ArticleMolecular therapy. Nucleic acids2023
Characterization of cooperative PS-oligo activation of human TLR9.
Article in Molecular therapy. Nucleic acids, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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Who cites it
6 citing papers in PubMed, 6 citations in OpenAlex.
- Immunogenicity Assessment for siRNA Therapeutics: A Risk-Based Proposal for Event-Driven Testing.The AAPS journal · 2026Review
- Phosphorothioate antisense oligonucleotide induced innate immune activation is attenuated by tryptophan oxidation products.Nucleic acids research · 2026Article
- Splice-modulating antisense oligonucleotides targeting a pathogenic intronic variant in adult polyglucosan body disease correct mis-splicing and restore enzyme activity in patient cells.Nucleic acids research · 2025Article
- Mitochondrial dysfunction in AMI: mechanisms and therapeutic perspectives.Journal of translational medicine · 2025Review
- Targeting ZC3H11A elicits immunogenic cancer cell death through augmentation of antigen presentation and interferon response.Molecular therapy. Nucleic acids · 2024Article
- Cooperative activation of human TLR9 and consequences for the clinical development of antisense and CpG oligodeoxynucleotides.Molecular therapy. Nucleic acids · 2023Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.