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

Resumo: Autophagy 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.

Imprenta: The Journal of Experimental Medicine, v. 209, n. 5, p. 1029-1047, 2012

Identificador do objeto digital: 10.1084/jem.20110996

Descritores: Chikungunya 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