TLR-7 and antiviral immunity

Abstract

How does the innate immune system recognize viruses? Much work has focused on protein kinase R as a receptor for viral RNA and recently, a role for Toll-like receptors (TLRs) in antiviral immunity has been suggested by studies demonstrating that synthetic double-stranded RNA (which mimics viral RNA) and F protein from respiratory syncytial virus are recognized by TLR-3 and TLR-4, respectively. Furthermore, vaccinia virus encodes two proteins, A46R and A52R, that antagonize TLR signal transduction.TLR-7 can now be added to the list of TLRs involved in antiviral immunity, owing to the observation that TLR-7-deficient mice do not respond to the antiviral compounds imidazoquinoline or R-848. These compounds are potent activators of immune cells that have antiviral and antitumor properties. Regarding their mechanism of action, it was known that they activate host defense signals, such as NF-κB and Jun N-terminal kinase, well-known responses activated by TLRs through the adapter protein MyD88. Therefore, Hemmi and colleagues [1xSmall anti-viral compounds activate immune cells via the TLR-7 MyD88-dependent signaling pathway. Hemmi, H et al. Nat. Immunol. 2002; 3: 196–200Crossref | PubMed | Scopus (1585)See all References][1] began their analysis by testing these compounds on cells from MyD88-deficient mice, to determine whether any of the TLRs might be involved in the response. Peritoneal macrophages from the mutant mice were unable to synthesize TNF or IL-12 in response to the compounds, pointing to the involvement of TLRs. The question was: which TLR? Macrophages from TLR-4-, TLR-2- and TLR-9-deficient mice all responded normally. However, macrophages from TLR-7-deficient mice, although having normal responses to a range of other TLR activators, were unresponsive to imidazoquinoline and R-848. These antiviral compounds induce B-cell proliferation and the expression of CD80 and CD86 on dendritic cells (DCs) also. Both responses were impaired in cells from TLR-7-deficient mice. The ectopic expression of TLR-7 in 293 cells rendered them sensitive to the compounds. Finally, the in vivo induction of expression of IFN-α, TNF and IL-12 was impaired in the knockout mice.This study demonstrates clearly that these antiviral compounds activate cells through TLR-7. An important target for the compounds might be plasmacytoid DCs, which express high levels of TLR-7 and are major producers of antiviral IFNs. One conclusion from the data is that the compounds mimic viral products, making TLR-7 a pattern-recognition receptor for virus-associated molecular patterns. It is not known what the viral products might be. Therefore, this study leaves TLR-8 and TLR-10 as the only TLRs without a function, with TLR-7 joining TLR-3 and TLR-4 on the list of antiviral TLRs. Future studies addressing the role of these TLRs in host–virus interactions are likely to yield much new information.