Autor(es)Joubert Pierre-Emmanuel, Werneke Scott W, de la Calle Claire, Guivel-Benhassine Florence, Giodini Alessandra, Peduto Lucie, Levine Beth, Schwartz Olivier, Lenschow Deborah J, Albert Matthew L

ResumoAutophagy is an important survival pathway - can participate in the host response to infection. Studying Chikungunya virus (CHIKV), the causative agent of a major epidemic in India, Southeast Asia, - southern Europe, we reveal a novel mechanism by which autophagy limits cell death - mortality after infection. We use biochemical studies - single cell multispectral assays to demonstrate that direct infection triggers both apoptosis - autophagy. CHIKV-induced autophagy is mediated by the independent induction of endoplasmic reticulum - oxidative stress pathways. These cellular responses delay apoptotic cell death by inducing the IRE1?-XBP-1 pathway in conjunction with ROS-mediated mTOR inhibition. Silencing of autophagy genes resulted in enhanced intrinsic - 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 - showed a higher sensitivity to CHIKV-induced apoptosis. Based on kinetic studies - the observation that features of apoptosis - 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.

ImprentaThe Journal of Experimental Medicine, v. 209, n. 5, p. 1029-1047, 2012

DescritoresChikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - DNA ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya virus - RNA ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Epidemic ; Chikungunya virus - Immunology

Data de Publicação:2012