Chikungunya virus-induced autophagy delays caspase-dependent cell death

Autophagy is an important survival pathway and can participate in the host response to infection. Studying Chikungunya virus (CHIKV), the causative agent of a major epidemic in India, Southeast Asia, and southern Europe, we reveal a novel mechanism by which autophagy limits cell death and mortality after infection. We use biochemical studies and single cell multispectral assays to demonstrate that direct infection triggers both apoptosis and autophagy. CHIKV-induced autophagy is mediated by the independent induction of endoplasmic reticulum and oxidative stress pathways. These cellular responses delay apoptotic cell death by inducing the IRE1α–XBP-1 pathway in conjunction with ROS-mediated mTOR inhibition. Silencing of autophagy genes resulted in enhanced intrinsic and extrinsic apoptosis, favoring viral propagation in cultured cells. Providing in vivo evidence for the relevance of our findings, Atg16L(HM) mice, which display reduced levels of autophagy, exhibited increased lethality and showed a higher sensitivity to CHIKV-induced apoptosis. Based on kinetic studies and the observation that features of apoptosis and autophagy were mutually exclusive, we conclude that autophagy inhibits caspase-dependent cell death but is ultimately overwhelmed by viral replication. Our study suggests that inducers of autophagy may limit the pathogenesis of acute Chikungunya disease

ISG15 Is Critical in the Control of Chikungunya Virus Infection Independent of UbE1L Mediated Conjugation

Chikungunya virus (CHIKV) is a re-emerging alphavirus that has caused significant disease in the Indian Ocean region since 2005. During this outbreak, in addition to fever, rash and arthritis, severe cases of CHIKV infection have been observed in infants. Challenging the notion that the innate immune response in infants is immature or defective, we demonstrate that both human infants and neonatal mice generate a robust type I interferon (IFN) response during CHIKV infection that contributes to, but is insufficient for, the complete control of infection. To characterize the mechanism by which type I IFNs control CHIKV infection, we evaluated the role of ISG15 and defined it as a central player in the host response, as neonatal mice lacking ISG15 were profoundly susceptible to CHIKV infection. Surprisingly, UbE1L−/− mice, which lack the ISG15 E1 enzyme and therefore are unable to form ISG15 conjugates, displayed no increase in lethality following CHIKV infection, thus pointing to a non-classical role for ISG15. No differences in viral loads were observed between wild-type (WT) and ISG15−/− mice, however, a dramatic increase in proinflammatory cytokines and chemokines was observed in ISG15−/− mice, suggesting that the innate immune response to CHIKV contributes to their lethality. This study provides new insight into the control of CHIKV infection, and establishes a new model for how ISG15 functions as an immunomodulatory molecule in the blunting of potentially pathologic levels of innate effector molecules during the host response to viral infection

Inhibition of polyamine biosynthesis is a broad-spectrum strategy against RNA viruses

International audienceRNA viruses present an extraordinary threat to human health, given their sudden and unpredictable appearance, the potential for rapid spread among the human population, and their ability to evolve resistance to antiviral therapies. The recent emergence of chikungunya virus, Zika virus, and Ebola virus highlights the struggles to contain outbreaks. A significant hurdle is the availability of antivirals to treat the infected or protect at-risk populations. While several compounds show promise in vitro and in vivo, these outbreaks underscore the need to accelerate drug discovery. The replication of several viruses has been described to rely on host polyamines, small and abundant positively charged molecules found in the cell. Here, we describe the antiviral effects of two molecules that alter polyamine levels: difluoromethylornithine (DFMO; also called eflornithine), which is a suicide inhibitor of ornithine decarboxylase 1 (ODC1), and diethylnorspermine (DENSpm), an activator of spermidine/spermine N1-acetyltransferase (SAT1). We show that reducing polyamine levels has a negative effect on diverse RNA viruses, including several viruses involved in recent outbreaks, in vitro and in vivo These findings highlight the importance of the polyamine biosynthetic pathway to viral replication, as well as its potential as a target in the development of further antivirals or currently available molecules, such as DFMO.IMPORTANCERNA viruses present a significant hazard to human health, and combatting these viruses requires the exploration of new avenuesfor targeting viral replication. Polyamines, small positively charged molecules within the cell, have been demonstrated to facili-tate infection for a few different viruses. Our study demonstrates that diverse RNA viruses rely on the polyamine pathway forreplication and highlights polyamine biosynthesis as a promising drug targe

The ATLAS Experiment at the CERN Large Hadron Collider

The ATLAS detector as installed in its experimental cavern at point 1 at CERN is described in this paper. A brief overview of the expected performance of the detector when the Large Hadron Collider begins operation is also presented

ATLAS

% ATLAS \\ \\ ATLAS is a general-purpose experiment for recording proton-proton collisions at LHC. The ATLAS collaboration consists of 144 participating institutions (June 1998) with more than 1750~physicists and engineers (700 from non-Member States). The detector design has been optimized to cover the largest possible range of LHC physics: searches for Higgs bosons and alternative schemes for the spontaneous symmetry-breaking mechanism; searches for supersymmetric particles, new gauge bosons, leptoquarks, and quark and lepton compositeness indicating extensions to the Standard Model and new physics beyond it; studies of the origin of CP violation via high-precision measurements of CP-violating B-decays; high-precision measurements of the third quark family such as the top-quark mass and decay properties, rare decays of B-hadrons, spectroscopy of rare B-hadrons, and $B ^0 _{s}$-mixing. \\ \\The ATLAS dectector, shown in the Figure includes an inner tracking detector inside a 2~T~solenoid providing an axial field, electromagnetic and hadronic calorimeters outside the solenoid and in the forward regions, and barrel and end-cap air-core-toroid muon spectrometers. The precision measurements for photons, electrons, muons and hadrons, and identification of photons, electrons, muons, $\tau$-leptons and b-quark jets are performed over $| \eta |$ < 2.5. The complete hadronic energy measurement extends over $| \eta |$ < 4.7. \\ \\The inner tracking detector consists of straw drift tubes interleaved with transition radiators for robust pattern recognition and electron identification, and several layers of semiconductor strip and pixel detectors providing high-precision space points. \\ \\The e.m. calorimeter is a lead-Liquid Argon sampling calorimeter with an integrated preshower detector and a presampler layer immediately behind the cryostat wall for energy recovery. The end-cap hadronic calorimeters also use Liquid Argon technology, with copper absorber plates. The end-cap cryostats house the e.m., hadronic and forward calorimeters (tungsten-Liquid Argon sampling). The barrel hadronic calorimeter is an iron-scintillating tile sampling calorimeter with longitudinal tile geometry. \\ \\Air-core toroids are used for the muon spectrometer. Eight superconducting coils with warm voussoirs are used in the barrel region complemented with superconducting end-cap toroids in the forward regions. The toroids will be instrumented with Monitored Drift Tubes (Cathode Strip Chambers at large rapidity where there are high radiation levels). The muon trigger and second coordinate measurement for muon tracks are provide