Toll-like receptor 7, also known as TLR7, is a
protein that in humans is encoded by the TLR7gene.
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
The 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
viralgenomes 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
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 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. Recent examples include TMX-202 delivery via liposomal formulation,[12] as well as the delivery of
resiquimod via nanoparticles formed from
beta-cyclodextrin.[13]
Loss-of-Function TLR7 Variants
Loss-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.[14] 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.[15] 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.[15] 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.[16]
Gain-of-Function TLR7 Variants
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 and
neuromyelitis optica in humans.[17][18]