Year: 2005
Type: article
Abstract: Do Not Ask for Whom the Receptor Tolls: It Tolls-Like for NS3Otsuka and coworkers in Tokyo perform a brilliant microdissection of the interactions between HCV-NS3 protein and the Tolllike 3 receptor (TLR-3) pathway.Their study builds on a prior study by Foy et al. (Science 2003) which demonstrated that NS3 protein inhibited the phosphorylation of interferon regulatory factor 3 (IRF-3), in turn inhibiting induction of IFN-, a key component of the innate immune response.This virus-specific inhibition of innate immunity was considered one of the early keys to establishing persistent infection.Otsuka et al. carry this observation further to more precisely define the mechanisms of NS3 inhibitory activity.As background, in the life cycle of RNA viruses, double-stranded RNA is generated and recognized by TLR-3 resulting in activation of IRF-3, a key regulator of type 1 interferons.To investigate these interactions at the molecular level, Otsuka et al. focused on TRIF, an adaptor molecule responsible for linking TRL-3 and IRF-3, and recently identified kinases, TANK-binding kinase-1 (TBK1) and IKK, that have been shown to associate with both IRF-3 and TRIF.Using HCV replicon-harboring cells and interferon cured cells, they demonstrated that transfection with a TRIF expression plasmid induced IRF-3 and IFN- promoter activation.They then showed that transient transfection with NS3 and NS3/4A inhibited TRIF-mediated induction of IFN- promoter whereas NS2, NS4A, NS4B, NS5A and NS5B had no inhibitory effect.(See Fig .)By inserting a stop codon into NS-3 RNA such that the expression of NS-3 protein was blocked, they showed that the inhibitory effect was due to NS-3 protein and not NS-3 RNA.Next in coimmunoprecipitation experiments, they showed that NS-3 bound to the kinase TBK1 and to IKK but they focused on TBK1 because it is ubiquitously expressed.It was further found using NS3-deleted expression plasmids that it is the helicase domain of NS3 that binds to TBK1 and not the protease domain.Having established that NS-3 binds to TBK1 and knowing that TBK1 binds to IRF-3, they then did critical experiments which showed that TBK1 binding to IRF-3 was inhibited in the pres-ence of NS3 protein as was TRIF-related phosphorylation of IRF-3, the latter necessary for IRF dimerization and its downstream effect on IFN- production.This is an important study that further builds on the concept that HCV proteins, especially, but not exclusively, NS3 inhibit the host innate and adaptive immune responses and foster viral persistence.While the bottom line of viral persistence may be diminished and dysfunctional cell-mediated immune responses, it is becoming increasingly clear that the virus plays a critical role in its own survival by its high mutability, quasispecies nature and the direct inhibitory effects of the proteins it expresses in abundance.This is a very clever virus that is clearly taking its Toll.
Source: Hepatology
DOI: 10.1002/hep.20786
Author: Harvey J. Alter
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4237357534