Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds.[5] It is a member of the toll-like receptor (TLR) family and detects single stranded RNA.
Function
editThe TLR family plays an important role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung, placenta, and spleen, and lies in close proximity to another family member, TLR8, on the human X chromosome.[6]
TLR7 recognizes single-stranded RNA in endosomes, which is a common feature of viral genomes which are internalized by macrophages and dendritic cells. TLR7 recognizes single-stranded RNA of viruses such as HIV and HCV.[7][8] TLR7 can recognize GU-rich single-stranded RNA.[7] However, the presence of GU-rich sequences in the single-stranded RNA is not sufficient to stimulate TLR7.[8]
Clinical significance
editTLR7 has been shown to play a significant role in the pathogenesis of autoimmune disorders (e.g. systemic lupus erythematous) as well as in the regulation of antiviral immunity (e.g. COVID-19). Although not yet fully elucidated, using an unbiased genome-scale screen with short hairpin RNA (shRNA), it has been demonstrated that the receptor TREML4 acts as an essential positive regulator of TLR7 signaling. In TREML4 -/- mice macrophages that are hyporesponsive to TLR7 agonists, macrophages fail to produce type I interferons due to impaired phosphorylation of the transcription factor STAT1 by the mitogen-activated protein kinase p38 and decreased recruitment of the adaptor MYD88 to TLR7. TREML4 deficiency reduced the production of inflammatory cytokines and autoantibodies in MRL/lpr mice, suggesting that TLR7 is a vital component of antiviral immunity and a predecessor factor in the pathogenesis of rheumatic diseases such as systemic lupus erythematosus (SLE).[9] A TLR7 agonist, imiquimod (Aldara),[10] has been approved for topical use in treating warts caused by papillomavirus and for actinic keratosis.[11] Due to their ability to induce robust production of anti-cancer cytokines such as interleukin-12, TLR7 agonists have also been investigated for cancer immunotherapy and as vaccine adjuvants.[12][13][14] Recent examples include TMX-202 delivery via liposomal formulation,[15] as well as the delivery of resiquimod via nanoparticles formed from beta-cyclodextrin.[16]
Loss-of-Function TLR7 Variants
editLoss-of-function variants in TLR7 diminish the innate immune response against viral infection by primarily affecting interferon production. In July 2020, it was discovered that TLR7 deficiency predisposes young, previously healthy, male patients to severe infection with SARS-CoV-2.[17] More recently in November 2023, a novel TLR7 hemizygous loss-of-function variant was identified in a pediatric patient with severe neurological deterioration following COVID-19 infection.[18] These findings suggest that TLR7 not only plays a key role in triggering the immune response against COVID-19 but may also mediate the post-infectious sequalae in critically ill patients.[18] Further research is required to fully delineate the mechanisms by which functional impairment of TLR7 influences the disease process and to explore the potential efficacy of targeting this pathway in the treatment of COVID-19.[19]
Gain-of-Function TLR7 Variants
editIn contrast, gain-of-function variation in TLR7 disrupts immune tolerance, potentially increasing the risk of autoimmune disorders. In May 2022, unregulated gain-of function TLR7 variants were found to cause systemic lupus erythematous and neuromyelitis optica in humans.[20][21]
References
edit- ^ a b c GRCh38: Ensembl release 89: ENSG00000196664 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000044583 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Du X, Poltorak A, Wei Y, Beutler B (September 2000). "Three novel mammalian toll-like receptors: gene structure, expression, and evolution". European Cytokine Network. 11 (3): 362–371. PMID 11022119.
- ^ "Entrez Gene: TLR7 toll-like receptor 7".
- ^ a b Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. (March 2004). "Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8". Science. 303 (5663): 1526–1529. Bibcode:2004Sci...303.1526H. doi:10.1126/science.1093620. PMID 14976262. S2CID 1680581.
- ^ a b Zhang Y, El-Far M, Dupuy FP, Abdel-Hakeem MS, He Z, Procopio FA, et al. (July 2016). "HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses". Scientific Reports. 6: 29447. Bibcode:2016NatSR...629447Z. doi:10.1038/srep29447. PMC 4935957. PMID 27385120.
- ^ Ramirez-Ortiz ZG, Prasad A, Griffith JW, Pendergraft WF, Cowley GS, Root DE, et al. (May 2015). "The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity". Nature Immunology. 16 (5): 495–504. doi:10.1038/ni.3143. PMC 4406861. PMID 25848864.
- ^ Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, et al. (February 2002). "Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway". Nature Immunology. 3 (2): 196–200. doi:10.1038/ni758. PMID 11812998. S2CID 1694900.
- ^ Vender RB, Goldberg O (January 2005). "Innovative uses of imiquimod". Journal of Drugs in Dermatology. 4 (1): 58–63. PMID 15696986.
- ^ Yin Q, Luo W, Mallajosyula V, Bo Y, Guo J, Xie J, et al. (March 2023). "A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2". Nature Materials. 22 (3): 380–390. doi:10.1038/s41563-022-01464-2. PMC 9981462. PMID 36717665.
- ^ Bagnoli F, Fontana MR, Soldaini E, Mishra RP, Fiaschi L, Cartocci E, et al. (March 2015). "Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus". Proceedings of the National Academy of Sciences of the United States of America. 112 (12): 3680–3685. doi:10.1073/pnas.1424924112. PMC 4378396. PMID 25775551.
- ^ Soni D, Borriello F, Scott DA, Feru F, DeLeon M, Brightman SE, et al. (July 2024). "From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation". Science Advances. 10 (27): eadg3747. doi:10.1126/sciadv.adg3747. PMC 11221515. PMID 38959314.
- ^ Klauber TC, Laursen JM, Zucker D, Brix S, Jensen SS, Andresen TL (April 2017). "Delivery of TLR7 agonist to monocytes and dendritic cells by DCIR targeted liposomes induces robust production of anti-cancer cytokines" (PDF). Acta Biomaterialia. 53: 367–377. doi:10.1016/j.actbio.2017.01.072. PMID 28153581. S2CID 3395044.
- ^ Rodell CB, Arlauckas SP, Cuccarese MF, Garris CS, Li R, Ahmed MS, et al. (August 2018). "TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy". Nature Biomedical Engineering. 2 (8): 578–588. doi:10.1038/s41551-018-0236-8. PMC 6192054. PMID 31015631.
- ^ van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, et al. (August 2020). "Presence of Genetic Variants Among Young Men With Severe COVID-19". JAMA. 324 (7): 663–673. doi:10.1001/jama.2020.13719. PMC 7382021. PMID 32706371.
- ^ a b Noor Eddin A, Al-Rimawi M, Peer-Zada F, Hundallah K, Alhashem A (2023). "Novel TLR7 hemizygous variant in post-COVID-19 neurological deterioration: a case report with literature review". Frontiers in Neurology. 14: 1268035. doi:10.3389/fneur.2023.1268035. PMC 10716429. PMID 38093758.
- ^ Pico A, Willighagen E, Ehrhart F, Pham N, Slenter D, Niarakis A, et al. "Type I interferon induction and signaling during SARS-CoV-2 infection (WP4868)". WikiPathways.
- ^ Brown GJ, Cañete PF, Wang H, Medhavy A, Bones J, Roco JA, et al. (May 2022). "TLR7 gain-of-function genetic variation causes human lupus". Nature. 605 (7909): 349–356. Bibcode:2022Natur.605..349B. doi:10.1038/s41586-022-04642-z. PMC 9095492. PMID 35477763. S2CID 248414899.
- ^ Jenks SA, Cashman KS, Zumaquero E, Marigorta UM, Patel AV, Wang X, et al. (October 2018). "Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus". Immunity. 49 (4): 725–739.e6. doi:10.1016/j.immuni.2018.08.015. PMC 6217820. PMID 30314758.
Further reading
edit- Lien E, Ingalls RR (January 2002). "Toll-like receptors". Critical Care Medicine. 30 (1 Suppl): S1-11. doi:10.1097/00003246-200201001-00001. PMID 11782555.
- Kaisho T, Akira S (February 2002). "Toll-like receptors as adjuvant receptors". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1589 (1): 1–13. doi:10.1016/S0167-4889(01)00182-3. PMID 11909637.
External links
edit- Toll-Like+Receptor+7 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)