflammatory cytokine secretion. Moreover, TLR9 sensing is involved in the rapid innate immune response to HD-Ad in vivo. TLR9 deficiency attenuates the innate immune response to HD-Ad, whereas TLR9 blockade reduces the acute inflammatory response after intravenous injection of the vector. Moreover, HD-Ad upregulates TLR9 gene expression independent of TLR9 function, suggesting that additional innate signaling pathways work cooperatively with TLR9. The identification of the components of the innate immune response to adenovirus will facilitate the development of combinatorial therapy directed at increasing the maximal tolerated dose of systemically delivered adenoviral vectors.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/sj.mt.6300031</identifier><identifier>PMID: 17235317</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenoviridae - genetics ; Adenoviruses ; Animals ; Cells ; Cytokines ; Cytokines - metabolism ; Cytomegalovirus ; Cytotoxicity ; Drug dosages ; Female ; Gene therapy ; Genetic Vectors - genetics ; Hemophilia ; Herpes viruses ; Immunity, Innate - immunology ; Immunoassay - methods ; Kinases ; Macrophages, Peritoneal - cytology ; Macrophages, Peritoneal - immunology ; Macrophages, Peritoneal - metabolism ; Mice ; Mice, Inbred C57BL ; Pattern recognition ; Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; Toll-Like Receptor 9 - deficiency ; Toll-Like Receptor 9 - genetics ; Toll-Like Receptor 9 - physiology ; Transfection ; Tumor necrosis factor-TNF ; Vectors (Biology) ; Viral infections</subject><ispartof>Molecular therapy, 2007-02, Vol.15 (2), p.378-385</ispartof><rights>2007 The American Society of Gene Therapy</rights><rights>Copyright Nature Publishing Group Feb 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-89d1b4367e9ee01460078c1c54d6ab56aa4f80a6a5365a97342f27d0fb7571dc3</citedby><cites>FETCH-LOGICAL-c428t-89d1b4367e9ee01460078c1c54d6ab56aa4f80a6a5365a97342f27d0fb7571dc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1792616892?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,64385,64387,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17235317$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cerullo, Vincenzo</creatorcontrib><creatorcontrib>Seiler, Michael P</creatorcontrib><creatorcontrib>Mane, Viraj</creatorcontrib><creatorcontrib>Brunetti-Pierri, Nicola</creatorcontrib><creatorcontrib>Clarke, Christian</creatorcontrib><creatorcontrib>Bertin, Terry K</creatorcontrib><creatorcontrib>Rodgers, John R</creatorcontrib><creatorcontrib>Lee, Brendan</creatorcontrib><title>Toll-like Receptor 9 Triggers an Innate Immune Response to Helper-dependent Adenoviral Vectors</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>A major obstacle to the clinical application of systemic adenoviral gene replacement therapy is the host innate immune response. Although recent studies have attempted to characterize the cellular basis for this response to systemically administered helper-dependent adenoviral vector (HD-Ad), the underlying molecular components of the innate immune repertoire required to recognize the viral vector have yet to be identified. Here, we show that primary macrophages can sense HD-Ad vectors via the Toll-like Receptor 9 (TLR9) and respond by increasing pro-inflammatory cytokine secretion. Moreover, TLR9 sensing is involved in the rapid innate immune response to HD-Ad in vivo. TLR9 deficiency attenuates the innate immune response to HD-Ad, whereas TLR9 blockade reduces the acute inflammatory response after intravenous injection of the vector. Moreover, HD-Ad upregulates TLR9 gene expression independent of TLR9 function, suggesting that additional innate signaling pathways work cooperatively with TLR9. 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Although recent studies have attempted to characterize the cellular basis for this response to systemically administered helper-dependent adenoviral vector (HD-Ad), the underlying molecular components of the innate immune repertoire required to recognize the viral vector have yet to be identified. Here, we show that primary macrophages can sense HD-Ad vectors via the Toll-like Receptor 9 (TLR9) and respond by increasing pro-inflammatory cytokine secretion. Moreover, TLR9 sensing is involved in the rapid innate immune response to HD-Ad in vivo. TLR9 deficiency attenuates the innate immune response to HD-Ad, whereas TLR9 blockade reduces the acute inflammatory response after intravenous injection of the vector. Moreover, HD-Ad upregulates TLR9 gene expression independent of TLR9 function, suggesting that additional innate signaling pathways work cooperatively with TLR9. The identification of the components of the innate immune response to adenovirus will facilitate the development of combinatorial therapy directed at increasing the maximal tolerated dose of systemically delivered adenoviral vectors.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>17235317</pmid><doi>10.1038/sj.mt.6300031</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenoviridae - genetics Adenoviruses Animals Cells Cytokines Cytokines - metabolism Cytomegalovirus Cytotoxicity Drug dosages Female Gene therapy Genetic Vectors - genetics Hemophilia Herpes viruses Immunity, Innate - immunology Immunoassay - methods Kinases Macrophages, Peritoneal - cytology Macrophages, Peritoneal - immunology Macrophages, Peritoneal - metabolism Mice Mice, Inbred C57BL Pattern recognition Proteins Reverse Transcriptase Polymerase Chain Reaction Toll-Like Receptor 9 - deficiency Toll-Like Receptor 9 - genetics Toll-Like Receptor 9 - physiology Transfection Tumor necrosis factor-TNF Vectors (Biology) Viral infections |
| title | Toll-like Receptor 9 Triggers an Innate Immune Response to Helper-dependent Adenoviral Vectors |
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