Chikungunya virus–induced autophagy delays caspase-dependent cell death

Unité Immunobiologie des Cellules Dendritiques, Department of Immunology, Institut Pasteur, Paris, France.
Journal of Experimental Medicine (Impact Factor: 12.52). 04/2012; 209(5):1029-47. DOI: 10.1084/jem.20110996
Source: PubMed


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.

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Available from: Pierre-Emmanuel Joubert, Oct 06, 2015
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    • "More recently, autophagy (Glick et al., 2010) was reported to be induced during active infection, further increasing viral replication (Krejbich-Trotot et al., 2011b). However, while autophagy was shown to increase CHIKV replication in a human cell line (Krejbich-Trotot et al., 2011b), a decrease in replication was observed in mouse embryonic fibroblasts (Joubert et al., 2012). This species-specific difference was later demonstrated to be due to interaction of the human autophagy receptor NDP52 with the viral nsP2 to promote viral replication, which was not observed with the mouse orthologue of NDP52 (Judith et al., 2013). "
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    ABSTRACT: Chikungunya virus (CHIKV) is an arthropod-borne virus that causes chikungunya fever, a disease characterized by the onset of fever and rashes, with arthralgia as its hallmark symptom. CHIKV has re-emerged over the past decade, causing numerous outbreaks around the world. Since late 2013, CHIKV has reached the shores of the Americas, causing more than a million cases of infection. Despite concentrated efforts to understand the pathogenesis of the disease, further outbreaks remain a threat. This review highlights important findings regarding CHIKV-associated immunopathogenesis and offers important insights into future directions. This article forms part of a symposium in Antiviral Research on "Chikungunya discovers the New World." Copyright © 2015. Published by Elsevier B.V.
    Antiviral research 06/2015; 120. DOI:10.1016/j.antiviral.2015.06.009 · 3.94 Impact Factor
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    • "This could suggest that SMURF1 ubiquitinates Sindbis virus capsids for degradation by autophagosomes. Such p62-mediated macroautophagic degradation has also been described for Chikungunya virus (Joubert et al., 2012; Judith et al., 2013). Interestingly, this phenotype, Chikungunya virus restriction by macroautophagy, only predominates in mouse cells. "
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    ABSTRACT: Innate immune responses are the first line of defense for an organism to restrict invading pathogens. They fulfill two main functions, namely detection of the pathogen to successively alarm the appropriate components of the immune system and early inhibition of the infection to prevent demise of the infected organism before a more tailored immune response, usually mediated by the adaptive immune system, can be mounted. Autophagy and phagocytosis, modified by the autophagic core machinery, contribute to these functions by regulating pathogen detection, influencing the production of innate immune mediators and directly restricting intracellular and extracellular pathogens as an effector mechanism of innate immunity. These aspects of the involvement of mainly macroautophagy in innate immune responses will be discussed in this review.
    Cellular Microbiology 09/2014; 16(11). DOI:10.1111/cmi.12358 · 4.92 Impact Factor
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    • "Knockdown of IRE1 or treated cells with the ROS inhibitor N-acetyl-l-cysteine inhibits formation of autophagosomes as well as the conversion of LC3-I to LC3-II. Moreover, an additive inhibitory effect on autophagosome formation was observed in infected cells silenced for IRE1mRNA and treated with N-acetyl-l-cysteine (Joubert et al., 2012). "
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    ABSTRACT: Endoplasmic reticulum (ER) stress is a general term for representing the pathway by which various stimuli affect ER functions. ER stress induces the evolutionarily conserved signaling pathways, called the unfolded protein response (UPR), which compromises the stimulus and then determines whether the cell survives or dies. In recent years, ongoing research has suggested that these pathways may be linked to the autophagic response, which plays a key role in the cell's response to various stressors. Autophagy performs a self-digestion function, and its activation protects cells against certain pathogens. However, the link between the UPR and autophagy may be more complicated. These two systems may act dependently, or the induction of one system may interfere with the other. Experimental studies have found that different viruses modulate these mechanisms to allow them to escape the host immune response or, worse, to exploit the host's defense to their advantage; thus, this topic is a critical area in antiviral research. In this review, we summarize the current knowledge about how RNA viruses, including influenza virus, poliovirus, coxsackievirus, enterovirus 71, Japanese encephalitis virus, hepatitis C virus, and dengue virus, regulate these processes. We also discuss recent discoveries and how these will produce novel strategies for antiviral treatment.
    Frontiers in Microbiology 08/2014; 5:388. DOI:10.3389/fmicb.2014.00388 · 3.99 Impact Factor
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