Chikungunya virus–induced autophagy delays caspase-dependent cell death

Journal of Experimental Medicine - Tập 209 Số 5 - Trang 1029-1047 - 2012
Pierre-Emmanuel Joubert1,2,3,4,5, Scott Werneke6, Claire de la Calle1,3,4,5, Florence Guivel‐Benhassine1,3,4,5, Alessandra Giodini1,2,3,4,5, Lucie Peduto1,3,4,5, Beth Levine7,8,9, Olivier Schwartz1,3,4,5, Deborah J. Lenschow6, Matthew L. Albert1,2,3,4,5
1Centre d’Immunologie Humaine 1 , 2 , and 3 , and 4
2INSERM U818, 75724 Paris, France 5
3Lymphoid Tissue Development Unit, Department of Immunology 1 , 2 , and 3 , and 4
4Unité Immunobiologie des Cellules Dendritiques 1 , 2 , and 3 , and 4
5Unité de recherche Virus et Immunité, Institut Pasteur, 75724 Paris, Cedex 15, France 1 , 2 , and 3 , and 4
6Department of Pathology and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 6
7Department of Internal Medicine 7 and 8
8Department of Internal Medicine and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390
9Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 7 and 8

Tóm tắt

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, Atg16LHM 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.

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