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Viruses and Autophagy

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 July 2017) | Viewed by 114643

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Prof. Dr. Christian Münz

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Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
Interests: antigen processing; LC3- associated phagocytosis; viral regulation of autophagy; MHC restricted antigen presentation; Atg supported exocytosis
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Special Issue Information

Dear Colleagues,

Autophagy is a group of cytoplasmic degradation pathways that utilize lysosmal hydrolysis to recycle intracellular organelles and macromolecules. More than 30 autophagy related gene (atg) products remodel cellular membranes to achieve this function. Viruses as some of the most successful intracellular pathogens face destruction by these pathways and have developed various strategies to inhibit autophagy or utilize autophagic membranes for their own replication. These include the assembly of their replication machineries on autophagic membranes and recruiting them for viral envelope acquisition. During viral evasion from autophagy and hijacking of autophagic membranes not only canonical autophagy functions of atgs are used, but also alternative roles of atgs in other membrane remodelling pathways.

The series of reviews and primary research articles in this special issue is dedicated to the rapidly growing field of interactions between the autophagic machinery and viruses. This series might include articles on viral restriction by autophagy, viral escape mechanisms from autophagy, utilization of autophagic membranes during viral replication, regulation of innate and adaptive immune responses to viruses by autophagy and utilization of autophagy for vaccination against viral diseases. It will provide a valuable overview over the many mechanisms, by which viruses interact with autophagy, and will hopefully point out new exciting research areas of how to study autophagy with viruses as well as how to use autophagy for therapeutic intervention against viral diseases.

Prof. Dr. Christian Münz
Guest Editor

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Keywords

Xenophagy
viral restriction by autophagy
intrinsic immunity by autophagy
viral immune escape from autophagy
viral exocytosis via autophagy
autophagic membranes in viral envelopes
LC3-associated phagocytosis during viral infections
autophagic regulation of cytokine production during viral infections
regulation of adaptive anti-viral immune responses by autophagy

Published Papers (13 papers)

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Research

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2355 KiB

Open AccessArticle

Importance of Autophagy in Mediating Human Immunodeficiency Virus (HIV) and Morphine-Induced Metabolic Dysfunction and Inflammation in Human Astrocytes

by Myosotys Rodriguez, Jessica Lapierre, Chet Raj Ojha, Hary Estrada-Bueno, Seth M. Dever, David A. Gewirtz, Fatah Kashanchi and Nazira El-Hage

Viruses 2017, 9(8), 201; https://doi.org/10.3390/v9080201 - 28 Jul 2017

Cited by 25 | Viewed by 5720

Abstract

Under physiological conditions, the function of astrocytes in providing brain metabolic support is compromised under pathophysiological conditions caused by human immunodeficiency virus (HIV) and opioids. Herein, we examined the role of autophagy, a lysosomal degradation pathway important for cellular homeostasis and survival, as a potential regulatory mechanism during pathophysiological conditions in primary human astrocytes. Blocking autophagy with small interfering RNA (siRNA) targeting BECN1, but not the Autophagy-related 5 (ATG5) gene, caused a significant decrease in HIV and morphine-induced intracellular calcium release. On the contrary, inducing autophagy pharmacologically with rapamycin further enhanced calcium release and significantly reverted HIV and morphine-decreased glutamate uptake. Furthermore, siBeclin1 caused an increase in HIV-induced nitric oxide (NO) release, while viral-induced NO in astrocytes exposed to rapamycin was decreased. HIV replication was significantly attenuated in astrocytes transfected with siRNA while significantly induced in astrocytes exposed to rapamycin. Silencing with siBeclin1, but not siATG5, caused a significant decrease in HIV and morphine-induced interleukin (IL)-8 and tumor necrosis factor alpha (TNF-α) release, while secretion of IL-8 was significantly induced with rapamycin. Mechanistically, the effects of siBeclin1 in decreasing HIV-induced calcium release, viral replication, and viral-induced cytokine secretion were associated with a decrease in activation of the nuclear factor kappa B (NF-κB) pathway. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Open AccessArticle

2BC Non-Structural Protein of Enterovirus A71 Interacts with SNARE Proteins to Trigger Autolysosome Formation

by Jeffrey K. F. Lai, I-Ching Sam, Pauline Verlhac, Joël Baguet, Eeva-Liisa Eskelinen, Mathias Faure and Yoke Fun Chan

Viruses 2017, 9(7), 169; https://doi.org/10.3390/v9070169 - 04 Jul 2017

Cited by 26 | Viewed by 7449

Abstract

Viruses have evolved unique strategies to evade or subvert autophagy machinery. Enterovirus A71 (EV-A71) induces autophagy during infection in vitro and in vivo. In this study, we report that EV-A71 triggers autolysosome formation during infection in human rhabdomyosarcoma (RD) cells to facilitate its replication. Blocking autophagosome-lysosome fusion with chloroquine inhibited virus RNA replication, resulting in lower viral titres, viral RNA copies and viral proteins. Overexpression of the non-structural protein 2BC of EV-A71 induced autolysosome formation. Yeast 2-hybrid and co-affinity purification assays showed that 2BC physically and specifically interacted with a N-ethylmaleimide-sensitive factor attachment receptor (SNARE) protein, syntaxin-17 (STX17). Co-immunoprecipitation assay further showed that 2BC binds to SNARE proteins, STX17 and synaptosome associated protein 29 (SNAP29). Transient knockdown of STX17, SNAP29, and microtubule-associated protein 1 light chain 3B (LC3B), crucial proteins in the fusion between autophagosomes and lysosomes) as well as the lysosomal-associated membrane protein 1 (LAMP1) impaired production of infectious EV-A71 in RD cells. Collectively, these results demonstrate that the generation of autolysosomes triggered by the 2BC non-structural protein is important for EV-A71 replication, revealing a potential molecular pathway targeted by the virus to exploit autophagy. This study opens the possibility for the development of novel antivirals that specifically target 2BC to inhibit formation of autolysosomes during EV-A71 infection. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Open AccessArticle

Distinct Contributions of Autophagy Receptors in Measles Virus Replication

by Denitsa S. Petkova, Pauline Verlhac, Aurore Rozières, Joël Baguet, Mathieu Claviere, Carole Kretz-Remy, Renaud Mahieux, Christophe Viret and Mathias Faure

Viruses 2017, 9(5), 123; https://doi.org/10.3390/v9050123 - 22 May 2017

Cited by 35 | Viewed by 6398

Abstract

Autophagy is a potent cell autonomous defense mechanism that engages the lysosomal pathway to fight intracellular pathogens. Several autophagy receptors can recognize invading pathogens in order to target them towards autophagy for their degradation after the fusion of pathogen-containing autophagosomes with lysosomes. However, numerous intracellular pathogens can avoid or exploit autophagy, among which is measles virus (MeV). This virus induces a complete autophagy flux, which is required to improve viral replication. We therefore asked how measles virus interferes with autophagy receptors during the course of infection. We report that in addition to NDP52/CALCOCO₂ and OPTINEURIN/OPTN, another autophagy receptor, namely T6BP/TAXIBP1, also regulates the maturation of autophagosomes by promoting their fusion with lysosomes, independently of any infection. Surprisingly, only two of these receptors, NDP52 and T6BP, impacted measles virus replication, although independently, and possibly through physical interaction with MeV proteins. Thus, our results suggest that a restricted set of autophagosomes is selectively exploited by measles virus to replicate in the course of infection. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Review

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10 pages, 831 KiB

Open AccessReview

EBV and KSHV Infection Dysregulates Autophagy to Optimize Viral Replication, Prevent Immune Recognition and Promote Tumorigenesis

by Mara Cirone

Viruses 2018, 10(11), 599; https://doi.org/10.3390/v10110599 - 31 Oct 2018

Cited by 39 | Viewed by 5808

Abstract

Autophagy is a catabolic process strongly involved in the immune response, and its dysregulation contributes to the onset of several diseases including cancer. The human oncogenic gammaherpesviruses, Epstein—Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), manipulate autophagy, either during the de novo infection or during the lytic reactivation, in naturally latently-infected lymphoma cells. In particular, the gammaherpesvirus infection reduces autophagy in immune cells, such as monocytes, resulting in the impairment of cell survival and cell differentiation into dendritic cells (DCs), which are essential for initiating and regulating the immune response. In the case of EBV, the reduction of autophagy in these cells, leading to p62 accumulation, activated the p62-NRF2-antioxidant response, reducing ROS, and further inhibiting autophagy. KSHV inhibits autophagy in monocytes by de-phosphorylating JNK2, altering the calpains–calpastatin balance and increasing the calpain activity responsible for the cleavage of ATG5. To further impair the immune response, KSHV also inhibits autophagy in differentiated DCs by hyper-phosphorylating STAT3. Conversely, when the lytic cycle is induced in vitro in latently-infected lymphoma B cells, both EBV and KSHV promote autophagy to enhance their replication, although the final autophagic steps are blocked through the down-regulation of Rab7. This strategy allows viruses to avoid the destructive environment of lysosomes, and to exploit the autophagic machinery for intracellular transportation. EBV and KSHV encode for proteins that may either inhibit or promote autophagy and, in addition, they can modulate the cellular pathways that control this process. In this review we will discuss the findings that indicate that autophagy is dysregulated by gammaherpesvirus to promote immune suppression, facilitate viral replication and contribute to the onset and maintenance of gammaherpesvirus-associated malignancies. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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8 pages, 762 KiB

Open AccessReview

Enterovirus Transmission by Secretory Autophagy

by Yael Mutsafi and Nihal Altan-Bonnet

Viruses 2018, 10(3), 139; https://doi.org/10.3390/v10030139 - 20 Mar 2018

Cited by 46 | Viewed by 7145

Abstract

Present in many cell types, non-degradative secretory autophagy is a newly discovered pathway in which autophagosomes fuse with the plasma membrane instead of lysosomes. Surprisingly, some viruses exploit secretory autophagy to exit cells non-lytically, shedding into the extracellular environment as particle populations contained within vesicles. As a result, this significantly enhances the infectivity of these viruses. In this paper, this novel cellular exit pathway is highlighted and its advantages for viral transmission discussed. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Open AccessReview

Implication of Different HIV-1 Genes in the Modulation of Autophagy

by Zhenlong Liu, Yong Xiao, Cynthia Torresilla, Éric Rassart and Benoit Barbeau

Viruses 2017, 9(12), 389; https://doi.org/10.3390/v9120389 - 18 Dec 2017

Cited by 16 | Viewed by 5470

Abstract

Autophagy is a complex cellular degradation pathway, which plays important roles in the regulation of several developmental processes, cellular stress responses, and immune responses induced by pathogens. A number of studies have previously demonstrated that HIV-1 was capable of altering the regulation of autophagy and that this biological process could be induced in uninfected and infected cells. Furthermore, previous reports have indicated that the involvement of HIV-1 in autophagy regulation is a complex phenomenon and that different viral proteins are contributing in its modulation upon viral infection. Herein, we review the recent literature over the complex crosstalk of the autophagy pathway and HIV-1, with a particular focus on HIV-1 viral proteins, which have been shown to modulate autophagy. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Open AccessReview

Herpesvirus and Autophagy: “All Right, Everybody Be Cool, This Is a Robbery!”

by Marion Lussignol and Audrey Esclatine

Viruses 2017, 9(12), 372; https://doi.org/10.3390/v9120372 - 04 Dec 2017

Cited by 44 | Viewed by 9191

Abstract

Autophagy is an essential vacuolar process of the cell, leading to lysosomal degradation and recycling of proteins and organelles, which is extremely important in maintaining homeostasis. Multiple roles have been now associated with autophagy, in particular a pro-survival role in nutrient starvation or in stressful environments, a role in life span extension, in development, or in innate and adaptive immunity. This cellular process can also take over microorganisms or viral proteins inside autophagosomes and degrade them directly in autolysosomes and is then called xenophagy and virophagy, respectively. Several Herpesviruses have developed strategies to escape this degradation, by expression of specific anti-autophagic proteins. However, we are increasingly discovering that Herpesviruses hijack autophagy, rather than just fight it. This beneficial effect is obvious since inhibition of autophagy will lead to decreased viral titers for human cytomegalovirus (HCMV), Epstein-Barr virus (EBV) or Varicella-Zoster virus (VZV), for example. Conversely, autophagy stimulation will improve viral multiplication. The autophagic machinery can be used in whole or in part, and can optimize viral propagation or persistence. Some viruses block maturation of autophagosomes to avoid the degradation step, then autophagosomal membranes are used to contribute to the envelopment and/or the egress of viral particles. On the other hand, VZV stimulates the whole process of autophagy to subvert it in order to use vesicles containing ATG (autophagy-related) proteins and resembling amphisomes for their transport in the cytoplasm. During latency, autophagy can also be activated by latent proteins encoded by different oncogenic Herpesviruses to promote cell survival and achieve long term viral persistence in vivo. Finally, reactivation of gammaherpesvirus Murid Herpesvirus 68 (MHV68) in mice appears to be positively modulated by autophagy, in order to control the level of inflammation. Therefore, Herpesviruses appear to behave more like thieves than fugitives. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Open AccessReview

Autophagy in Measles Virus Infection

by Aurore Rozières, Christophe Viret and Mathias Faure

Viruses 2017, 9(12), 359; https://doi.org/10.3390/v9120359 - 24 Nov 2017

Cited by 28 | Viewed by 6836

Abstract

Autophagy is a biological process that helps cells to recycle obsolete cellular components and which greatly contributes to maintaining cellular integrity in response to environmental stress factors. Autophagy is also among the first lines of cellular defense against invading microorganisms, including viruses. The autophagic destruction of invading pathogens, a process referred to as xenophagy, involves cytosolic autophagy receptors, such as p62/SQSTM1 (Sequestosome 1) or NDP52/CALCOCO2 (Nuclear Dot 52 KDa Protein/Calcium Binding And Coiled-Coil Domain 2), which bind to microbial components and target them towards growing autophagosomes for degradation. However, most, if not all, infectious viruses have evolved molecular tricks to escape from xenophagy. Many viruses even use autophagy, part of the autophagy pathway or some autophagy-associated proteins, to improve their infectious potential. In this regard, the measles virus, responsible for epidemic measles, has a unique interface with autophagy as the virus can induce multiple rounds of autophagy in the course of infection. These successive waves of autophagy result from distinct molecular pathways and seem associated with anti- and/or pro-measles virus consequences. In this review, we describe what the autophagy–measles virus interplay has taught us about both the biology of the virus and the mechanistic orchestration of autophagy. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Open AccessReview

Autophagy Proteins in Viral Exocytosis and Anti-Viral Immune Responses

by Christian Münz

Viruses 2017, 9(10), 288; https://doi.org/10.3390/v9100288 - 04 Oct 2017

Cited by 20 | Viewed by 7742

Abstract

Abstract: Autophagy-related (Atg) gene-encoded proteins were originally described for their crucial role in macroautophagy, a catabolic pathway for cytoplasmic constituent degradation in lysosomes. Recently it has become clear that modules of this machinery can also be used to influence endo- and exocytosis. This mini review discusses how these alternative Atg functions support virus replication and viral antigen presentation on major histocompatibility (MHC) class I and II molecules. A better understanding of the modular use of the macroautophagy machinery might enable us to manipulate these alternative functions of Atg proteins during anti-viral therapies and to attenuate virus-induced immune pathologies. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Open AccessReview

Canonical and Non-Canonical Autophagy in HIV-1 Replication Cycle

by Olivier Leymarie, Leslie Lepont and Clarisse Berlioz-Torrent

Viruses 2017, 9(10), 270; https://doi.org/10.3390/v9100270 - 23 Sep 2017

Cited by 30 | Viewed by 11524

Abstract

Autophagy is a lysosomal-dependent degradative process essential for maintaining cellular homeostasis, and is a key player in innate and adaptive immune responses to intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). In HIV-1 target cells, autophagy mechanisms can (i) selectively direct viral proteins and viruses for degradation; (ii) participate in the processing and presentation of viral-derived antigens through major histocompatibility complexes; and (iii) contribute to interferon production in response to HIV-1 infection. As a consequence, HIV-1 has evolved different strategies to finely regulate the autophagy pathway to favor its replication and dissemination. HIV-1 notably encodes accessory genes encoding Tat, Nef and Vpu proteins, which are able to perturb and hijack canonical and non-canonical autophagy mechanisms. This review outlines the current knowledge on the complex interplay between autophagy and HIV-1 replication cycle, providing an overview of the autophagy-mediated molecular processes deployed both by infected cells to combat the virus and by HIV-1 to evade antiviral response. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Open AccessReview

Hepatitis C Virus-Induced Autophagy and Host Innate Immune Response

by Stephanie T. Chan and Jing-hsiung James Ou

Viruses 2017, 9(8), 224; https://doi.org/10.3390/v9080224 - 12 Aug 2017

Cited by 74 | Viewed by 12809

Abstract

Autophagy is a catabolic process that is important for maintaining cellular homeostasis. This pathway in hepatocytes is stimulated and controlled by the hepatitis C virus (HCV)—upon infection—to promote its own replication. HCV induces autophagy indirectly and directly through different mechanisms and temporally controls the autophagic flux. This enables the virus to maximize its replication and attenuate the innate immune responses that it activates. In this review, we discuss the relationship between HCV and autophagy, and the crosstalk between HCV-induced autophagy and host innate immune responses. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Open AccessFeature PaperReview

The Interaction between Nidovirales and Autophagy Components

by Yingying Cong, Pauline Verlhac and Fulvio Reggiori

Viruses 2017, 9(7), 182; https://doi.org/10.3390/v9070182 - 11 Jul 2017

Cited by 31 | Viewed by 18503

Abstract

Autophagy is a conserved intracellular catabolic pathway that allows cells to maintain homeostasis through the degradation of deleterious components via specialized double-membrane vesicles called autophagosomes. During the past decades, it has been revealed that numerous pathogens, including viruses, usurp autophagy in order to promote their propagation. Nidovirales are an order of enveloped viruses with large single-stranded positive RNA genomes. Four virus families (Arterividae, Coronaviridae, Mesoniviridae, and Roniviridae) are part of this order, which comprises several human and animal pathogens of medical and veterinary importance. In host cells, Nidovirales induce membrane rearrangements including autophagosome formation. The relevance and putative mechanism of autophagy usurpation, however, remain largely elusive. Here, we review the current knowledge about the possible interplay between Nidovirales and autophagy. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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Open AccessReview

Interplay between Autophagy, Exosomes and HIV-1 Associated Neurological Disorders: New Insights for Diagnosis and Therapeutic Applications

by Chet Raj Ojha, Jessica Lapierre, Myosotys Rodriguez, Seth M. Dever, Mohammad Asad Zadeh, Catherine DeMarino, Michelle L. Pleet, Fatah Kashanchi and Nazira El-Hage

Viruses 2017, 9(7), 176; https://doi.org/10.3390/v9070176 - 06 Jul 2017

Cited by 45 | Viewed by 8865

Abstract

The autophagy–lysosomal pathway mediates a degradative process critical in the maintenance of cellular homeostasis as well as the preservation of proper organelle function by selective removal of damaged proteins and organelles. In some situations, cells remove unwanted or damaged proteins and RNAs through the release to the extracellular environment of exosomes. Since exosomes can be transferred from one cell to another, secretion of unwanted material to the extracellular environment in exosomes may have an impact, which can be beneficial or detrimental, in neighboring cells. Exosome secretion is under the influence of the autophagic system, and stimulation of autophagy can inhibit exosomal release and vice versa. Neurons are particularly vulnerable to degeneration, especially as the brain ages, and studies indicate that imbalances in genes regulating autophagy are a common feature of many neurodegenerative diseases. Cognitive and motor disease associated with severe dementia and neuronal damage is well-documented in the brains of HIV-infected individuals. Neurodegeneration seen in the brain in HIV-1 infection is associated with dysregulation of neuronal autophagy. In this paradigm, we herein provide an overview on the role of autophagy in HIV-associated neurodegenerative disease, focusing particularly on the effect of autophagy modulation on exosomal release of HIV particles and how this interplay impacts HIV infection in the brain. Specific autophagy–regulating agents are being considered for therapeutic treatment and prevention of a broad range of human diseases. Various therapeutic strategies for modulating specific stages of autophagy and the current state of drug development for this purpose are also evaluated. Full article

(This article belongs to the Special Issue Viruses and Autophagy)

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