Characterization of cooperative PS-oligo activation of human TLR9
Single-stranded phosphorothioate oligonucleotides (PS-oligos) can activate TLR9, leading to an innate immune response. This can occur with PS-oligos containing unmethylated CpG sites, the canonical motif, or PS-oligos that do not contain those motifs (non-CpG). Structural evidence shows that TLR9 co...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123002202 |
| _version_ | 1797736678787383296 |
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| author | Adam J. Pollak Luyi Zhao Stanley T. Crooke |
| author_facet | Adam J. Pollak Luyi Zhao Stanley T. Crooke |
| author_sort | Adam J. Pollak |
| collection | DOAJ |
| description | Single-stranded phosphorothioate oligonucleotides (PS-oligos) can activate TLR9, leading to an innate immune response. This can occur with PS-oligos containing unmethylated CpG sites, the canonical motif, or PS-oligos that do not contain those motifs (non-CpG). Structural evidence shows that TLR9 contains two PS-oligo binding sites, and recent data suggest that synergistic cooperative activation of TLR9 can be achieved by adding two separate PS-oligos to cells, each engaging with a separate site on TLR9 to enhance TLR9 activation as a pair. Here, we demonstrate and characterize this cooperativity phenomenon using PS-oligos in human cell lines, and we introduce several novel PS-oligo pairs (CpG and non-CpG pairs) that show cooperative activation. Indeed, we find that cooperative PS-oligos likely bind at different sites on TLR9. Interestingly, we find that PS-oligos that generate little TLR9 activation on their own can prime TLR9 to be activated by other PS-oligos. Finally, we determine that previous models of TLR9 activation cannot be used to fully explain data from systems using human TLR9 and PS-oligos. Overall, we reveal new details of TLR9 activation, but we also find that more work needs to be done to determine where certain PS-oligos are binding to TLR9. |
| first_indexed | 2024-03-12T13:16:24Z |
| format | Article |
| id | doaj.art-4f3cba99e8d34c71ad01fbcae30d0bc0 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-03-12T13:16:24Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-4f3cba99e8d34c71ad01fbcae30d0bc02023-08-27T04:27:23ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-09-0133832844Characterization of cooperative PS-oligo activation of human TLR9Adam J. Pollak0Luyi Zhao1Stanley T. Crooke2Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA; Corresponding author: Adam J. Pollak, Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USAIonis Pharmaceuticals, Inc., Carlsbad, CA 92010, USASingle-stranded phosphorothioate oligonucleotides (PS-oligos) can activate TLR9, leading to an innate immune response. This can occur with PS-oligos containing unmethylated CpG sites, the canonical motif, or PS-oligos that do not contain those motifs (non-CpG). Structural evidence shows that TLR9 contains two PS-oligo binding sites, and recent data suggest that synergistic cooperative activation of TLR9 can be achieved by adding two separate PS-oligos to cells, each engaging with a separate site on TLR9 to enhance TLR9 activation as a pair. Here, we demonstrate and characterize this cooperativity phenomenon using PS-oligos in human cell lines, and we introduce several novel PS-oligo pairs (CpG and non-CpG pairs) that show cooperative activation. Indeed, we find that cooperative PS-oligos likely bind at different sites on TLR9. Interestingly, we find that PS-oligos that generate little TLR9 activation on their own can prime TLR9 to be activated by other PS-oligos. Finally, we determine that previous models of TLR9 activation cannot be used to fully explain data from systems using human TLR9 and PS-oligos. Overall, we reveal new details of TLR9 activation, but we also find that more work needs to be done to determine where certain PS-oligos are binding to TLR9.http://www.sciencedirect.com/science/article/pii/S2162253123002202MT: Oligonucleotides: Therapies and ApplicationsTLR9PS-ASOCpGinnate immunityreceptor cooperativity |
| spellingShingle | Adam J. Pollak Luyi Zhao Stanley T. Crooke Characterization of cooperative PS-oligo activation of human TLR9 Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications TLR9 PS-ASO CpG innate immunity receptor cooperativity |
| title | Characterization of cooperative PS-oligo activation of human TLR9 |
| title_full | Characterization of cooperative PS-oligo activation of human TLR9 |
| title_fullStr | Characterization of cooperative PS-oligo activation of human TLR9 |
| title_full_unstemmed | Characterization of cooperative PS-oligo activation of human TLR9 |
| title_short | Characterization of cooperative PS-oligo activation of human TLR9 |
| title_sort | characterization of cooperative ps oligo activation of human tlr9 |
| topic | MT: Oligonucleotides: Therapies and Applications TLR9 PS-ASO CpG innate immunity receptor cooperativity |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123002202 |
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