Toll-like receptor 7, also known asTLR7, is aprotein that in humans is encoded by theTLR7gene.Orthologs are found in mammals and birds.[5] It is a member of thetoll-like receptor (TLR) family and detects single stranded RNA.
The TLR family plays an important role in pathogen recognition and activation ofinnate immunity. TLRs are highly conserved fromDrosophila to humans and share structural and functional similarities. They recognizepathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production ofcytokines necessary for the development of effectiveimmunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed inlung,placenta, andspleen, and lies in close proximity to another family member,TLR8, on the human X chromosome.[6]
TLR7 recognizes single-strandedRNA inendosomes, which is a common feature ofviralgenomes which are internalized bymacrophages anddendritic cells. TLR7 recognizes single-stranded RNA of viruses such asHIV andHCV.[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]
TLR7 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 withshort 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 factorSTAT1 by themitogen-activated protein kinase p38 and decreased recruitment of the adaptorMYD88 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 ofrheumatic diseases such assystemic lupus erythematosus (SLE).[9] A TLR7 agonist,imiquimod (Aldara),[10] has been approved for topical use in treating warts caused bypapillomavirus and foractinic keratosis.[11] Due to their ability to induce robust production of anti-cancer cytokines such asinterleukin-12, TLR7 agonists have also been investigated forcancer immunotherapy and as vaccineadjuvants.[12][13][14] Recent examples include TMX-202 delivery via liposomal formulation,[15] as well as the delivery ofresiquimod via nanoparticles formed frombeta-cyclodextrin.[16]
Loss-of-function variants in TLR7 diminish theinnate immune response against viral infection by primarily affectinginterferon production. In July 2020, it was discovered that TLR7 deficiency predisposes young, previously healthy, male patients to severe infection withSARS-CoV-2.[17] More recently in November 2023, a novel TLR7hemizygous loss-of-function variant was identified in a pediatric patient with severe neurological deterioration followingCOVID-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]
In 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 andneuromyelitis optica in humans.[20][21]
