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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Autophagy to promote antiviral innate immunity
  5. Manipulation of autophagy by viruses to counteract innate immunity
  6. Autophagy and cell death in virus infection
  7. Conclusions
  8. Acknowledgements
  9. References

Several autonomous arms of innate immunity help cells to combat viral infections. One of these is autophagy, a central cytosolic lysosomal-dependent catabolic process constitutively competent to destroy infectious viruses as well as essential viral components that links virus detection to antiviral innate immune signals. Ongoing autophagy can be upregulated upon virus detection by pathogen receptors, including membrane bound and cytosolic pattern recognition receptors, and may further facilitate pattern recognition receptor-dependent signalling. Autophagy or autophagy proteins also contribute to the synthesis of antiviral innate type I interferon cytokines as well as to antiviral interferon γ signalling. Additionally, autophagy may play a crucial role during viral infections in containing an excessive cellular response by regulating the intensity of the inflammatory response. As a consequence, viruses have evolved strategies to counteract antiviral innate immunity through manipulation of autophagy. This review highlights recent findings on the cross-talk between autophagy and innate immunity during viral infections.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Autophagy to promote antiviral innate immunity
  5. Manipulation of autophagy by viruses to counteract innate immunity
  6. Autophagy and cell death in virus infection
  7. Conclusions
  8. Acknowledgements
  9. References

Innate immunity is a combination of essential defence mechanisms that can be rapidly solicited to combat microorganism invaders. Viruses are obligatory intracellular parasites and are detected through cellular autonomous innate elements which synergize efficient antiviral responses. Virus recognition is mediated by dozens of membrane bound or cytosolic germ line-encoded pattern recognition receptors (PRRs) which detect virus-conserved pathogen-associated molecular patterns (PAMPs) and transduce intracellular signals to elicit innate immune responses.

Toll-like receptors (TLRs) are membrane-expressed signalling PRRs. For example, TLR2 and TLR4, distributed on the cell surface, and TLR3/7/8/9, located within endosomal compartments, can recognize viral molecular determinants (Faure and Rabourdin-Combe, 2011). With the exception of TLR3, all these TLRs recruit the adaptor MyD88 upon engagement. TLR4 recruits in addition the adaptor TRIF, which is also used by TLR3. MyD88 associates with a serine protease to transduce signals to activate nuclear factor-kappa B (NF-κB), a transcription factor that regulates the synthesis of inflammatory cytokines during viral infection. TRIF relays signals leading to the activation of type I IFN (IFN-I) regulatory transcription factors (IRF), for IFN-I synthesis. A MyD88-dependent signal may also trigger IFN-I production upon virus infection (Barbalat et al., 2009). Newly synthesized IFN-I are the major effector cytokines of the host immune response against viral infections. They bind to the IFN-I receptor (IFNAR) which transduces signals leading to the expression of hundreds of IFN stimulating genes (ISGs) that have a direct antiviral effect.

Detection of cytosolic-located viral PAMPs can be achieved by PRRs of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) and Nod-like receptors (NLR) families. The RLR receptors RIG-I and MDA5 which recognize RNA viral genomes are both expressed at low level in cells but are upregulated upon viral infection or IFN-I stimulation. Upon ligand binding, both receptors bind to the mitochondria-associated adaptor IPS-1 which transduces signals that ultimately activate NF-κB and IRF for antiviral inflammatory and IFN-I cytokine synthesis. Although essential for bacterial product detection, the NLR receptor NOD2 can also recognize cytosolic single-stranded (ss) viral RNA to trigger an antiviral IFN-I response, via recruitment of IPS-1 (Sabbah et al., 2009). In addition, the protein kinase regulated by RNA (PKR) is also a key player in the antiviral actions, its expression being upregulated downstream of IFNAR activation. PKR recognizes double-stranded (ds) viral RNA PAMPs leading to subsequent phosphorylation of the protein synthesis initiation factor eIF2α thereby altering most protein translation in cells. Finally, viral infection may also trigger an inflammatory response by activation of the inflammasome, mediated by cytosolic proteins that assemble to trigger caspase1-dependent cleavage and maturation of bioactive inflammatory cytokines such as IL-1β, from a pool of pro-IL-1β induced upon PRRs/NF-κB pathway stimulation. Secreted IL-1β binds to its own receptor in cis whose intracellular signals amplify the antiviral inflammatory response.

Although quickly triggered following virus contact/entry into a cell, all these innate responses are delayed due to a requirement for gene transcription. In contrast, autophagy is an ongoing cellular process that can trap pathogens for degradation immediately following infection. Autophagy is a lysosomal-dependent catabolic cytosolic process for which three major mammalian pathways are known: (i) chaperone-mediated autophagy directly targets cytosolic proteins into lysosomes, (ii) microautophagy degrades cytosolic proteins through lysosomal membrane invagination and (iii) macroautophagy, usually referred to as autophagy, sequesters large components of the cytoplasm into autophagosomes which ultimately fuse with lysosomes. Hereafter, we will discuss only (macro)autophagy and its associated proteins.

Autophagy was initially described as the non-selective entrapment of bulk portions of cytoplasm under conditions of nutrient privation, for cellular recycling and metabolite production, contributing to cell survival. Nevertheless, ongoing autophagy is now thought to be essential for clearing the cytosol of senescent or damaged organelles such as mitochondria or peroxysomes, as well as long-lived proteins and protein aggregates. Autophagy thus plays a crucial rheostat function to maintain cellular homeostasis under physiological conditions.

Autophagy engulfs cytosolic elements within double-membraned autophagosome vesicles formed from an isolation membrane called the phagophore, which ultimately fuse with lysosomes to form autolysosomes where degradation occurs (Fig. 1). In addition to yeast orthologue autophagy-related genes (ATG) proteins, several other autophagy-associated proteins contribute to autophagy execution and regulation in mammalian cells. According to the nature of the cellular stress and/or the cell type, a phagophore could originate from several sources: the endoplasmic reticulum, the Golgi apparatus, the plasma membrane or the mitochondria (Mari et al., 2011).

figure

Figure 1. Initiation, elongation and maturation steps of autophagy. Under starvation, an ULK1 (the mammalian orthologue of yeast ATG1)-including complex found at the forming phagophore and phosphatidylinositol 3-phosphate (PI3P) is produced by the AMBRA1/ATG14L/BECLIN-1(ATG6)/VPS34/VPS15 complex. The phagophore elongates under the impulsion of two ATG5-dependent ubiquitin-like conjugation systems. The first system involves ATG7, ATG10, ATG12, ATG5 and ATG16L1, and contributes to the activation of the second system depending on ATG4, ATG7, ATG3 and LC3 (ATG8). During the autophagy process, the diffusely expressed cytosolic LC3 protein is linked to phosphatidylethanolamine (PE) allowing anchoring to the extending phagophore membrane of newly formed LC3-II. The recruitment of new lipids to the phagophore in expansion involves ATG9. The autophagosome results finally from the fusion of both extremities of the phagophore, and matures along the endocytic pathway, finally merging with lysosomes to generate catalytic autolysosomes. This maturation step is promoted, or inhibited, by two BECLIN-1-containing complexes: UVRAG/BECLIN-1/VPS34/VPS15 or RUBICON/UVRAG/BECLIN-1/VPS34/VPS15 respectively (Matsunaga et al., 2009). Thus, by interacting with BECLIN-1, viruses may interfere with the autophagy process. Eventually, prior to the formation of autolysosomes, autophagosomes may fuse with endosomes, thereby structuring the so-called amphisomes.

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Beyond its role in homeostasis maintenance, autophagy is an innate mechanism that can destroy intracellular microorganisms through their selective targeting. Xenophagy is thus defined as the ability of a cell to capture intracellular pathogens into autophagosomes for subsequent killing (Levine, 2005). However, autophagy can also selectively target essential components of pathogens. Recent studies have highlighted how cells distinguish between bulk non-selective autophagy and the selective autophagy of deleterious substrates such as pathogens. Several autophagy adaptors of the sequestosome-like receptor (SLR) family – SQSTM1 (also called p62), CALCOCO2 (also called NDP52), NBR1 and optineurin – share similar capacities. On one hand they can bind ubiquitinated substrates such as intracellular pathogens, and on the other, they bind to LC3 through a LC3-interacting region (LIR) (Deretic, 2012). Furthermore, beyond its direct innate immune function, autophagy contributes to the regulation of innate immune signalling derived from PRR engagements.

Here, we will review recent developments in our understanding of the role of autophagy and autophagy-associated proteins in viral infections, how it is involved in virus xenophagy, how it contributes to antiviral innate immune responses and how viruses counteract autophagy in order to escape innate immune responses.

Autophagy to promote antiviral innate immunity

  1. Top of page
  2. Summary
  3. Introduction
  4. Autophagy to promote antiviral innate immunity
  5. Manipulation of autophagy by viruses to counteract innate immunity
  6. Autophagy and cell death in virus infection
  7. Conclusions
  8. Acknowledgements
  9. References

Detection of viruses for autophagy induction

Several TLRs recognize viral molecular determinants (Fig. 2). For example, the engagement of TLR4, which binds certain exposed viral proteins, and the engagement of TLR3, TLR7 and TLR8, which bind virus RNA genome PAMPs, induce autophagy upon ligand binding (Xu et al., 2007; Shi and Kehrl, 2008; Delgado et al., 2009). Although shown in a primary study to be MyD88-independent (Xu et al., 2007), it has since been reported that this adaptor can also mediate autophagy (Delgado et al., 2009). Moreover, BECLIN-1 may form complexes with both MyD88 and TRIF which trigger autophagy upon TLR engagement (Fig. 2) (Shi and Kehrl, 2008). PKR can also trigger autophagy upon dsRNA binding through a pathway involving eIF2α phosphorylation (Talloczy et al., 2002). Moreover, NOD2, which may recognize virus ssRNA, has also been shown to trigger autophagy by recruiting ATG16L1 (Fig. 2; Travassos et al., 2010). Recently, autophagy induction was observed upon HSV-1 and human cytomegalovirus (HCMV) herpes virus infection (McFarlane et al., 2011). Interestingly, although viral protein synthesis was not required for autophagy induction, the viral DNA genome was shown to promote autophagy, suggesting that intracellular DNA sensor PPRs, such as AIM2 or DAI, can also trigger autophagy. Thus, several virus-detecting PRRs can induce autophagy upon infection, but whether the majority of these PRR are indeed solicited upon virus infection with infectious particles remains to be clearly analysed in mammalian cells and in vivo. However, in drosophila, autophagy, which is essential to protect adult flies from vesicular stomatitis virus (VSV) infection, is triggered by TLR7 through its physical interaction with the VSV glycoprotein (Nakamoto et al., 2012). The signalling pathway linking TLR7 to autophagy remains to be fully determined, but this study argues for a role for PRRs in autophagy induction upon infection with complete infectious viral particles.

figure

Figure 2. Virus sensitivity or resistance to autophagy-related innate immunity. Autophagy may relay negatively or positively innate immune signalling emanating from cellular PRRs (membrane bound or cytosolic receptors and the inflammasome), and autophagy proteins also contribute to IFNγ signalling. Note that all mechanisms represented in the scheme have been reported in cellular models but not as yet during virus infection. Viruses are represented in dark blue. See text for details.

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Finally, beyond PRRs, other virus binding receptors may trigger autophagy. For example, entry of attenuated measles virus induces autophagy through the engagement of its cellular receptor CD46-Cyt-1. This protein interacts with the scaffold protein GOPC that, in turn, binds to the autophagosome formation complex BECLIN-1/VPS34 (Joubert et al., 2009).

Virus xenophagy and virophagy

In contrast to what has been found with bacteria, xenophagy does not appear to be the main means by which autophagy controls viral infections. To date, few reports have observed complete viral particles within autophagosomes. One such study showed that HSV-1 lacking ICP34.5 (a virulent factor able to bind to BECLIN-1 in order to inhibit autophagy) induces PKR-dependent autophagy, and is found inside autophagosomes for ultimate degradation (Talloczy et al., 2006). However, this virus replicates in permissive cells as efficiently as wild-type HSV-1 in autophagy-competent or -deficient cells suggesting virus xenophagy is not an important antiviral arm of cellular immunity (Alexander et al., 2007; Orvedahl et al., 2007). Nevertheless, this process is potentially a way used by cells to control viral infections immediately following virus entry. Indeed, to enter a cell, viruses can use different pathways, including clathrin-dependent endocytosis and phagocytosis. Interestingly, autophagy-associated proteins can be recruited to nascent phagosomes to accelerate phagosome maturation and the degradation of its content. Moreover, the clathrin-associated plasma membrane can contribute to the formation of autophagosomes (Sanjuan et al., 2007; Ravikumar et al., 2010). Thus, both pathways might contribute to the xenophagy of cell-entering viral particles. Furthermore, following endocytosis, damage on bacteria-containing vesicles is recognized through vesicle-exposed endogenous danger signals, such as ubiquitination, cytosolic glycans or diacylglycerol, eliciting autophagy recruitment for bacterial degradation (Dupont et al., 2009; Shahnazari et al., 2010; Thurston et al., 2012). Although virus-containing endosomes exposing subtle damage/modifications or viral proteins for selective autophagy targeting have not yet been reported, this represents an interesting perspective. However, beyond the capacity of virus xenophagy to limit virus infectivity, autophagy might be more evolved to eliminate individual viral components, such as those essential for the virus life cycle, a process referred to as virophagy (Orvedahl et al., 2011). For example, SQSTM1 binds to the Sindbis virus capsid and targets this viral protein to autophagy for degradation, thereby protecting cells from capsid accumulation-induced cell death. However, in contrast to most targets of SQSTM1 for selective autophagy, this interaction appears to be independent of ubiquitination. Thus, cellular autophagy adaptors might recognize viral components for selective autophagy that are virus-specific, or conserved among virus families. Indeed, a recent mammalian genetic screen highlighted 141 genes involved in the selective targeting of the Sindbis virus capsid to autophagy (Orvedahl et al., 2011). These genes belong to different cellular biological functions, suggesting that multiple molecular pathways may contribute to virophagy. Interestingly, one of these genes, SMURF1, may also contribute to the targeting of HSV-1ΔICP34.5 to autophagosomes, suggesting that viral components shared by different virus families might be detected through similar molecular processes for virus selective autophagy. Moreover, through a protein–protein interactome analysis, more than 35% of 44 proteins of the autophagy network, including SLRs, were reported to interact with RNA virus proteins belonging to five different RNA virus families (Gregoire et al., 2011). Interestingly, whereas some autophagy-associated proteins are targeted only by one RNA virus, others are commonly targeted by several RNA virus families. Whether any of these interactions contribute to virophagy remains to be determined, but together these high-throughput approaches open up interesting new perspectives to identify molecular pathways combating viral infection via selective autophagy.

Autophagy and antiviral interferons

The first contribution of autophagy in innate immunity signalling was reported by Lee et al. (2007). In murine plasmacytoid dendritic cells (pDC), ongoing autophagosomes trap viral replication RNA from Sendai viruses or VSVs before fusing with TLR7-containing endosomes which signal antiviral IFN-I synthesis. In human pDC, autophagy has also been shown to be required for HIV-1-induced IFN-I production, however, independently of viral replication (Zhou et al., 2012). Moreover, in human pDC, TLR7 signalling is required first to induce autophagy. This provides a positive loop to regulate TLR7-dependent activation of the transcription factor IRF7 for IFN-I production. The molecular relationship between autophagy and IFN-I production in pDC remains to be determined as positive regulation of IFN-I synthesis by autophagy may concern other cell types. Recently, it was shown that autophagy induction upon respiratory syncytial virus (RVS) infection contributes to IFN-I production in murine bone marrow-derived dendritic cells (Morris et al., 2011). However, such IFN-I production could result from in vitro differentiated contaminant pDC. Thus, it will be important to understand the molecular interplay between autophagy and IFN-I synthesis signalling in pDC.

Beyond IFN-I, IFN-II (IFNγ) also plays an antiviral function that may compensate or substitute for the inhibition of the IFN-I pathway driven by numerous viruses. IFNγ receptor (IFNGR) engagement by IFNγ induces autophagy in murine embryonic fibroblasts (MEF) to ameliorate inflammatory cytokine synthesis. Indeed, autophagy prevents mitochondria reactive oxygen species (ROS) production, which otherwise activates SHP2 tyrosine phosphatase which inhibits IFNGR signalling (Fig. 2; Chang et al., 2010). Furthermore, HSV-1 replication is sensitive to IFNγ, but not in Atg5-deficient MEFs. In accordance with this, it was recently shown that the ATG12 conjugation system-linked ATG12/5/16L1 and ATG7 proteins are all required for the IFNγ-mediated antiviral response against murine norovirus (MNV) infection, in vitro and in vivo (Fig. 2), but not against other IFNγ-sensitive viruses such as murine hepatitis virus or West Nile virus (Hwang et al., 2012). However, neither the autophagy catabolic process nor the ATG4B autophagy protein is required in this anti-MNV response, indicating an unusual contribution of ATG proteins to the antiviral response. ATG12/5/16L1 and ATG7 contribute to blocking MNV infection by preventing early formation of the virus replication complex (Fig. 2). To our knowledge, this study is the first example of the use of autophagy proteins in antiviral defence, independent of the canonical autophagy process. However, the list could become extended since a growing number of studies have reported similar observations in the context of bacterial or parasitic infections (Zhao et al., 2008; Starr et al., 2012).

IFNγ has also been described to induce autophagy via the cellular protein IRGM, to combat intracellular mycobacteria (Singh et al., 2006). Interestingly, IRGM has been identified to be a frequent target of proteins from RNA viruses that subvert autophagy (Gregoire et al., 2011). IRGM might play a role in viral sensing leading to an autophagy-mediated antiviral response. Further studies are required to fully decipher the molecular mechanism involving IRGM during virus-induced autophagy as well as to determine whether IRGM is associated with the IFNγ-mediated antiviral function.

Manipulation of autophagy by viruses to counteract innate immunity

  1. Top of page
  2. Summary
  3. Introduction
  4. Autophagy to promote antiviral innate immunity
  5. Manipulation of autophagy by viruses to counteract innate immunity
  6. Autophagy and cell death in virus infection
  7. Conclusions
  8. Acknowledgements
  9. References

Viruses hijack autophagy to prevent inflammatory responses

By manipulating autophagy, viruses can evade antiviral innate immunity and thus enhance their replication. An elegant strategy used by viruses to achieve this was recently reported. The murine cytomegalovirus (MCMV) M45 protein was shown to interact with the NF-κB regulatory subunit NEMO, thereby allowing its targeting and degradation by autophagy (Fig. 2; Fliss et al., 2012). As a consequence, subsequent NF-κB activation is impaired and the antiviral loop of inflammatory cytokine synthesis prevented. MCMV M45 protein overexpression induces protein aggregates which could be the selective target for autophagy degradation. To dampen the antiviral immune response, similar strategies might be shared by other viruses inducing protein aggregate formation.

Activation of the inflammasome is an innate antiviral mechanism which leads to the production of inflammatory cytokines such as IL-1β. Strikingly, inhibition of autophagy results in an enhanced production of IL-1β, whereas autophagy promotion prevents inflammasome activation (Shi et al., 2012). Autophagy may contribute to the attenuation of the inflammatory response in physiological conditions. Moreover, autophagy is induced in macrophages in response to activation of the AIM2 or NLRP3 inflammasome via activation of the G protein RalB. However, the inflammasome signal intermediate ASC is ubiquitinated. This leads to its selective targeting to autophagy by SQSTM1, leading to a downmodulation of the inflammasome response (Fig. 2).

Strikingly, the proton-specific ion channel M2 protein of influenza virus has been described to both activate the inflammasome and inhibit autophagy (Fig. 2). During infection by influenza virus, TLR7 signalling allows the transcription of pro-IL-1β which is then cleaved to a mature form through a M2-dependent NLRP3 activation. The ion channel activity of M2 enables export of H+ from the acidified Golgi, which allows the formation and activation of the NLRP3 inflammasome complex (Ichinohe et al., 2011). The influenza A M2 protein also inhibits autophagosome maturation in infected cells due to a blockage of their fusion with lysosomes (Gannage et al., 2009). However, M2 proton channel activity is not involved in this function. Whether M2-induced autophagy maturation blockage modulates M2-dependent inflammasome activation remains, however, to be determined. Moreover, it has been recently shown that autophagy can dampen IL-1β production, independently of direct inflammasome inhibition, by restricting IL1β transcription. While the mechanism responsible for this process remains unclear, viruses might use it to avoid the antiviral inflammatory response (Crisan et al., 2011).

HIV has been reported to inhibit autophagy in dendritic cells early post infection. Inhibition of autophagy is mediated by the viral envelope protein which triggers signalling events, in part through the CD4 receptor. Following endocytosis, HIV-1 is targeted to so-called immunoamphisomes and inhibits autophagy to escape degradation. Indeed, downregulation of autophagy leads to an increased HIV-1 content in DCs and enhances transfer of HIV-1 to CD4+T cells. Most importantly, HIV-1-mediated downregulation of autophagy in DCs impairs innate immune responses as revealed by markedly decreased TNF-α production upon TLR stimulation. Thus, immunoamphisomes in DCs engulf incoming pathogens and appear to amplify pathogen degradation as well as TLR responses – which may explain why HIV-1 evolved to inhibit autophagy (Blanchet et al., 2010).

Another virus which has been shown to inhibit autophagy in order to escape degradation and avoid activation of innate immunity is the HCMV. HCMV interacts with autophagy at two different stages of infection. At the early stages of infection, there is an induction of a complete autophagy flux. This is induced by factors independent of de novo viral protein synthesis since UV-inactivated HCMV also induces autophagy. At later time points of infection, HCMV blocks autophagy maturation by a mechanism that requires de novo expression of the viral protein TRS1. However, blockage of autophagosome maturation is independent of the previously reported interaction between PKR and TRS1 but it is due to the interaction of TRS1 with BECLIN-1. Thus, HCMV TSR1 is able to inhibit innate immunity by two different mechanisms: first by inhibiting antiviral PKR, an autophagy inducer, and second by directly blocking autophagosome maturation through BECLIN-1 interaction (Chaumorcel et al., 2012).

Virus-induced autophagy and prevention of IFN-I synthesis

As discussed above, whereas in virus-infected pDC autophagy may regulate IFN-I production positively, in non-pDC cells autophagy proteins have been shown to restrict virus-induced RLR-dependent IFN-I production. Indeed, ATG5/12 has been shown to constitutively interact with RIG-I and the signalling intermediate IPS-1 (Fig. 2). This interaction is further increased upon VSV infection and leads to the prevention of RIG-I-mediated activation and subsequent IFN-I antiviral production (Jounai et al., 2007). However, it is not yet known exactly how ATG5/12 inhibits IFN-I production, in particular whether canonical autophagy relies on this process. Interestingly, ongoing autophagy in MEF and murine macrophages also inhibits RIG-I signalling by eliminating mitochondrial ROS production which otherwise contributes to increase of intracellular IPS-1 expression and amplification of VSV-mediated RIG-I signalling for IFN-I production (Tal et al., 2009).

Hepatitis C virus (HCV) can inhibit IFN-I production by promoting autophagy. Indeed, HCV infection induces the unfolded protein response (UPR) which, in turn, activates a complete autophagy flux necessary to promote HCV RNA replication in human hepatoma cells (Fig. 2; Ke and Chen, 2011). This proviral role of autophagy has been shown to be mediated by the suppression of IFN-I. Indeed, HCV infection leads to an activation of the IFNβ promoter through the recognition of HCV-derived PAMPs by RIG-I, and the inhibition of either autophagy or UPR enhances IFNβ promoter activation. The completion of autolysosomes is required for this purpose since chloroquine treatment, which inhibits autophagosome maturation, enhances IFNβ promoter activation, whereas rapamycin treatment, which promotes autophagy flux, decreases it. This process could contribute to HCV persistent infection. Similarly, it has been reported that HCV infection or HCV-NS5A overexpression induces IFN-I production through signalling involving ROS production by mitochondria in autophagy-deficient cells (Shrivastava et al., 2012). Interestingly, the NS3/4A HCV protease can cleave IPS-1 to shut off its ability to signal within infected cells and NS3/4A has been reported to interact with IRGM to promote autophagy induction (Gregoire et al., 2011). Since IRGM, like IPS-1, is located in mitochondria and can bind to ATG5 (Gregoire et al., 2011) it might be interesting to determine whether IPS-1 cleavage by NS3/4A involves IRGM. Thus, HCV appears to have evolved several different molecular strategies to counteract innate immunity through exploitation of autophagy.

Autophagy and cell death in virus infection

  1. Top of page
  2. Summary
  3. Introduction
  4. Autophagy to promote antiviral innate immunity
  5. Manipulation of autophagy by viruses to counteract innate immunity
  6. Autophagy and cell death in virus infection
  7. Conclusions
  8. Acknowledgements
  9. References

Apoptotic death of infected cells may contribute to limiting viral replication and propagation. As autophagy is a prosurvival cellular process, by preventing apoptosis, it could play an undesirable proviral function. Indeed, the human flavivirus dengue virus type 2 and the murine flavivirus Modoc induce autophagy in infected epithelial cells that allows the cells to be protected from experimentally induced cell death (McLean et al., 2011). Inhibition of autophagy leads to a decrease in viral replication demonstrating the proviral role of autophagy. However, autophagy-mediated cell death protection by dengue and Modoc virus infections was not observed in macrophages, suggesting a cell type-specific process. Interestingly, dengue virus and Modoc virus infections also protect the cell from death induced by cytopathic viral infections such as influenza A infection. As influenza A has been reported to inhibit autophagy maturation to regulate cell death fate (Gannage et al., 2009), it would be interesting to analyse autophagy function within cells coinfected with pathogens that have evolved different strategies to manipulate autophagy.

However, the relationship between autophagy and apoptosis during virus infection could reach an equilibrium more complicated than expected within infected organisms. It has recently been reported that Chikungunya virus induces autophagy in infected cells through both the activation of endoplasmic reticulum stress and the production of ROS (Joubert et al., 2012). Autophagy delayed apoptosis since cell death occurs earlier in ATG5-deficient MEFs, but prevention of apoptosis results in fewer infected cells and limits viral propagation. Indeed, although infected Bax−/−/Bak−/− MEFs expressed more viral proteins per se, fewer neighbouring cells are infected by the virus. By contrast, the percentage of infected cells is enhanced in ATG5−/− MEFs compared with control cells. Thus, whether the antiapoptotic role of autophagy plays an anti- or a proviral function depends on the viral life cycle and on the need for the virus to promote cell survival or to induce cell death.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Autophagy to promote antiviral innate immunity
  5. Manipulation of autophagy by viruses to counteract innate immunity
  6. Autophagy and cell death in virus infection
  7. Conclusions
  8. Acknowledgements
  9. References

Our understanding of the relationship between viruses and autophagy remains rudimentary, especially with regard to innate signalling cross-talk. Several PRRs able to recognize virus components are known to induce autophagy, but the mechanisms remain to be clarified. Moreover, other PRRs that can recognize viruses and mediate virus uptake, such as the mannose receptor, scavenger receptors and dendritic cell-specific ICAM grabbing non-integrin (DC-SIGN), could be linked to autophagy. In addition, more attention should be paid to the reciprocal benefit between autophagy and innate receptor signalling in antiviral innate immunity, as suggested in recent studies. It would also be important to investigate the role of autophagy in innate immunity during viral coinfections. Depending on the degree of a pathogen's sensitivity to autophagy, the steps at which coinfecting pathogens may counteract the process, as well as the timing, order of infection and the cell types involved, autophagy could turn out to be the cell biological keystone by which early pathogen infectivity escapes the innate immune response.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Autophagy to promote antiviral innate immunity
  5. Manipulation of autophagy by viruses to counteract innate immunity
  6. Autophagy and cell death in virus infection
  7. Conclusions
  8. Acknowledgements
  9. References

We apologize to colleagues whose work has not been cited here due to space limitations. We acknowledge Dr Robin Buckland for checking English language in this manuscript. This work was funded by grants from INSERM, UCBLyon-1 and ANR-08-JCJC-0064-01. C. R. is the recipient of a fellowship from the Ministère de la Recherche and the ARC Fondation pour la Recherche sur le Cancer DOC 20120605239.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Autophagy to promote antiviral innate immunity
  5. Manipulation of autophagy by viruses to counteract innate immunity
  6. Autophagy and cell death in virus infection
  7. Conclusions
  8. Acknowledgements
  9. References
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