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Viral Infection and Apoptosis

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A special issue of Viruses (ISSN 1999-4915).

Deadline for manuscript submissions: closed (30 June 2017) | Viewed by 124347

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Prof. Dr. Marc Kvansakul

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Department of Biochemistry & Chemistry, La Trobe University, Kingsbury Drive, Melbourne 3086, Australia
Interests: apoptosis; structural biology; polarity; defensins
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Dear Colleagues,

Apoptosis is a form of programmed cell death that enables the removal of damaged, infected, or otherwise unwanted cells in a controlled manner. Apoptosis can be initiated by multiple independent pathways that ultimately converge at a point where proteolytic enzymes belonging to the caspase family are activated, which dismantle the apoptotic cell.

Multicellular organism have employed apoptotic mechanisms during host defence in response to viral infection to limit or prevent viral spread and replication. Consequently, viruses have evolved sophisticated molecular countermeasures to disarm host apoptotic defences, and this series of reviews and primary research articles in this Special Issue explores the intricate molecular interplay between viruses and their hosts when they battle for control of host apoptotic check-points.

Dr. Marc Kvansakul
Guest Editor

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Keywords

Apoptosis
caspase
host defence

Published Papers (14 papers)

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Editorial

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123 KiB

Open AccessEditorial

Viral Infection and Apoptosis

by Marc Kvansakul

Viruses 2017, 9(12), 356; https://doi.org/10.3390/v9120356 - 23 Nov 2017

Cited by 49 | Viewed by 6562

Abstract

Viruses are master molecular manipulators, and evolved to thrive and survive in all species.[...] Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

Research

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6597 KiB

Open AccessArticle

Structural and Functional Insight into Canarypox Virus CNP058 Mediated Regulation of Apoptosis

by Mohd Ishtiaq Anasir, Amy A. Baxter, Ivan K. H. Poon, Mark D. Hulett and Marc Kvansakul

Viruses 2017, 9(10), 305; https://doi.org/10.3390/v9100305 - 20 Oct 2017

Cited by 17 | Viewed by 5284

Abstract

Programmed cell death or apoptosis is an important component of host defense systems against viral infection. The B-cell lymphoma 2 (Bcl-2) proteins family is the main arbiter of mitochondrially mediated apoptosis, and viruses have evolved sequence and structural mimics of Bcl-2 to subvert premature host cell apoptosis in response to viral infection. The sequencing of the canarypox virus genome identified a putative pro-survival Bcl-2 protein, CNP058. However, a role in apoptosis inhibition for CNP058 has not been identified to date. Here, we report that CNP058 is able to bind several host cell pro-death Bcl-2 proteins, including Bak and Bax, as well as several BH3 only-proteins including Bim, Bid, Bmf, Noxa, Puma, and Hrk with high to moderate affinities. We then defined the structural basis for CNP058 binding to pro-death Bcl-2 proteins by determining the crystal structure of CNP058 bound to Bim BH3. CNP058 adopts the conserved Bcl-2 like fold observed in cellular pro-survival Bcl-2 proteins, and utilizes the canonical ligand binding groove to bind Bim BH3. We then demonstrate that CNP058 is a potent inhibitor of ultraviolet (UV) induced apoptosis in a cell culture model. Our findings suggest that CNP058 is a potent inhibitor of apoptosis that is able to bind to BH3 domain peptides from a broad range of pro-death Bcl-2 proteins, and may play a key role in countering premature host apoptosis. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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2780 KiB

Open AccessArticle

Infectious Bronchitis Virus Infection Induces Apoptosis during Replication in Chicken Macrophage HD11 Cells

by Xiaoxiao Han, Yiming Tian, Ru Guan, Wenqian Gao, Xin Yang, Long Zhou and Hongning Wang

Viruses 2017, 9(8), 198; https://doi.org/10.3390/v9080198 - 26 Jul 2017

Cited by 40 | Viewed by 6667

Abstract

Avian infectious bronchitis has caused huge economic losses in the poultry industry. Previous studies have reported that infectious bronchitis virus (IBV) infection can produce cytopathic effects (CPE) and apoptosis in some mammalian cells and primary cells. However, there is little research on IBV-induced immune cell apoptosis. In this study, chicken macrophage HD11 cells were established as a cellular model that is permissive to IBV infection. Then, IBV-induced apoptosis was observed through a cell viability assay, morphological changes, and flow cytometry. The activity of caspases, the inhibitory efficacy of caspase-inhibitors and the expression of apoptotic genes further suggested the activation of apoptosis through both intrinsic and extrinsic pathways in IBV-infected HD11 cells. Additionally, ammonium chloride (NH₄Cl) pretreated HD11 cells blocked IBV from entering cells and inhibited IBV-induced apoptosis. UV-inactivated IBV also lost the ability of apoptosis induction. IBV replication was increased by blocking caspase activation. This study presents a chicken macrophage cell line that will enable further analysis of IBV infection and offers novel insights into the mechanisms of IBV-induced apoptosis in immune cells. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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1975 KiB

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Upregulation of miRNA-4776 in Influenza Virus Infected Bronchial Epithelial Cells Is Associated with Downregulation of NFKBIB and Increased Viral Survival

by Sreekumar Othumpangat, Nicole B. Bryan, Donald H. Beezhold and John D. Noti

Viruses 2017, 9(5), 94; https://doi.org/10.3390/v9050094 - 27 Apr 2017

Cited by 28 | Viewed by 5476

Abstract

Influenza A virus (IAV) infection remains a significant cause of morbidity and mortality worldwide. One key transcription factor that is activated upon IAV infection is nuclear factor Kappa B (NF-κB). NF-κB regulation involves the inhibitor proteins NF-κB inhibitor beta (NFKBIB), (also known as IκB β), which form complexes with NF-κB to sequester it in the cytoplasm. In this study, microarray data showed differential expression of several microRNAs (miRNAs) on exposure to IAV. Target scan analysis revealed that miR-4776, miR-4514 and miR-4742 potentially target NFKBIB messenger RNA (mRNA). Time-course analysis of primary bronchial epithelial cells (HBEpCs) showed that miR-4776 expression is increased within 1 h of infection, followed by its downregulation 4 h post-exposure to IAV. NFKBIB upregulation of miR-4776 correlated with a decrease in NFKBIB expression within 1 h of infection and a subsequent increase in NFKBIB expression 4 h post-infection. In addition, miRNA ago-immunoprecipitation studies and the three prime untranslated region (3’ UTR) luciferase assay confirmed that miR-4776 targets NFKBIB mRNA. Furthermore, uninfected HBEpCs transfected with miR-4776 mimic showed decreased expression of NFKBIB mRNA. Overexpression of NFKBIB protein in IAV infected cells led to lower levels of IAV. Taken together, our data suggest that miRNA-4776 modulates IAV production in infected cells through NFKBIB expression, possibly through the modulation of NF-κB. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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Review

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Open AccessReview

EBV and Apoptosis: The Viral Master Regulator of Cell Fate?

by Leah Fitzsimmons and Gemma L. Kelly

Viruses 2017, 9(11), 339; https://doi.org/10.3390/v9110339 - 13 Nov 2017

Cited by 57 | Viewed by 10850

Abstract

Epstein–Barr virus (EBV) was first discovered in cells from a patient with Burkitt lymphoma (BL), and is now known to be a contributory factor in 1–2% of all cancers, for which there are as yet, no EBV-targeted therapies available. Like other herpesviruses, EBV adopts a persistent latent infection in vivo and only rarely reactivates into replicative lytic cycle. Although latency is associated with restricted patterns of gene expression, genes are never expressed in isolation; always in groups. Here, we discuss (1) the ways in which the latent genes of EBV are known to modulate cell death, (2) how these mechanisms relate to growth transformation and lymphomagenesis, and (3) how EBV genes cooperate to coordinately regulate key cell death pathways in BL and lymphoblastoid cell lines (LCLs). Since manipulation of the cell death machinery is critical in EBV pathogenesis, understanding the mechanisms that underpin EBV regulation of apoptosis therefore provides opportunities for novel therapeutic interventions. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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Open AccessReview

Virus Infection and Death Receptor-Mediated Apoptosis

by Xingchen Zhou, Wenbo Jiang, Zhongshun Liu, Shuai Liu and Xiaozhen Liang

Viruses 2017, 9(11), 316; https://doi.org/10.3390/v9110316 - 27 Oct 2017

Cited by 124 | Viewed by 9633

Abstract

Virus infection can trigger extrinsic apoptosis. Cell-surface death receptors of the tumor necrosis factor family mediate this process. They either assist persistent viral infection or elicit the elimination of infected cells by the host. Death receptor-mediated apoptosis plays an important role in viral pathogenesis and the host antiviral response. Many viruses have acquired the capability to subvert death receptor-mediated apoptosis and evade the host immune response, mainly by virally encoded gene products that suppress death receptor-mediated apoptosis. In this review, we summarize the current information on virus infection and death receptor-mediated apoptosis, particularly focusing on the viral proteins that modulate death receptor-mediated apoptosis. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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1749 KiB

Open AccessReview

The Bcl-2 Family in Host-Virus Interactions

by Marc Kvansakul, Sofia Caria and Mark G. Hinds

Viruses 2017, 9(10), 290; https://doi.org/10.3390/v9100290 - 06 Oct 2017

Cited by 85 | Viewed by 9454

Abstract

Members of the B cell lymphoma-2 (Bcl-2) family are pivotal arbiters of mitochondrially mediated apoptosis, a process of fundamental importance during tissue development, homeostasis, and disease. At the structural and mechanistic level, the mammalian members of the Bcl-2 family are increasingly well understood, with their interplay ultimately deciding the fate of a cell. Dysregulation of Bcl-2-mediated apoptosis underlies a plethora of diseases, and numerous viruses have acquired homologs of Bcl-2 to subvert host cell apoptosis and autophagy to prevent premature death of an infected cell. Here we review the structural biology, interactions, and mechanisms of action of virus-encoded Bcl-2 proteins, and how they impact on host-virus interactions to ultimately enable successful establishment and propagation of viral infections. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus

by Wolfram Brune and Christopher E. Andoniou

Viruses 2017, 9(9), 249; https://doi.org/10.3390/v9090249 - 02 Sep 2017

Cited by 55 | Viewed by 8625

Abstract

Multicellular organisms have evolved multiple genetically programmed cell death pathways that are essential for homeostasis. The finding that many viruses encode cell death inhibitors suggested that cellular suicide also functions as a first line of defence against invading pathogens. This theory was confirmed by studying viral mutants that lack certain cell death inhibitors. Cytomegaloviruses, a family of species-specific viruses, have proved particularly useful in this respect. Cytomegaloviruses are known to encode multiple death inhibitors that are required for efficient viral replication. Here, we outline the mechanisms used by the host cell to detect cytomegalovirus infection and discuss the methods employed by the cytomegalovirus family to prevent death of the host cell. In addition to enhancing our understanding of cytomegalovirus pathogenesis we detail how this research has provided significant insights into the cross-talk that exists between the various cell death pathways. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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Regulation of Apoptosis during Flavivirus Infection

by Toru Okamoto, Tatsuya Suzuki, Shinji Kusakabe, Makoto Tokunaga, Junki Hirano, Yuka Miyata and Yoshiharu Matsuura

Viruses 2017, 9(9), 243; https://doi.org/10.3390/v9090243 - 28 Aug 2017

Cited by 58 | Viewed by 10589

Abstract

Apoptosis is a type of programmed cell death that regulates cellular homeostasis by removing damaged or unnecessary cells. Its importance in host defenses is highlighted by the observation that many viruses evade, obstruct, or subvert apoptosis, thereby blunting the host immune response. Infection with Flaviviruses such as Japanese encephalitis virus (JEV), Dengue virus (DENV) and West Nile virus (WNV) has been shown to activate several signaling pathways such as endoplasmic reticulum (ER)-stress and AKT/PI3K pathway, resulting in activation or suppression of apoptosis in virus-infected cells. On the other hands, expression of some viral proteins induces or protects apoptosis. There is a discrepancy between induction and suppression of apoptosis during flavivirus infection because the experimental situation may be different, and strong links between apoptosis and other types of cell death such as necrosis may make it more difficult. In this paper, we review the effects of apoptosis on viral propagation and pathogenesis during infection with flaviviruses. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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Investigations of Pro- and Anti-Apoptotic Factors Affecting African Swine Fever Virus Replication and Pathogenesis

by Linda K. Dixon, Pedro J. Sánchez-Cordón, Inmaculada Galindo and Covadonga Alonso

Viruses 2017, 9(9), 241; https://doi.org/10.3390/v9090241 - 25 Aug 2017

Cited by 46 | Viewed by 10663

Abstract

African swine fever virus (ASFV) is a large DNA virus that replicates predominantly in the cell cytoplasm and is the only member of the Asfarviridae family. The virus causes an acute haemorrhagic fever, African swine fever (ASF), in domestic pigs and wild boar resulting in the death of most infected animals. Apoptosis is induced at an early stage during virus entry or uncoating. However, ASFV encodes anti-apoptotic proteins which facilitate production of progeny virions. These anti-apoptotic proteins include A179L, a Bcl-2 family member; A224L, an inhibitor of apoptosis proteins (IAP) family member; EP153R a C-type lectin; and DP71L. The latter acts by inhibiting activation of the stress activated pro-apoptotic pathways pro-apoptotic pathways. The mechanisms by which these proteins act is summarised. ASF disease is characterised by massive apoptosis of uninfected lymphocytes which reduces the effectiveness of the immune response, contributing to virus pathogenesis. Mechanisms by which this apoptosis is induced are discussed. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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Host and Viral Factors in HIV-Mediated Bystander Apoptosis

by Himanshu Garg and Anjali Joshi

Viruses 2017, 9(8), 237; https://doi.org/10.3390/v9080237 - 22 Aug 2017

Cited by 27 | Viewed by 5825

Abstract

Human immunodeficiency virus (HIV) infections lead to a progressive loss of CD4 T cells primarily via the process of apoptosis. With a limited number of infected cells and vastly disproportionate apoptosis in HIV infected patients, it is believed that apoptosis of uninfected bystander cells plays a significant role in this process. Disease progression in HIV infected individuals is highly variable suggesting that both host and viral factors may influence HIV mediated apoptosis. Amongst the viral factors, the role of Envelope (Env) glycoprotein in bystander apoptosis is well documented. Recent evidence on the variability in apoptosis induction by primary patient derived Envs underscores the role of Env glycoprotein in HIV disease. Amongst the host factors, the role of C-C Chemokine Receptor type 5 (CCR5), a coreceptor for HIV Env, is also becoming increasingly evident. Polymorphisms in the CCR5 gene and promoter affect CCR5 cell surface expression and correlate with both apoptosis and CD4 loss. Finally, chronic immune activation in HIV infections induces multiple defects in the immune system and has recently been shown to accelerate HIV Env mediated CD4 apoptosis. Consequently, those factors that affect CCR5 expression and/or immune activation in turn indirectly regulate HIV mediated apoptosis making this phenomenon both complex and multifactorial. This review explores the complex role of various host and viral factors in determining HIV mediated bystander apoptosis. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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Interference of Apoptosis by Hepatitis B Virus

by Shaoli Lin and Yan-Jin Zhang

Viruses 2017, 9(8), 230; https://doi.org/10.3390/v9080230 - 18 Aug 2017

Cited by 37 | Viewed by 10829

Abstract

Hepatitis B virus (HBV) causes liver diseases that have been a consistent problem for human health, leading to more than one million deaths every year worldwide. A large proportion of hepatocellular carcinoma (HCC) cases across the world are closely associated with chronic HBV infection. Apoptosis is a programmed cell death and is frequently altered in cancer development. HBV infection interferes with the apoptosis signaling to promote HCC progression and viral proliferation. The HBV-mediated alteration of apoptosis is achieved via interference with cellular signaling pathways and regulation of epigenetics. HBV X protein (HBX) plays a major role in the interference of apoptosis. There are conflicting reports on the HBV interference of apoptosis with the majority showing inhibition of and the rest reporting induction of apoptosis. In this review, we described recent studies on the mechanisms of the HBV interference with the apoptosis signaling during the virus infection and provided perspective. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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Influenza Virus Infection, Interferon Response, Viral Counter-Response, and Apoptosis

by Jung Min Shim, Jinhee Kim, Tanel Tenson, Ji-Young Min and Denis E. Kainov

Viruses 2017, 9(8), 223; https://doi.org/10.3390/v9080223 - 12 Aug 2017

Cited by 90 | Viewed by 12480

Abstract

Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here, we describe how IAV infection triggers cellular apoptosis and how this process can be exploited towards the development of new therapeutics, which might be more effective than the currently available anti-influenza drugs. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis

by Daniel Brian Nichols, William De Martini and Jessica Cottrell

Viruses 2017, 9(8), 215; https://doi.org/10.3390/v9080215 - 08 Aug 2017

Cited by 44 | Viewed by 9049

Abstract

Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: Orthopoxvirus, Molluscipoxvirus, and Leporipoxvirus. All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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