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  1. Article: Epigenetic Lens to Visualize the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Infection in COVID-19 Pandemic.

    Saksena, Nitin / Bonam, Srinivasa Reddy / Miranda-Saksena, Monica

    Frontiers in genetics

    2021  Volume 12, Page(s) 581726

    Abstract: In <20 years, we have witnessed three different epidemics with coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2 in human populations, causing widespread mortality. SARS-CoV-2, through its rapid global spread, has led to the pandemic that we call COVID- ... ...

    Abstract In <20 years, we have witnessed three different epidemics with coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2 in human populations, causing widespread mortality. SARS-CoV-2, through its rapid global spread, has led to the pandemic that we call COVID-19. As of February 1, 2021, the global infections linked to SARS-CoV-2 stand at 103,503,340, with 2,236,960 deaths, and 75,108,099 recoveries. This review attempts to highlight host-pathogen interaction with particular emphasis on the role of epigenetic machinery in regulating the disease. Although researchers, since the start of the pandemic, have been intensely engaged in diverse areas to understand the mechanisms involved in SARS-CoV-2 infection to find answers that can bring about innovative ways to swiftly treat and prevent disease progression, this review provides an overview on how the host epigenetics is modulated and subverted by SARS-CoV-2 to enter the host cells and drive immunopathogenesis. Epigenetics is the study that combines genetic and non-genetic factors controlling phenotypic variation, which are primarily a consequence of external and environmental stimuli. These stimuli alter the activity of a gene without impinging on the DNA code. In viral-host interactions, DNA/RNA methylation, non-coding RNAs, chromatin remodeling, and histone modifications are known to regulate and modulate host gene expression patterns. Viruses such as Coronaviruses (an RNA virus) show intrinsic association with these processes. They have evolved the ability to tamper with host epigenetic machinery to interfere with immune sensing pathways to evade host immune response, thereby enhancing its replication and pathogenesis post-entry. These epigenetic alterations allow the virus to weaken the host's immune response to successfully spread infection. How this occurs, and what epigenetic mechanisms are altered is poorly understood both for coronaviruses and other respiratory RNA viruses. The review highlights several cutting-edge aspects of epigenetic work primarily pertinent to SARS-CoV-2, which has been published between 2019 and 2020 to showcase the current knowledge both in terms of success and failures and take lessons that will assist us in understanding the disease to develop better treatments suited to kill SARS-CoV-2.
    Language English
    Publishing date 2021-03-22
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606823-0
    ISSN 1664-8021
    ISSN 1664-8021
    DOI 10.3389/fgene.2021.581726
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Herpes Simplex Virus Type 1 Interactions with the Interferon System.

    Danastas, Kevin / Miranda-Saksena, Monica / Cunningham, Anthony L

    International journal of molecular sciences

    2020  Volume 21, Issue 14

    Abstract: The interferon (IFN) system is one of the first lines of defense activated against invading viral pathogens. Upon secretion, IFNs activate a signaling cascade resulting in the production of several interferon stimulated genes (ISGs), which work to limit ... ...

    Abstract The interferon (IFN) system is one of the first lines of defense activated against invading viral pathogens. Upon secretion, IFNs activate a signaling cascade resulting in the production of several interferon stimulated genes (ISGs), which work to limit viral replication and establish an overall anti-viral state. Herpes simplex virus type 1 is a ubiquitous human pathogen that has evolved to downregulate the IFN response and establish lifelong latent infection in sensory neurons of the host. This review will focus on the mechanisms by which the host innate immune system detects invading HSV-1 virions, the subsequent IFN response generated to limit viral infection, and the evasion strategies developed by HSV-1 to evade the immune system and establish latency in the host.
    MeSH term(s) Animals ; Herpes Simplex/immunology ; Herpesvirus 1, Human/genetics ; Herpesvirus 1, Human/metabolism ; Herpesvirus 1, Human/pathogenicity ; Host-Pathogen Interactions/immunology ; Humans ; Immunity, Innate ; Interferons/metabolism ; Signal Transduction/genetics ; Signal Transduction/immunology ; Toll-Like Receptors/immunology ; Virus Replication/genetics
    Chemical Substances Toll-Like Receptors ; Interferons (9008-11-1)
    Language English
    Publishing date 2020-07-21
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21145150
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  3. Article ; Online: Herpes simplex virus-1 utilizes the host actin cytoskeleton for its release from axonal growth cones.

    Danastas, Kevin / Larsen, Ava / Jobson, Sophie / Guo, Gerry / Cunningham, Anthony L / Miranda-Saksena, Monica

    PLoS pathogens

    2022  Volume 18, Issue 1, Page(s) e1010264

    Abstract: Herpes simplex virus type 1 (HSV-1) has evolved mechanisms to exploit the host cytoskeleton during entry, replication and exit from cells. In this study, we determined the role of actin and the molecular motor proteins, myosin II and myosin V, in the ... ...

    Abstract Herpes simplex virus type 1 (HSV-1) has evolved mechanisms to exploit the host cytoskeleton during entry, replication and exit from cells. In this study, we determined the role of actin and the molecular motor proteins, myosin II and myosin V, in the transport and release of HSV-1 from axon termini, or growth cones. Using compartmentalized neuronal devices, we showed that inhibition of actin polymerization, but not actin branching, significantly reduced the release of HSV-1 from axons. Furthermore, we showed that inhibition of myosin V, but not myosin II, also significantly reduced the release of HSV-1 from axons. Using confocal and electron microscopy, we determined that viral components are transported along axons to growth cones, despite actin or myosin inhibition. Overall, our study supports the role of actin in virus release from axonal growth cones and suggests myosin V as a likely candidate involved in this process.
    MeSH term(s) Actin Cytoskeleton/virology ; Animals ; Axonal Transport/physiology ; Growth Cones/ultrastructure ; Growth Cones/virology ; Herpes Simplex/virology ; Herpesvirus 1, Human ; Rats ; Rats, Wistar ; Virus Release/physiology
    Language English
    Publishing date 2022-01-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1010264
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  4. Article ; Online: Interferon inhibits the release of herpes simplex virus-1 from the axons of sensory neurons.

    Danastas, Kevin / Guo, Gerry / Merjane, Jessica / Hong, Nathan / Larsen, Ava / Miranda-Saksena, Monica / Cunningham, Anthony L

    mBio

    2023  Volume 14, Issue 5, Page(s) e0181823

    Abstract: Importance: Herpes simplex virus-1 (HSV-1) is a human pathogen known to cause cold sores and genital herpes. HSV-1 establishes lifelong infections in our sensory neurons, with no cure or vaccine available. HSV-1 can reactivate sporadically and travel ... ...

    Abstract Importance: Herpes simplex virus-1 (HSV-1) is a human pathogen known to cause cold sores and genital herpes. HSV-1 establishes lifelong infections in our sensory neurons, with no cure or vaccine available. HSV-1 can reactivate sporadically and travel back along sensory nerves, where it can form lesions in the oral and genital mucosa, eye, and skin, or be shed asymptomatically. New treatment options are needed as resistance is emerging to current antiviral therapies. Here, we show that interferons (IFNs) are capable of blocking virus release from nerve endings, potentially stopping HSV-1 transmission into the skin. Furthermore, we show that IFNγ has the potential to have widespread antiviral effects in the neuron and may have additional effects on HSV-1 reactivation. Together, this study identifies new targets for the development of immunotherapies to stop the spread of HSV-1 from the nerves into the skin.
    MeSH term(s) Humans ; Herpesvirus 1, Human/physiology ; Interferons ; Sensory Receptor Cells/pathology ; Axons/pathology ; Antiviral Agents ; Herpes Simplex
    Chemical Substances Interferons (9008-11-1) ; Antiviral Agents
    Language English
    Publishing date 2023-09-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.01818-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: SARS-CoV-2 variants, its recombinants and epigenomic exploitation of host defenses.

    Saksena, Nitin K / Reddy, Srinivasa Bonam / Miranda-Saksena, Monica / Cardoso, Thyago H S / Silva, Edson M A / Ferreira, Juliana C / Rabeh, Wael M

    Biochimica et biophysica acta. Molecular basis of disease

    2023  Volume 1869, Issue 8, Page(s) 166836

    Abstract: Since 2003, we have seen the emergence of novel viruses, such as SARS-CoV-1, MERS, ZIKA, swine flu virus H1N1, Marburg, Monkeypox, Ebola, and SARS-CoV-2, but none of them gained pandemic proportions similar to SARS-CoV-2. This could be attributed to ... ...

    Abstract Since 2003, we have seen the emergence of novel viruses, such as SARS-CoV-1, MERS, ZIKA, swine flu virus H1N1, Marburg, Monkeypox, Ebola, and SARS-CoV-2, but none of them gained pandemic proportions similar to SARS-CoV-2. This could be attributed to unique viral traits, allowing its rapid global dissemination following its emergence in October 2019 in Wuhan, China, which appears to be primarily driven by the emergence of highly transmissible and virulent variants that also associate, in some cases, with severe disease and considerable mortality caused by fatal pneumonia, acute respiratory distress syndrome (ARDS) in infected individuals. Mechanistically, several factors are involved in viral pathogenesis, and epigenetic alterations take the front seat in host-virus interactions. The molecular basis of all viral infections, including SARS-CoV-2, tightly hinges on the transitory silencing of the host gene machinery via epigenetic modulation. SARS-CoV-2 also hijacks and subdues the host gene machinery, leading to epigenetic modulation of the critical host elements responsible for antiviral immunity. Epigenomics is a powerful, unexplored avenue that can provide a profound understanding of virus-host interactions and lead to the development of epigenome-based therapies and vaccines to counter viruses. This review discusses current developments in SARS-CoV-2 variation and its role in epigenetic modulation in infected hosts. This review provides an overview, especially in the context of emerging viral strains, their recombinants, and their possible roles in the epigenetic exploitation of host defense and viral pathogenesis. It provides insights into host-virus interactions at the molecular, genomic, and immunological levels and sheds light on the future of epigenomics-based therapies for SARS-CoV-2 infection.
    MeSH term(s) Humans ; SARS-CoV-2/genetics ; COVID-19/genetics ; Epigenomics ; Influenza A Virus, H1N1 Subtype ; Zika Virus ; Zika Virus Infection
    Language English
    Publishing date 2023-08-05
    Publishing country Netherlands
    Document type Review ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 60-7
    ISSN 1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbadis.2023.166836
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Preparation of Herpes Simplex Virus-Infected Primary Neurons for Transmission Electron Microscopy.

    Miranda-Saksena, Monica / Boadle, Ross A / Cunningham, Anthony L

    Methods in molecular biology (Clifton, N.J.)

    2019  Volume 2060, Page(s) 343–354

    Abstract: Transmission electron microscopy (TEM) provides the resolution necessary to identify both viruses and subcellular components of cells infected with many types of viruses, including herpes simplex virus. Recognized as a powerful tool in both diagnostic ... ...

    Abstract Transmission electron microscopy (TEM) provides the resolution necessary to identify both viruses and subcellular components of cells infected with many types of viruses, including herpes simplex virus. Recognized as a powerful tool in both diagnostic and research-based virology laboratories, TEM has made possible the identification of new viruses and has contributed to the elucidation of virus life cycle and virus-host cell interaction.While there are many sample preparation techniques for TEM, conventional processing using chemical fixation and resin embedding remains a useful technique, available in virtually all EM laboratories, for studying virus/cell ultrastructure. In this chapter, we describe the preparation of herpes simplex virus infected primary neurons, grown on plastic coverslips, to allow for sectioning of neurons and axons in their growth plane. This technique allows for TEM examination of cell bodies, axons, growth cones and varicosities, providing powerful insights into virus-cell interaction.
    MeSH term(s) Herpes Simplex/metabolism ; Herpes Simplex/pathology ; Herpesvirus 1, Human/metabolism ; Herpesvirus 1, Human/ultrastructure ; Humans ; Microscopy, Electron, Transmission ; Neurons/metabolism ; Neurons/ultrastructure ; Neurons/virology
    Language English
    Publishing date 2019-10-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-9814-2_20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: The Use of Microfluidic Neuronal Devices to Study the Anterograde Axonal Transport of Herpes Simplex Virus-1.

    Danastas, Kevin / Cunningham, Anthony L / Miranda-Saksena, Monica

    Methods in molecular biology (Clifton, N.J.)

    2019  Volume 2060, Page(s) 409–418

    Abstract: Understanding how herpes simplex virus-1 (HSV-1) interacts with different parts of the neuron is fundamental in understanding the mechanisms behind HSV-1 transport during primary and recurrent infections. In this chapter, we describe a unique neuronal ... ...

    Abstract Understanding how herpes simplex virus-1 (HSV-1) interacts with different parts of the neuron is fundamental in understanding the mechanisms behind HSV-1 transport during primary and recurrent infections. In this chapter, we describe a unique neuronal culture system that is capable of compartmentalizing neuronal cell bodies from their axons to study the transport of HSV-1 along axons. The ability to separate neuronal cell bodies and axons provides a unique model to investigate the mechanisms used by HSV-1 for viral transport, assembly, and exit from different parts of the neuron.
    MeSH term(s) Animals ; Axonal Transport ; Axons/metabolism ; Axons/pathology ; Axons/virology ; Ganglia, Spinal/metabolism ; Ganglia, Spinal/pathology ; Ganglia, Spinal/virology ; Herpesvirus 1, Human/metabolism ; Lab-On-A-Chip Devices ; Microfluidic Analytical Techniques ; Rats ; Rats, Wistar
    Language English
    Publishing date 2019-10-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-9814-2_25
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  8. Article ; Online: Transmission Immunoelectron Microscopy of Herpes Simplex Virus-1-Infected Dorsal Root Ganglia Neurons Sectioned in Growth Plane.

    Miranda-Saksena, Monica / Boadle, Ross A / Cunningham, Anthony L

    Methods in molecular biology (Clifton, N.J.)

    2019  Volume 2060, Page(s) 355–364

    Abstract: Transmission immunoelectron microscopy allows for the ultrastructural detection and localization of herpes simplex virus-1 (HSV-1) particles and viral proteins within the infected cell and their relation to the cell cytoskeleton, cellular proteins, ... ...

    Abstract Transmission immunoelectron microscopy allows for the ultrastructural detection and localization of herpes simplex virus-1 (HSV-1) particles and viral proteins within the infected cell and their relation to the cell cytoskeleton, cellular proteins, vesicles, membranes, and organelles. For the successful application of immunoelectron microscopy, preservation of cell ultrastructure and of epitope antigenicity is essential during sample preparation. This chapter describes the use of chemical fixation followed by rapid cooling of HSV-1 infected sensory neurons in the presence of sucrose as a cryoprotectant to achieve optimal preservation of cell morphology and the use of freeze substitution and resin polymerization at low temperatures for preservation of protein antigenicity. In order to examine HSV-1 infection in the specialized compartments of the neurons (cell body, axons, and growth cones), neurons cultured on plastic coverslips are flat embedded prior to resin polymerization. Overall, this method allows for the ultrathin sectioning and immunogold labeling of the neurons and their axons in growth plane.
    MeSH term(s) Animals ; Chickens ; Ganglia, Spinal/metabolism ; Ganglia, Spinal/ultrastructure ; Ganglia, Spinal/virology ; Herpes Simplex/metabolism ; Herpes Simplex/pathology ; Herpes Simplex/virology ; Herpesvirus 1, Human/metabolism ; Herpesvirus 1, Human/ultrastructure ; Humans ; Mice ; Microscopy, Electron, Transmission ; Microscopy, Immunoelectron ; Neurons/metabolism ; Neurons/ultrastructure ; Neurons/virology ; Rats
    Language English
    Publishing date 2019-10-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-9814-2_21
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: A putative WAVE regulatory complex (WRC) interacting receptor sequence (WIRS) in the cytoplasmic tail of HSV-1 gE does not function in WRC recruitment or neuronal transport.

    Denes, Christopher E / Newsome, Timothy P / Miranda-Saksena, Monica / Cunningham, Anthony L / Diefenbach, Russell J

    Access microbiology

    2021  Volume 3, Issue 3, Page(s) 206

    Abstract: HSV-1 envelope glycoprotein E (gE) is important for viral egress and cell-to-cell spread but the host protein(s) involved in these functions have yet to be determined. We aimed to investigate a role for the Arp2/3 complex and actin regulation in viral ... ...

    Abstract HSV-1 envelope glycoprotein E (gE) is important for viral egress and cell-to-cell spread but the host protein(s) involved in these functions have yet to be determined. We aimed to investigate a role for the Arp2/3 complex and actin regulation in viral egress based on the identification of a WAVE Regulatory Complex (WRC) Interacting Receptor Sequence (WIRS) in the cytoplasmic tail (CT) of gE. A WIRS-dependent interaction between the gE(CT) and subunits of the WRC was demonstrated by GST-pulldown assay and a role for the Arp2/3 complex in cell-to-cell spread was also observed by plaque assay. Subsequent study of a recombinant HSV-1 gE WIRS-mutant found no significant changes to viral production and release based on growth kinetics studies, or changes to plaque and comet size in various cell types, suggesting no function for the motif in cell-to-cell spread. GFP-Trap pulldown and proximity ligation assays were unable to confirm a WIRS-dependent interaction between gE and the WRC in human cell lines though the WIRS-independent interaction observed
    Language English
    Publishing date 2021-03-04
    Publishing country England
    Document type Journal Article
    ISSN 2516-8290
    ISSN (online) 2516-8290
    DOI 10.1099/acmi.0.000206
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Identifying HSV-1 Inhibitors from Natural Compounds via Virtual Screening Targeting Surface Glycoprotein D.

    Wu, Jiadai / Power, Helen / Miranda-Saksena, Monica / Valtchev, Peter / Schindeler, Aaron / Cunningham, Anthony L / Dehghani, Fariba

    Pharmaceuticals (Basel, Switzerland)

    2022  Volume 15, Issue 3

    Abstract: Herpes simplex virus (HSV) infections are a worldwide health problem in need of new effective treatments. Of particular interest is the identification of antiviral agents that act via different mechanisms compared to current drugs, as these could ... ...

    Abstract Herpes simplex virus (HSV) infections are a worldwide health problem in need of new effective treatments. Of particular interest is the identification of antiviral agents that act via different mechanisms compared to current drugs, as these could interact synergistically with first-line antiherpetic agents to accelerate the resolution of HSV-1-associated lesions. For this study, we applied a structure-based molecular docking approach targeting the nectin-1 and herpesvirus entry mediator (HVEM) binding interfaces of the viral glycoprotein D (gD). More than 527,000 natural compounds were virtually screened using Autodock Vina and then filtered for favorable ADMET profiles. Eight top hits were evaluated experimentally in African green monkey kidney cell line (VERO) cells, which yielded two compounds with potential antiherpetic activity. One active compound (1-(1-benzofuran-2-yl)-2-[(5Z)-2H,6H,7H,8H-[1,3] dioxolo[4,5-g]isoquinoline-5-ylidene]ethenone) showed weak but significant antiviral activity. Although less potent than antiherpetic agents, such as acyclovir, it acted at the viral inactivation stage in a dose-dependent manner, suggesting a novel mode of action. These results highlight the feasibility of in silico approaches for identifying new antiviral compounds, which may be further optimized by medicinal chemistry approaches.
    Language English
    Publishing date 2022-03-16
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph15030361
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