Poxviral Strategies to Overcome Host Cell Apoptosis

Apoptosis is a form of cellular suicide initiated either via extracellular (extrinsic apoptosis) or intracellular (intrinsic apoptosis) cues. This form of programmed cell death plays a crucial role in development and tissue homeostasis in multicellular organisms and its dysregulation is an underlying cause for many diseases. Intrinsic apoptosis is regulated by members of the evolutionarily conserved B-cell lymphoma-2 (Bcl-2) family, a family that consists of pro- and anti-apoptotic members. Bcl-2 genes have also been assimilated by numerous viruses including pox viruses, in particular the sub-family of chordopoxviridae, a group of viruses known to infect almost all vertebrates. The viral Bcl-2 proteins are virulence factors and aid the evasion of host immune defenses by mimicking the activity of their cellular counterparts. Viral Bcl-2 genes have proved essential for the survival of virus infected cells and structural studies have shown that though they often share very little sequence identity with their cellular counterparts, they have near-identical 3D structures. However, their mechanisms of action are varied. In this review, we examine the structural biology, molecular interactions, and detailed mechanism of action of poxvirus encoded apoptosis inhibitors and how they impact on host–virus interactions to ultimately enable successful infection and propagation of viral infections.

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Crystal structures of the sheeppoxvirus encoded inhibitor of apoptosis SPPV14 bound to Hrk and Bax BH3 peptides

10.1101/2020.03.10.986331 ◽

2020 ◽

Cited By ~ 1

Author(s):

Chathura D. Suraweera ◽

Denis R. Burton ◽

Mark G. Hinds ◽

Marc Kvansakul

Keyword(s):

Crystal Structures ◽

Viral Infections ◽

Structural Basis ◽

Ionic Interaction ◽

Apoptosis Inhibition ◽

Programmed Death ◽

Infected Cells ◽

Binding Groove ◽

Almost All ◽

Multicellular Organisms

AbstractProgrammed death of infected cells is used by multicellular organisms to counter viral infections. Sheeppoxvirus encodes for SPPV14, a potent inhibitor of Bcl-2 mediated apoptosis. We reveal the structural basis of apoptosis inhibition by determining crystal structures of SPPV14 bound to BH3 motifs of proapoptotic Bax and Hrk. The structures show that SPPV14 engages BH3 peptides using the canonical ligand binding groove. Unexpectedly, Arg84 from SPPV14 forms an ionic interaction with the conserved Asp in the BH3 motif in a manner that replaces the canonical ionic interaction seen in almost all host Bcl-2:BH3 motif complexes. These results reveal the flexibility of virus encoded Bcl-2 proteins to mimic key interactions from endogenous host signalling pathways to retain BH3-binding and pro-survival functionality.

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Role of Mitochondria in Viral Infections

Life ◽

10.3390/life11030232 ◽

2021 ◽

Vol 11 (3) ◽

pp. 232

Author(s):

Srikanth Elesela ◽

Nicholas W. Lukacs

Keyword(s):

Viral Infections ◽

Mitochondrial Dynamics ◽

The Body ◽

Viral Diseases ◽

Multiple Organs ◽

Innate Immune Signaling ◽

Mitochondrial Functions ◽

Host Virus Interactions ◽

Virus Interactions

Viral diseases account for an increasing proportion of deaths worldwide. Viruses maneuver host cell machinery in an attempt to subvert the intracellular environment favorable for their replication. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections. Viruses affect mitochondrial functions and impact mitochondrial metabolism, and innate immune signaling. Resurgence of host-virus interactions in recent literature emphasizes the key role of mitochondria and host metabolism on viral life processes. Mitochondrial dysfunction leads to damage of mitochondria that generate toxic compounds, importantly mitochondrial DNA, inducing systemic toxicity, leading to damage of multiple organs in the body. Mitochondrial dynamics and mitophagy are essential for the maintenance of mitochondrial quality control and homeostasis. Therefore, metabolic antagonists may be essential to gain a better understanding of viral diseases and develop effective antiviral therapeutics. This review briefly discusses how viruses exploit mitochondrial dynamics for virus proliferation and induce associated diseases.

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Alternative Experimental Models for Studying Influenza Proteins, Host–Virus Interactions and Anti-Influenza Drugs

Pharmaceuticals ◽

10.3390/ph12040147 ◽

2019 ◽

Vol 12 (4) ◽

pp. 147 ◽

Cited By ~ 3

Author(s):

Sonja C. J. H. Chua ◽

Hui Qing Tan ◽

David Engelberg ◽

Lina H. K. Lim

Keyword(s):

Protein Function ◽

Viral Infections ◽

Experimental Models ◽

Host Proteins ◽

Physiological Basis ◽

Host Interactions ◽

Experimental Systems ◽

Host Virus Interactions ◽

Virus Interactions ◽

Unique Potential

Ninety years after the discovery of the virus causing the influenza disease, this malady remains one of the biggest public health threats to mankind. Currently available drugs and vaccines only partially reduce deaths and hospitalizations. Some of the reasons for this disturbing situation stem from the sophistication of the viral machinery, but another reason is the lack of a complete understanding of the molecular and physiological basis of viral infections and host–pathogen interactions. Even the functions of the influenza proteins, their mechanisms of action and interaction with host proteins have not been fully revealed. These questions have traditionally been studied in mammalian animal models, mainly ferrets and mice (as well as pigs and non-human primates) and in cell lines. Although obviously relevant as models to humans, these experimental systems are very complex and are not conveniently accessible to various genetic, molecular and biochemical approaches. The fact that influenza remains an unsolved problem, in combination with the limitations of the conventional experimental models, motivated increasing attempts to use the power of other models, such as low eukaryotes, including invertebrate, and primary cell cultures. In this review, we summarized the efforts to study influenza in yeast, Drosophila, zebrafish and primary human tissue cultures and the major contributions these studies have made toward a better understanding of the disease. We feel that these models are still under-utilized and we highlight the unique potential each model has for better comprehending virus–host interactions and viral protein function.

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Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection

10.1101/2020.11.25.398008 ◽

2020 ◽

Cited By ~ 1

Author(s):

Wael Kamel ◽

Marko Noerenberg ◽

Berati Cerikan ◽

Honglin Chen ◽

Aino I. Järvelin ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Metabolic Pathways ◽

Rna Binding ◽

Rna Binding Proteins ◽

Global Analysis ◽

Viral Proteins ◽

Antiviral Therapies ◽

Infected Cells ◽

Host Virus Interactions ◽

Virus Interactions

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control SARS-CoV-2 infection remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively which cellular and viral RBPs are involved in SARS-CoV-2 infection. We reveal that the cellular RNA-bound proteome is remodelled upon SARS-CoV-2 infection, having widespread effects on RNA metabolic pathways, non-canonical RBPs and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Amongst them, several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.

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The Multifarious Role of 14-3-3 Family of Proteins in Viral Replication

Viruses ◽

10.3390/v12040436 ◽

2020 ◽

Vol 12 (4) ◽

pp. 436 ◽

Cited By ~ 4

Author(s):

Kavitha Ganesan Nathan ◽

Sunil K. Lal

Keyword(s):

Protein Interactions ◽

Viral Infections ◽

Pharmaceutical Research ◽

Host Protein ◽

Dna Viruses ◽

Wide Range ◽

Host Virus Interactions ◽

Virus Interactions ◽

Rna And Dna

The 14-3-3 proteins are a family of ubiquitous and exclusively eukaryotic proteins with an astoundingly significant number of binding partners. Their binding alters the activity, stability, localization, and phosphorylation state of a target protein. The association of 14-3-3 proteins with the regulation of a wide range of general and specific signaling pathways suggests their crucial role in health and disease. Recent studies have linked 14-3-3 to several RNA and DNA viruses that may contribute to the pathogenesis and progression of infections. Therefore, comprehensive knowledge of host–virus interactions is vital for understanding the viral life cycle and developing effective therapeutic strategies. Moreover, pharmaceutical research is already moving towards targeting host proteins in the control of virus pathogenesis. As such, targeting the right host protein to interrupt host–virus interactions could be an effective therapeutic strategy. In this review, we generated a 14-3-3 protein interactions roadmap in viruses, using the freely available Virusmentha network, an online virus–virus or virus–host interaction tool. Furthermore, we summarize the role of the 14-3-3 family in RNA and DNA viruses. The participation of 14-3-3 in viral infections underlines its significance as a key regulator for the expression of host and viral proteins.

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Nudivirus Remnants in the Genomes of Arthropods

Genome Biology and Evolution ◽

10.1093/gbe/evaa074 ◽

2020 ◽

Vol 12 (5) ◽

pp. 578-588 ◽

Cited By ~ 1

Author(s):

Ruo-Lin Cheng ◽

Xiao-Feng Li ◽

Chuan-Xi Zhang

Keyword(s):

Viral Infections ◽

Phylogenetic Analyses ◽

Open Reading Frames ◽

Endogenous Viral Elements ◽

Host Virus Interactions ◽

Fossil Records ◽

Virus Interactions ◽

Flanking Regions ◽

Eukaryotic Genomes ◽

Reading Frames

Abstract Endogenous viral elements (EVEs), derived from all major types of viruses, have been discovered in many eukaryotic genomes, representing “fossil records” of past viral infections. The endogenization of nudiviruses has been reported in several insects, leading to the question of whether genomic integration is a common phenomenon for these viruses. In this study, genomic assemblies of insects and other arthropods were analyzed to identify endogenous sequences related to Nudiviridae. A total of 359 nudivirus-like genes were identified in 43 species belonging to different groups; however, none of these genes were detected in the known hosts of nudiviruses. A large proportion of the putative EVEs identified in this study encode intact open reading frames or are transcribed as mRNAs, suggesting that they result from recent endogenization of nudiviruses. Phylogenetic analyses of the identified EVEs and inspections of their flanking regions indicated that integration of nudiviruses has occurred recurrently during the evolution of arthropods. This is the first report of a comprehensive screening for nudivirus-derived EVEs in arthropod genomes. The results of this study demonstrated that a large variety of arthropods, especially hemipteran and hymenopteran insects, have previously been or are still infected by nudiviruses. These findings have greatly extended the host range of Nudiviridae and provide new insights into viral diversity, evolution, and host–virus interactions.

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To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Journal of General Virology ◽

10.1099/jgv.0.001341 ◽

2019 ◽

Vol 100 (12) ◽

pp. 1641-1662 ◽

Cited By ~ 12

Author(s):

Adam Hage ◽

Ricardo Rajsbaum

Keyword(s):

Innate Immunity ◽

Viral Replication ◽

Viral Infections ◽

Ubiquitin Ligases ◽

Innate Immune ◽

Future Research ◽

Post Translational Modifications ◽

Ubiquitin System ◽

Host Virus Interactions ◽

Virus Interactions

The innate immune system responds rapidly to protect against viral infections, but an overactive response can cause harmful damage. To avoid this, the response is tightly regulated by post-translational modifications (PTMs). The ubiquitin system represents a powerful PTM machinery that allows for the reversible linkage of ubiquitin to activate and deactivate a target’s function. A precise enzymatic cascade of ubiquitin-activating, conjugating and ligating enzymes facilitates ubiquitination. Viruses have evolved to take advantage of the ubiquitin pathway either by targeting factors to dampen the antiviral response or by hijacking the system to enhance their replication. The tripartite motif (TRIM) family of E3 ubiquitin ligases has garnered attention as a major contributor to innate immunity. Many TRIM family members limit viruses either indirectly as components in innate immune signalling, or directly by targeting viral proteins for degradation. In spite of this, TRIMs and other ubiquitin ligases can be appropriated by viruses and repurposed as valuable tools in viral replication. This duality of function suggests a new frontier of research for TRIMs and raises new challenges for discerning the subtleties of these pro-viral mechanisms. Here, we review current findings regarding the involvement of TRIMs in host–virus interactions. We examine ongoing developments in the field, including novel roles for unanchored ubiquitin in innate immunity, the direct involvement of ubiquitin ligases in promoting viral replication, recent controversies on the role of ubiquitin and TRIM25 in activation of the pattern recognition receptor RIG-I, and we discuss the implications these studies have on future research directions.

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Restriction of Retroviral Replication by Tetherin/BST-2

Molecular Biology International ◽

10.1155/2012/424768 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Jason Hammonds ◽

Jaang-Jiun Wang ◽

Paul Spearman

Keyword(s):

Restriction Factor ◽

Initial Report ◽

Host Restriction ◽

Host Restriction Factor ◽

Infected Cells ◽

Important Host ◽

Retroviral Replication ◽

Host Virus Interactions ◽

And Function ◽

Virus Interactions

Tetherin/BST-2 is an important host restriction factor that limits the replication of HIV and other enveloped viruses. Tetherin is a type II membrane glycoprotein with a very unusual domain structure that allows it to engage budding virions and retain them on the plasma membrane of infected cells. Following the initial report identifying tetherin as the host cell factor targeted by the HIV-1 Vpu gene, knowledge of the molecular, structural, and cellular biology of tetherin has rapidly advanced. This paper summarizes the discovery and impact of tetherin biology on the HIV field, with a focus on recent advances in understanding its structure and function. The relevance of tetherin to replication and spread of other retroviruses is also reviewed. Tetherin is a unique host restriction factor that is likely to continue to provide new insights into host-virus interactions and illustrates well the varied ways by which host organisms defend against viral pathogens.

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Gene expression profiling of monkeypox virus-infected cells reveals novel interfaces for host-virus interactions

Virology Journal ◽

10.1186/1743-422x-7-173 ◽

2010 ◽

Vol 7 (1) ◽

Cited By ~ 17

Author(s):

Abdulnaser Alkhalil ◽

Rasha Hammamieh ◽

Justin Hardick ◽

Mohamed Ait Ichou ◽

Marti Jett ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Monkeypox Virus ◽

Infected Cells ◽

Host Virus Interactions ◽

Virus Interactions

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Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

Viruses ◽

10.3390/v12080844 ◽

2020 ◽

Vol 12 (8) ◽

pp. 844 ◽

Cited By ~ 2

Author(s):

Frank W. Charlton ◽

Hayley M. Pearson ◽

Samantha Hover ◽

Jon D. Lippiat ◽

Juan Fontana ◽

...

Keyword(s):

Ion Channels ◽

Ion Channel ◽

Viral Infections ◽

Drug Repurposing ◽

Potential Contribution ◽

Future Perspectives ◽

Human Usage ◽

Ion Channel Blocking ◽

Almost All ◽

Virus Interactions

Ion channels play key roles in almost all facets of cellular physiology and have emerged as key host cell factors for a multitude of viral infections. A catalogue of ion channel-blocking drugs have been shown to possess antiviral activity, some of which are in widespread human usage for ion channel-related diseases, highlighting new potential for drug repurposing. The emergence of ion channel–virus interactions has also revealed the intriguing possibility that channelopathies may explain some commonly observed virus induced pathologies. This field is rapidly evolving and an up-to-date summary of new discoveries can inform future perspectives. We herein discuss the role of ion channels during viral lifecycles, describe the recently identified ion channel drugs that can inhibit viral infections, and highlight the potential contribution of ion channels to virus-mediated disease.

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