20962078
not annotated - annotated - LINNAEUS only
Chikungunya virus induces IPS-1-dependent innate immune activation and protein kinase R-independent translational shutoff.
Chikungunya virus (CHIKV) is an arthritogenic mosquito-transmitted alphavirus that is undergoing reemergence in areas around the Indian Ocean. Despite the current and potential danger posed by this virus, we know surprisingly little about the induction and evasion of CHIKV-associated antiviral immune responses. With this in mind we investigated innate immune reactions to CHIKV in human fibroblasts, a demonstrable in vivo target of virus replication and spread. We show that CHIKV infection leads to activation of the transcription factor interferon regulatory factor 3 (IRF3) and subsequent transcription of IRF3-dependent antiviral genes, including beta interferon (IFN-Beta). IRF3 activation occurs by way of a virus-induced innate immune signaling pathway that includes the adaptor molecule interferon promoter stimulator 1 (IPS-1). Despite strong transcriptional upregulation of these genes, however, translation of the corresponding proteins is not observed. We further demonstrate that translation of cellular (but not viral) genes is blocked during infection and that although CHIKV is found to trigger inactivation of the translational molecule eukaryotic initiation factor subunit 2alpha by way of the double-stranded RNA sensor protein kinase R, this response is not required for the block to protein synthesis. Furthermore, overall diminution of cellular RNA synthesis is also observed in the presence of CHIKV and transcription of IRF3-dependent antiviral genes appears specifically blocked late in infection. We hypothesize that the observed absence of IFN-Beta and antiviral proteins during infection results from an evasion mechanism exhibited by CHIKV that is dependent on widespread shutoff of cellular protein synthesis and a targeted block to late synthesis of antiviral mRNA transcripts.
Ann file
T1 Species 0 17 Chikungunya virus
N1 Reference T1 Taxonomy:37124
T2 Species 125 142 Chikungunya virus
N2 Reference T2 Taxonomy:37124
T3 Species 144 149 CHIKV
N3 Reference T3 Taxonomy:37124
T4 Species 393 398 CHIKV
N4 Reference T4 Taxonomy:37124
T5 Species 499 504 CHIKV
N5 Reference T5 Taxonomy:37124
T6 Species 508 513 human
N6 Reference T6 Taxonomy:9606
T7 Species 603 608 CHIKV
N7 Reference T7 Taxonomy:37124
T8 Species 1213 1218 CHIKV
N8 Reference T8 Taxonomy:37124
T9 Species 1545 1550 CHIKV
N9 Reference T9 Taxonomy:37124
T10 Species 1791 1796 CHIKV
N10 Reference T10 Taxonomy:37124