Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA
Open accessAbstract
DNA and RNA stimulate the mammalian innate immune system through activation of Toll-like receptors (TLRs). DNA containing methylated CpG motifs, however, is not stimulatory. Selected nucleosides in naturally occurring RNA are also methylated or otherwise modified, but the immunomodulatory effects of these alterations remain untested. We show that RNA signals through human TLR3, TLR7, and TLR8, but incorporation of modified nucleosides m5C, m6A, m5U, s2U, or pseudouridine ablates activity. Dendritic cells (DCs) exposed to such modified RNA express significantly less cytokines and activation markers than those treated with unmodified RNA. DCs and TLR-expressing cells are potently activated by bacterial and mitochondrial RNA, but not by mammalian total RNA, which is abundant in modified nucleosides. We conclude that nucleoside modifications suppress the potential of RNA to activate DCs. The innate immune system may therefore detect RNA lacking nucleoside modification as a means of selectively responding to bacteria or necrotic tissue.
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Chemical modification is widely believed to be critical to the recent success of mRNA vaccines.
“which is widely believed to be critical to the recent success of mRNA vaccines1,2,10,37,38”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [37]
Modifications to the spike protein are intended to reduce the innate immune response by inhibiting proinflammatory cytokines, while the lipid nanoparticle vehicle/EV for the mRNA acts as an adjuvant to enhance the immune response.
“Modifications to the spike protein are intended to reduce the innate immune response by inhibiting proinflammatory cytokines, while at the same time, the lipid nanoparticle vehicle/EV for the mRNA acts as an adjuvant to enhance the immune response. 194-196”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [194]
In vitro transcribed mRNA has the risk of triggering pattern recognition receptors in the endosome or cytoplasm, leading to an anti-viral response and shutdown of translation that can lower expression of the mRNA-encoded protein.
“In general, in vitro transcribed mRNA has the risk of triggering various pattern recognition receptors in the endosome (e.g., TLR7/8) or the cytoplasm (e.g., RIG-I), which lead to an anti-viral response, followed by a shutdown of translation that can lower expression of the mRNA-encoded protein.25”
From Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines (2017) · cites this paper as [25]
Pseudouridine-containing mRNAs reduced activation of known RNA sensors substantially.
“Transferring this concept to in vitro transcribed mRNA, for instance, pseudouridine-containing mRNAs reduced activation of known RNA sensors substantially.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [20]
Cytokine secretion by RNA-transfected cells strongly correlated with the extent of nucleoside modifications.
“Obviously, cytokine secretion by RNA-transfected cells strongly correlated with the extent of nucleoside modifications.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [20]
Nucleoside modifications are well known to limit or even inhibit RNA sensor engagement.
“In addition, nucleoside modifications are well known to limit or even inhibit RNA sensor engagement.20,21,22”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [20]
Strategies to impair pattern recognition receptor recognition of IVT mRNA include modified nucleosides, uridine depletion in the coding sequence, or dephosphorylation of 5′PPP mRNAs.
“Others strategies aim to impair the PRR recognition of IVT mRNA with the use of modified nucleosides,16 uridine depletion in the coding sequence,17 or dephosphorylation of 5′PPP mRNAs.18”
From Combining an optimized mRNA template with a double purification process allows strong expression of in vitro transcribed mRNA (2021) · cites this paper as [16]
ψ and m1ψ substitutions for U have been widely adopted for mRNA therapeutics and vaccines due to improved in-cell translation and better control of innate immune responses.
“In particular, we focused on ψ and m1ψ, since these substitutions for U have been widely adopted for mRNA therapeutics and vaccines due to improved in-cell translation and to better control of innate immune responses2,3,8,67 through avoidance of recognition by cellular toll-like receptors (TLR7 and TLR8)68, RIG‑I, and PKR69–71.”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [70]
Replacing original nucleosides with m6A and s2U inhibits activation of TLR3, whereas activation of TLR7 and TLR8 is blocked when using ψ, 5-methyluridine (m5U), m6A, and s2U, thereby inhibiting the innate immune responses and improving protein translation efficiency.
“Studies have found that replacing original nucleosides with m6A and s2U inhibits activation of TLR3, whereas activation of TLR7 and TLR8 is blocked when using ψ, 5-methyluridine (m5U), m6A, and s2U, thereby inhibiting the innate immune responses and improving protein translation efficiency.81,159,171”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [81]
Nucleoside-modified mRNA can reduce the activation of TLRs, retinoic acid-inducible gene I (RIG-I), protein kinase R (PKR), and 2′-5′-oligoadenylate synthetase (OAS); additionally, nucleoside modification increases translation activity and resistance against RNase L-mediated degradation.
“Nucleoside-modified mRNA can reduce the activation of TLRs, retinoic acid-inducible gene I (RIG-I), protein kinase R (PKR), and 2′-5′-oligoadenylate synthetase (OAS). Additionally, nucleoside modification increases translation activity and resistance against RNase L-mediated degradation.54,81,173–176”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [81]
Adding modified nucleosides during IVT of mRNA can significantly reduce the host inflammatory response without affecting protein expression.
“To avoid this, Karikó and colleagues found that adding modified nucleosides during IVT of mRNA can significantly reduce the host inflammatory response without affecting protein expression.81,159”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [81]
Incorporation of modified nucleosides into mRNA can significantly improve biological stability and translational capacity while decreasing the innate immune response.
“However, the incorporation of modified nucleosides into mRNA can significantly improve the biological stability and translational capacity of the mRNA while decreasing the innate immune response.36, 37, 38”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [36]
Not only viral RNA, but also endogenous mRNA associated with apoptotic cells and in vitro transcribed mRNA can bind and activate TLR3, TLR7 and TLR8.
“not only viral RNA, but also endogenous mRNA associated with apoptotic cells as well as in vitro transcribed (IVT) mRNA could bind and activate TLR3, TLR7 and TLR8 [4,5]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [5]
Many modifications observed in natural mRNA are a way to avoid immune recognition, allowing the immune system to distinguish self from non-self RNA.
“the many modifications observed in natural mRNA are in fact a way to avoid immune recognition, allowing the immune system to distinguish self from non-self RNA [5]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [5]
Chemical modifications of specific IVT mRNA nucleotides, such as pseudouridine (ψ) and N1-methylpseudouridine (m1ψ), can reduce innate immune sensing of exogenous mRNA translation.
“Chemical modifications of specific IVT mRNA nucleotides, such as pseudouridine (ψ) and N1-methylpseudouridine (m1ψ), can reduce innate immune sensing of exogenous mRNA translation2,4,7,182.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [182]
Karikó and colleagues observed that ex vivo human dendritic cells tolerated mammalian mRNA, while strong inflammatory cytokine responses were detected upon delivery of mRNA derived from bacteria, necrotic mammalian cells and IVT mRNA.
“In 2004, Karikó and colleagues observed, while exposing ex vivo human DCs to mRNA from different sources, that these cells tolerated mammalian mRNA, while strong inflammatory cytokine responses were detected upon the delivery of mRNA derived from bacteria, necrotic mammalian cells and IVT mRNA [39,40].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [39]
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- Authors
- Karikó, K., Buckstein, M., Ni, H., & Weissman, D.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Karikó, Katalin
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2005-08
- Volume
- 23
- Issue
- 2
- Pages
- 165-175
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2025980739
- Cited by
- 2,728
- References
- 35
- Citations by year
- 2026: 319 · 2025: 387 · 2024: 355 · 2023: 323 · 2022: 296 · 2021: 267 · 2020: 86 · 2019: 76 · 2018: 80 · 2017: 58 · 2016: 66 · 2015: 58 · 2014: 48 · 2013: 46 · 2012: 39
- FWCI
- 13.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI-50484, AI 060505, R01AI050484, R01AI060505)
- National Institute of Dental and Craniofacial Research (R01DE014825, DE 14825)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- Toll-like receptors, RNA recognition, nucleoside modification, TLR3, TLR7, TLR8, m5C, N6-methyladenosine, pseudouridine, dendritic cells, innate immunity, CpG methylation, mitochondrial RNA, bacterial RNA, RNA evolution, cytokine expression
- MeSH terms
- CD83 Antigen, Cell Line, Dendritic Cells, HLA-DR Antigens, Humans, Immunoglobulins, Membrane Glycoproteins, Nucleosides, Phosphatidylethanolamines, Receptors, Cell Surface, RNA, Signal Transduction, Biomarkers, Antigens, CD, Cytokines, Evolution, Molecular, Toll-Like Receptors, Toll-Like Receptor 3, Toll-Like Receptor 7, Toll-Like Receptor 8
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