Chikungunya virus–induced autophagy delays caspase-dependent cell death

• DOI: 10.1084/jem.20110996
• Publication Date: 2012-04-17T05:29:58Z
• Authors: Pierre-Emmanuel J...; Scott W. Werneke; Claire de la Calle; Florence Guivel-B...; Alessandra Giodini; Lucie Peduto; Beth Levine; Olivier Schwartz; Deborah J. Lenschow; Matthew L. Albert
• Keywords: 0301 basic medicine; Blotting, Western; Autophagy-Related Proteins; Fluorescent Antibody Technique; Apoptosis; Protein Serine-Threonine Kinases; Endoplasmic Reticulum; Article; Cell Line; Mice; 03 medical and health sciences; Endoribonucleases; Medicine and Health Sciences; Autophagy; Image Processing, Computer-Assisted; Animals; Alphavirus Infections; Flow Cytometry; Mice, Mutant Strains; 3. Good health; DNA-Binding Proteins; Oxidative Stress; Caspases; Chikungunya Fever; Carrier Proteins

Autophagy is an important survival pathway and can participate in the host response to infection. Studying Chikungunya virus (CHIKV), causative agent of a major epidemic India, Southeast Asia, southern Europe, we reveal novel mechanism by which autophagy limits cell death mortality after We use biochemical studies single multispectral assays demonstrate that direct infection triggers both apoptosis autophagy. CHIKV-induced mediated independent induction endoplasmic reticulum oxidative stress pathways. These cellular responses delay apoptotic inducing IRE1α–XBP-1 conjunction with ROS-mediated mTOR inhibition. Silencing genes resulted enhanced intrinsic extrinsic apoptosis, favoring viral propagation cultured cells. Providing vivo evidence for relevance our findings, Atg16LHM mice, display reduced levels autophagy, exhibited increased lethality showed higher sensitivity apoptosis. Based on kinetic observation features were mutually exclusive, conclude inhibits caspase-dependent but ultimately overwhelmed replication. Our study suggests inducers may limit pathogenesis acute disease.