Abstract
Hepatitis A virus (HAV) antagonizes the innate immune response by inhibition of double-stranded RNA (dsRNA)-induced beta interferon (IFN-beta) gene expression. In this report, we show that this is due to an interaction of HAV with the intracellular dsRNA-induced retinoic acid-inducible gene I (RIG-I)-mediated signaling pathway upstream of the kinases responsible for interferon regulatory factor 3 (IRF-3) phosphorylation (TBK1 and IKKepsilon). In consequence, IRF-3 is not activated for nuclear translocation and gene induction. In addition, we found that HAV reduces TRIF (TIR domain-containing adaptor inducing IFN-beta)-mediated IRF-3 activation, which is part of the Toll-like receptor 3 signaling pathway. As IRF-3 is necessary for IFN-beta transcription, inhibition of this factor results in efficient suppression of IFN-beta synthesis. This ability of HAV seems to be of considerable importance for HAV replication, as HAV is not resistant to IFN-beta, and it may allow the virus to establish infection and preserve the sites of virus production in later stages of the infection.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
DEAD Box Protein 58
-
DEAD-box RNA Helicases
-
DNA-Binding Proteins / metabolism*
-
Hepatitis A / immunology*
-
Hepatitis A / metabolism
-
Hepatitis A virus / growth & development
-
Hepatitis A virus / pathogenicity*
-
Humans
-
I-kappa B Kinase
-
Interferon Regulatory Factor-3
-
Interferon-beta / antagonists & inhibitors*
-
Interferon-beta / genetics
-
Membrane Glycoproteins / chemistry
-
Membrane Glycoproteins / metabolism
-
Phosphorylation
-
Protein Serine-Threonine Kinases / metabolism
-
Protein Structure, Tertiary
-
RNA Helicases / metabolism*
-
Receptors, Cell Surface / chemistry
-
Receptors, Cell Surface / metabolism
-
Receptors, Immunologic
-
Signal Transduction*
-
Toll-Like Receptor 3
-
Toll-Like Receptors
-
Transcription Factors / metabolism*
-
Transcription, Genetic
Substances
-
DNA-Binding Proteins
-
IRF3 protein, human
-
Interferon Regulatory Factor-3
-
Membrane Glycoproteins
-
Receptors, Cell Surface
-
Receptors, Immunologic
-
TLR3 protein, human
-
Toll-Like Receptor 3
-
Toll-Like Receptors
-
Transcription Factors
-
Interferon-beta
-
Protein Serine-Threonine Kinases
-
TBK1 protein, human
-
CHUK protein, human
-
I-kappa B Kinase
-
IKBKB protein, human
-
IKBKE protein, human
-
RIGI protein, human
-
DEAD Box Protein 58
-
DEAD-box RNA Helicases
-
RNA Helicases