9 research outputs found
Hepatitis C Virus Controls Interferon Production through PKR Activation
Hepatitis C virus is a poor inducer of interferon (IFN), although its structured viral RNA can bind the RNA helicase RIG-I, and activate the IFN-induction pathway. Low IFN induction has been attributed to HCV NS3/4A protease-mediated cleavage of the mitochondria-adapter MAVS. Here, we have investigated the early events of IFN induction upon HCV infection, using the cell-cultured HCV JFH1 strain and the new HCV-permissive hepatoma-derived Huh7.25.CD81 cell subclone. These cells depend on ectopic expression of the RIG-I ubiquitinating enzyme TRIM25 to induce IFN through the RIG-I/MAVS pathway. We observed induction of IFN during the first 12 hrs of HCV infection, after which a decline occurred which was more abrupt at the protein than at the RNA level, revealing a novel HCV-mediated control of IFN induction at the level of translation. The cellular protein kinase PKR is an important regulator of translation, through the phosphorylation of its substrate the eIF2α initiation factor. A comparison of the expression of luciferase placed under the control of an eIF2α-dependent (IRESEMCV) or independent (IRESHCV) RNA showed a specific HCV-mediated inhibition of eIF2α-dependent translation. We demonstrated that HCV infection triggers the phosphorylation of both PKR and eIF2α at 12 and 15 hrs post-infection. PKR silencing, as well as treatment with PKR pharmacological inhibitors, restored IFN induction in JFH1-infected cells, at least until 18 hrs post-infection, at which time a decrease in IFN expression could be attributed to NS3/4A-mediated MAVS cleavage. Importantly, both PKR silencing and PKR inhibitors led to inhibition of HCV yields in cells that express functional RIG-I/MAVS. In conclusion, here we provide the first evidence that HCV uses PKR to restrain its ability to induce IFN through the RIG-I/MAVS pathway. This opens up new possibilities to assay PKR chemical inhibitors for their potential to boost innate immunity in HCV infection
L'épée et la plume : Amérindiens et soldats des troupes de la Marine en Louisiane et au Pays d'en Haut (1683-1763)
Québec Université Laval, BibliothÚque 201
Performance monitoring and control for an additive manufacturing factory - A case study in the aerospace industry
International audienc
Sedimentological and geochemical records of past trophic state and hypolimnetic anoxia in large, hard-water Lake Bourget, French Alps
Multiple interdependent sequence elements control splicing of a fibroblast growth factor receptor 2 alternative exon
Reconstruction of the recent history of a large deep prealpine lake (Lake Bourget, France) using subfossil chironomids, diatoms, and organic matter analysis: towards the definition of a lake-specific reference state
This paper presents the recent history of a large prealpine lake (Lake
Bourget) using chironomids, diatoms and organic matter analysis, and
deals with the ability of paleolimnological approach to define an
ecological reference state for the lake in the sense of the European
Framework Directive. The study at low resolution of subfossil
chironomids in a 4-m-long core shows the remarkable stability over the
last 2.5 kyrs of the profundal community dominated by a
Micropsectra-association until the beginning of the twentieth century,
when oxyphilous taxa disappeared. Focusing on this key recent period, a
high resolution and multiproxy study of two short cores reveals a
progressive evolution of the lake's ecological state. Until AD 1880,
Lake Bourget showed low organic matter content in the deep sediments
(TOC less than 1%) and a well-oxygenated hypolimnion that allowed the
development of a profundal oxyphilous chironomid fauna
(Micropsectra-association). Diatom communities were characteristic of
oligotrophic conditions. Around AD 1880, a slight increase in the TOC
was the first sign of changes in lake conditions. This was followed by a
first limited decline in oligotrophic diatom taxa and the disappearance
of two oxyphilous chironomid taxa at the beginning of the twentieth
century. The 1940s were a major turning point in recent lake history.
Diatom assemblages and accumulation of well preserved planktonic organic
matter in the sediment provide evidence of strong eutrophication. The
absence of profundal chironomid communities reveals permanent
hypolimnetic anoxia. From AD 1995 to 2006, the diatom assemblages
suggest a reduction in nutrients, and a return to mesotrophic
conditions, a result of improved wastewater management. However, no
change in hypolimnion benthic conditions has been shown by either the
organic matter or the subfossil chironomid profundal community. Our
results emphasize the relevance of the paleolimnological approach for
the assessment of reference conditions for modern lakes. Before AD 1900,
the profundal Micropsectra-association and the Cyclotella dominated
diatom community can be considered as the Lake Bourget reference
community, which reflects the reference ecological state of the lake