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Viruses
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Omics of Virus-Host Interactions
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Omics of Virus-Host Interactions

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 36714

Special Issue Editor

Dr. Kevin M. Coombs

E-Mail Website
Guest Editor
Department of Medical Microbiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Interests: virus–host interactions; anti-virals; molecular genetics; proteomics; macromolecular structure/function

Special Issue Information

Dear Colleagues,

Viruses are obligate intracellular parasites. Thus, they must enter host cells in order to usurp cellular functions to use for their own propagation and to cause disease, during which viral components must interact with cellular components. This often results in viruses causing enormous perturbations in cellular and organismal function. These intimate interactions between viral and cellular constituents lead to both the host and the pathogen influencing each other. Significant progress has been made during the past few decades thanks to advances in technologies, gene sequencing and bioinformatics, that now allow global analyses of thousands of genes and proteins. This has allowed the unprecedented analyses of changes that take place in both the virus and the cell as they interact with each other.

In this Special Issue of Viruses, we want to compile examples of the types of analyses and studies that contribute towards a better understanding of virus–host interactions. These include, but are not limited to, new observations regarding:

  • How viruses modify the cellular transcriptomic profile;
  • Quantitative cellular protein alterations induced by virus infections;
  • Global cellular protein modifications induced by virus infection, such as phosphorylation pattern alterations;
  • Analyses of which viral proteins interact with which cellular proteins;
  • Functional cellular protein alterations (e.g., activity-based protein profiling) induced by virus infection;
  • Alterations in cellular pathways (e.g., apoptosis, autophagy, immune, unfolded protein response) induced by virus infection;
  • Advances in technologies and in bioinformatics that contribute to better understanding virus–host interactions.

Dr. Kevin M Coombs
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • virus
  • cellular genes/proteins
  • transcriptomics
  • proteomics
  • interactomics
  • functional protein interactions
  • Systems Biology
  • bioinformatics

Published Papers (16 papers)

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26 pages, 31292 KiB  
Article
Chloride Intracellular Channel Protein 1 (CLIC1) Is a Critical Host Cellular Factor for Influenza A Virus Replication
by Mahamud-ur Rashid and Kevin M. Coombs
Viruses 2024, 16(1), 129; https://doi.org/10.3390/v16010129 - 16 Jan 2024
Viewed by 1444
Abstract
(1) Background: Influenza A Virus (IAV) uses host cellular proteins during replication in host cells. IAV infection causes elevated expression of chloride intracellular channel protein 1 (CLIC1) in lung epithelial cells, but the importance of this protein in IAV replication is unknown. (2) [...] Read more.
(1) Background: Influenza A Virus (IAV) uses host cellular proteins during replication in host cells. IAV infection causes elevated expression of chloride intracellular channel protein 1 (CLIC1) in lung epithelial cells, but the importance of this protein in IAV replication is unknown. (2) In this study, we determined the role of CLIC1 in IAV replication by investigating the effects of CLIC1 knockdown (KD) on IAV viral protein translation, genomic RNA transcription, and host cellular proteome dysregulation. (3) Results: CLIC1 KD in A549 human lung epithelial cells resulted in a significant decrease in progeny supernatant IAV, but virus protein expression was unaffected. However, a significantly larger number of viral RNAs accumulated in CLIC1 KD cells. Treatment with a CLIC1 inhibitor also caused a significant reduction in IAV replication, suggesting that CLIC1 is an important host factor in IAV replication. SomaScan®, which measures 1322 proteins, identified IAV-induced dysregulated proteins in wild-type cells and in CLIC1 KD cells. The expression of 116 and 149 proteins was significantly altered in wild-type and in CLIC1 KD cells, respectively. A large number of the dysregulated proteins in CLIC1 KD cells were associated with cellular transcription and predicted to be inhibited during IAV replication. (4) Conclusions: This study suggests that CLIC1 is involved in later stages of IAV replication. Further investigation should clarify mechanism(s) for the development of anti-IAV drugs targeting CLIC1 protein. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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23 pages, 6449 KiB  
Article
Specialized DNA Structures Act as Genomic Beacons for Integration by Evolutionarily Diverse Retroviruses
by Hinissan P. Kohio, Hannah O. Ajoge, Macon D. Coleman, Emmanuel Ndashimye, Richard M. Gibson, Eric J. Arts and Stephen D. Barr
Viruses 2023, 15(2), 465; https://doi.org/10.3390/v15020465 - 7 Feb 2023
Cited by 2 | Viewed by 1428
Abstract
Retroviral integration site targeting is not random and plays a critical role in expression and long-term survival of the integrated provirus. To better understand the genomic environment surrounding retroviral integration sites, we performed a meta-analysis of previously published integration site data from evolutionarily [...] Read more.
Retroviral integration site targeting is not random and plays a critical role in expression and long-term survival of the integrated provirus. To better understand the genomic environment surrounding retroviral integration sites, we performed a meta-analysis of previously published integration site data from evolutionarily diverse retroviruses, including new experimental data from HIV-1 subtypes A, B, C and D. We show here that evolutionarily divergent retroviruses exhibit distinct integration site profiles with strong preferences for integration near non-canonical B-form DNA (non-B DNA). We also show that in vivo-derived HIV-1 integration sites are significantly more enriched in transcriptionally silent regions and transcription-silencing non-B DNA features of the genome compared to in vitro-derived HIV-1 integration sites. Integration sites from individuals infected with HIV-1 subtype A, B, C or D viruses exhibited different preferences for common genomic and non-B DNA features. In addition, we identified several integration site hotspots shared between different HIV-1 subtypes, all of which were located in the non-B DNA feature slipped DNA. Together, these data show that although evolutionarily divergent retroviruses exhibit distinct integration site profiles, they all target non-B DNA for integration. These findings provide new insight into how retroviruses integrate into genomes for long-term survival. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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13 pages, 2665 KiB  
Article
The Landscape of Expressed Chimeric Transcripts in the Blood of Severe COVID-19 Infected Patients
by Sunanda Biswas Mukherjee, Rajesh Detroja, Sumit Mukherjee and Milana Frenkel-Morgenstern
Viruses 2023, 15(2), 433; https://doi.org/10.3390/v15020433 - 4 Feb 2023
Viewed by 1741
Abstract
The ongoing COVID-19 pandemic caused by SARS-CoV-2 infections has quickly developed into a global public health threat. COVID-19 patients show distinct clinical features, and in some cases, during the severe stage of the condition, the disease severity leads to an acute respiratory disorder. [...] Read more.
The ongoing COVID-19 pandemic caused by SARS-CoV-2 infections has quickly developed into a global public health threat. COVID-19 patients show distinct clinical features, and in some cases, during the severe stage of the condition, the disease severity leads to an acute respiratory disorder. In spite of several pieces of research in this area, the molecular mechanisms behind the development of disease severity are still not clearly understood. Recent studies demonstrated that SARS-CoV-2 alters the host cell splicing and transcriptional response to overcome the host immune response that provides the virus with favorable conditions to replicate efficiently within the host cells. In several disease conditions, aberrant splicing could lead to the development of novel chimeric transcripts that could promote the functional alternations of the cell. As severe SARS-CoV-2 infection was reported to cause abnormal splicing in the infected cells, we could expect the generation and expression of novel chimeric transcripts. However, no study so far has attempted to check whether novel chimeric transcripts are expressed in severe SARS-CoV-2 infections. In this study, we analyzed several publicly available blood transcriptome datasets of severe COVID-19, mild COVID-19, other severe respiratory viral infected patients, and healthy individuals. We identified 424 severe COVID-19 -specific chimeric transcripts, 42 of which were recurrent. Further, we detected 189 chimeric transcripts common to severe COVID-19 and multiple severe respiratory viral infections. Pathway and gene enrichment analysis of the parental genes of these two subsets of chimeric transcripts reveals that these are potentially involved in immune-related processes, interferon signaling, and inflammatory responses, which signify their potential association with immune dysfunction leading to the development of disease severity. Our study provides the first detailed expression landscape of chimeric transcripts in severe COVID-19 and other severe respiratory viral infections. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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23 pages, 3517 KiB  
Article
The HIV Restriction Factor Profile in the Brain Is Associated with the Clinical Status and Viral Quantities
by Nazanin Mohammadzadeh, Na Zhang, William G. Branton, Ouafa Zghidi-Abouzid, Eric A. Cohen, Benjamin B. Gelman, Jerome Estaquier, Linglong Kong and Christopher Power
Viruses 2023, 15(2), 316; https://doi.org/10.3390/v15020316 - 23 Jan 2023
Cited by 2 | Viewed by 1745
Abstract
HIV-encoded DNA, RNA and proteins persist in the brain despite effective antiretroviral therapy (ART), with undetectable plasma and cerebrospinal fluid viral RNA levels, often in association with neurocognitive impairments. Although the determinants of HIV persistence have garnered attention, the expression and regulation of [...] Read more.
HIV-encoded DNA, RNA and proteins persist in the brain despite effective antiretroviral therapy (ART), with undetectable plasma and cerebrospinal fluid viral RNA levels, often in association with neurocognitive impairments. Although the determinants of HIV persistence have garnered attention, the expression and regulation of antiretroviral host restriction factors (RFs) in the brain for HIV and SIV remain unknown. We investigated the transcriptomic profile of antiretroviral RF genes by RNA-sequencing with confirmation by qRT-PCR in the cerebral cortex of people who are uninfected (HIV[−]), those who are HIV-infected without pre-mortem brain disease (HIV[+]), those who are HIV-infected with neurocognitive disorders (HIV[+]/HAND) and those with neurocognitive disorders with encephalitis (HIV[+]/HIVE). We observed significant increases in RF expression in the brains of HIV[+]/HIVE in association with the brain viral load. Machine learning techniques identified MAN1B1 as a key gene that distinguished the HIV[+] group from the HIV[+] groups with HAND. Analyses of SIV-associated RFs in brains from SIV-infected Chinese rhesus macaques with different ART regimens revealed diminished RF expression among ART-exposed SIV-infected animals, although ART interruption resulted in an induced expression of several RF genes including OAS3, RNASEL, MX2 and MAN1B1. Thus, the brain displays a distinct expression profile of RFs that is associated with the neurological status as well as the brain viral burden. Moreover, ART interruption can influence the brain’s RF profile, which might contribute to disease outcomes. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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18 pages, 2084 KiB  
Article
A Counterintuitive Neutrophil-Mediated Pattern in COVID-19 Patients Revealed through Transcriptomics Analysis
by Melih Özbek, Halil Ibrahim Toy, Işil Takan, Seyedehsadaf Asfa, Reza Arshinchi Bonab, Gökhan Karakülah, Panagiota I. Kontou, Styliani A. Geronikolou and Athanasia Pavlopoulou
Viruses 2023, 15(1), 104; https://doi.org/10.3390/v15010104 - 30 Dec 2022
Cited by 1 | Viewed by 2206
Abstract
The COVID-19 pandemic has persisted for almost three years. However, the mechanisms linked to the SARS-CoV-2 effect on tissues and disease severity have not been fully elucidated. Since the onset of the pandemic, a plethora of high-throughput data related to the host transcriptional [...] Read more.
The COVID-19 pandemic has persisted for almost three years. However, the mechanisms linked to the SARS-CoV-2 effect on tissues and disease severity have not been fully elucidated. Since the onset of the pandemic, a plethora of high-throughput data related to the host transcriptional response to SARS-CoV-2 infections has been generated. To this end, the aim of this study was to assess the effect of SARS-CoV-2 infections on circulating and organ tissue immune responses. We profited from the publicly accessible gene expression data of the blood and soft tissues by employing an integrated computational methodology, including bioinformatics, machine learning, and natural language processing in the relevant transcriptomics data. COVID-19 pathophysiology and severity have mainly been associated with macrophage-elicited responses and a characteristic “cytokine storm”. Our counterintuitive findings suggested that the COVID-19 pathogenesis could also be mediated through neutrophil abundance and an exacerbated suppression of the immune system, leading eventually to uncontrolled viral dissemination and host cytotoxicity. The findings of this study elucidated new physiological functions of neutrophils, as well as tentative pathways to be explored in asymptomatic-, ethnicity- and locality-, or staging-associated studies. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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26 pages, 4851 KiB  
Article
HLA-A, HSPA5, IGFBP5 and PSMA2 Are Restriction Factors for Zika Virus Growth in Astrocytic Cells
by Affan A. Sher, Ying Tenny Lao and Kevin M. Coombs
Viruses 2023, 15(1), 97; https://doi.org/10.3390/v15010097 - 29 Dec 2022
Cited by 1 | Viewed by 2110
Abstract
(1) Background: Zika virus (ZIKV), an arbo-flavivirus, is transmitted via Aeges aegyptii mosquitoes Following its major outbreaks in 2013, 2014 and 2016, WHO declared it a Public Health Emergency of International Concern. Symptoms of ZIKV infection include acute fever, conjunctivitis, headache, muscle & [...] Read more.
(1) Background: Zika virus (ZIKV), an arbo-flavivirus, is transmitted via Aeges aegyptii mosquitoes Following its major outbreaks in 2013, 2014 and 2016, WHO declared it a Public Health Emergency of International Concern. Symptoms of ZIKV infection include acute fever, conjunctivitis, headache, muscle & joint pain and malaise. Cases of its transmission also have been reported via perinatal, sexual and transfusion transmission. ZIKV pathologies include meningo-encephalitis and myelitis in the central nervous system (CNS) and Guillain-Barré syndrome and acute transient polyneuritis in the peripheral nervous system (PNS). Drugs like azithromycin have been tested as inhibitors of ZIKV infection but no vaccines or treatments are currently available. Astrocytes are the most abundant cells in the CNS and among the first cells in CNS infected by ZIKV; (2) Methods: We previously used SOMAScan proteomics to study ZIKV-infected astrocytic cells. Here, we use mass spectrometric analyses to further explain dysregulations in the cellular expression profile of glioblastoma astrocytoma U251 cells. We also knocked down (KD) some of the U251 cellular proteins using siRNAs and observed the impact on ZIKV replication and infectivity; (3) Results & Conclusions: The top ZIKV dysregulated cellular networks were antimicrobial response, cell death, and energy production while top dysregulated functions were antigen presentation, viral replication and cytopathic impact. Th1 and interferon signaling pathways were among the top dysregulated canonical pathways. siRNA-mediated KD of HLA-A, IGFBP5, PSMA2 and HSPA5 increased ZIKV titers and protein synthesis, indicating they are ZIKV restriction factors. ZIKV infection also restored HLA-A expression in HLA-A KD cells by 48 h post-infection, suggesting interactions between this gene product and ZIKV. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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17 pages, 1391 KiB  
Article
Cell Type Variability in the Incorporation of Lipids in the Dengue Virus Virion
by Atitaya Hitakarun, Maia Kavanagh Williamson, Nathamon Yimpring, Wannapa Sornjai, Nitwara Wikan, Christopher J. Arthur, Julien Pompon, Andrew D. Davidson and Duncan R. Smith
Viruses 2022, 14(11), 2566; https://doi.org/10.3390/v14112566 - 19 Nov 2022
Cited by 4 | Viewed by 1993
Abstract
A lipid bilayer produced from the host membrane makes up around 20% of the weight of the dengue virus (DENV) virion and is crucial for virus entry. Despite its significance, the virion’s lipid composition is still poorly understood. In tandem with lipid profiles [...] Read more.
A lipid bilayer produced from the host membrane makes up around 20% of the weight of the dengue virus (DENV) virion and is crucial for virus entry. Despite its significance, the virion’s lipid composition is still poorly understood. In tandem with lipid profiles of the cells utilised to generate the virions, this work determined a partial lipid profile of DENV virions derived from two cell lines (C6/36 and LLC-MK2). The results showed distinctive profiles between the two cell types. In the mammalian LLC-MK2 cells, 30.8% (73/237 identified lipid species; 31 upregulated, 42 downregulated) of lipid species were altered in response to infection, whilst in insect C6/36 cells only 12.0% (25/208; 19 upregulated, 6 downregulated) of lipid species showed alterations in response to infection. For virions from LLC-MK2 cells, 14 lipids were detected specifically in virions with a further seven lipids being enriched (over mock controls). For virions from C6/36 cells, 43 lipids were detected that were not seen in mock preparations, with a further 16 being specifically enriched (over mock control). These results provide the first lipid description of DENV virions produced in mammalian and mosquito cells, as well as the lipid changes in the corresponding infected cells. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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14 pages, 1807 KiB  
Article
Network Analysis for Uncovering the Relationship between Host Response and Clinical Factors to Virus Pathogen: Lessons from SARS-CoV-2
by Milan Sova, Milos Kudelka, Milan Raska, Jan Mizera, Zuzana Mikulkova, Marketa Trajerova, Eliska Ochodkova, Samuel Genzor, Petr Jakubec, Alena Borikova, Ladislav Stepanek, Petr Kosztyu and Eva Kriegova
Viruses 2022, 14(11), 2422; https://doi.org/10.3390/v14112422 - 31 Oct 2022
Cited by 1 | Viewed by 1441
Abstract
Analysing complex datasets while maintaining the interpretability and explainability of outcomes for clinicians and patients is challenging, not only in viral infections. These datasets often include a variety of heterogeneous clinical, demographic, laboratory, and personal data, and it is not a single factor [...] Read more.
Analysing complex datasets while maintaining the interpretability and explainability of outcomes for clinicians and patients is challenging, not only in viral infections. These datasets often include a variety of heterogeneous clinical, demographic, laboratory, and personal data, and it is not a single factor but a combination of multiple factors that contribute to patient characterisation and host response. Therefore, multivariate approaches are needed to analyse these complex patient datasets, which are impossible to analyse with univariate comparisons (e.g., one immune cell subset versus one clinical factor). Using a SARS-CoV-2 infection as an example, we employed a patient similarity network (PSN) approach to assess the relationship between host immune factors and the clinical course of infection and performed visualisation and data interpretation. A PSN analysis of ~85 immunological (cellular and humoral) and ~70 clinical factors in 250 recruited patients with coronavirus disease (COVID-19) who were sampled four to eight weeks after a PCR-confirmed SARS-CoV-2 infection identified a minimal immune signature, as well as clinical and laboratory factors strongly associated with disease severity. Our study demonstrates the benefits of implementing multivariate network approaches to identify relevant factors and visualise their relationships in a SARS-CoV-2 infection, but the model is generally applicable to any complex dataset. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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18 pages, 2380 KiB  
Article
Association of ScV-LA Virus with Host Protein Metabolism Determined by Proteomics Analysis and Cognate RNA Sequencing
by Juliana Lukša, Enrika Celitan, Elena Servienė and Saulius Serva
Viruses 2022, 14(11), 2345; https://doi.org/10.3390/v14112345 - 25 Oct 2022
Cited by 2 | Viewed by 1539
Abstract
Saccharomyces yeasts are highly dispersed in the environment and microbiota of higher organisms. The yeast killing phenotype, encoded by the viral system, was discovered to be a significant property for host survival. Minor alterations in transcription patterns underpin the reciprocal relationship between LA [...] Read more.
Saccharomyces yeasts are highly dispersed in the environment and microbiota of higher organisms. The yeast killing phenotype, encoded by the viral system, was discovered to be a significant property for host survival. Minor alterations in transcription patterns underpin the reciprocal relationship between LA and M viruses and their hosts, suggesting the fine-tuning of the transcriptional landscape. To uncover the principal targets of both viruses, we performed proteomics analysis of virus-enriched subsets of host proteins in virus type-specific manner. The essential pathways of protein metabolism–from biosynthesis and folding to degradation–were found substantially enriched in virus-linked subsets. The fractionation of viruses allowed separation of virus-linked host RNAs, investigated by high-content RNA sequencing. Ribosomal RNA was found to be inherently associated with LA-lus virus, along with other RNAs essential for ribosome biogenesis. This study provides a unique portrayal of yeast virions through the characterization of the associated proteome and cognate RNAs, and offers a background for understanding ScV-LA viral infection persistency. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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25 pages, 3080 KiB  
Article
Proteome Analysis of Swine Macrophages after Infection with Two Genotype II African Swine Fever Isolates of Different Pathogenicity
by Elisabeth Wöhnke, Gwenny Cackett, Finn Werner, Sandra Blome, Thomas C. Mettenleiter and Axel Karger
Viruses 2022, 14(10), 2140; https://doi.org/10.3390/v14102140 - 28 Sep 2022
Cited by 2 | Viewed by 2260
Abstract
Since the introduction of a highly pathogenic genotype II isolate of the African swine fever virus (ASFV) into Georgia in 2007, African swine fever (ASF) has gone panzootic. Outbreaks have been reported in Europe, Asia and, more recently, Latin America. Thus, ASFV has [...] Read more.
Since the introduction of a highly pathogenic genotype II isolate of the African swine fever virus (ASFV) into Georgia in 2007, African swine fever (ASF) has gone panzootic. Outbreaks have been reported in Europe, Asia and, more recently, Latin America. Thus, ASFV has become a major threat to the pig industry worldwide, as broadly applicable vaccines are not available. While the majority of ASFV strains show high virulence in domestic pigs and wild boar, variations within the ASFV genome have resulted in the emergence of attenuated strains with low or moderate virulence. However, the molecular basis of the differences in virulence has not yet been discovered. To reveal virulence-associated protein expression patterns, we analysed the proteomes of the natural target cells of ASFV, primary porcine macrophages, after infection with two genotype II ASFV strains displaying high (Armenia 2008) and moderate (Estonia 2014) virulence using quantitative mass spectrometry. Very similar expression patterns were observed for the viral genes, and any differences were limited to the deletions within the Estonia 2014 genome. In addition to the canonical ASFV proteins, twelve novel protein products from recently described transcripts were confirmed in both isolates. Pathway analyses showed that both isolates evoked a similar host proteome response, despite their difference in virulence. However, subtle differences in the manipulation of the proteins involved in the proinflammatory response mediated by the MAPK14/p38 signalling cascade were observed Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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16 pages, 3649 KiB  
Article
Coxsackievirus Protease 2A Targets Host Protease ATG4A to Impair Autophagy
by Yiyun Michelle Fan, Yizhuo Lyanne Zhang, Amirhossein Bahreyni, Honglin Luo and Yasir Mohamud
Viruses 2022, 14(9), 2026; https://doi.org/10.3390/v14092026 - 13 Sep 2022
Cited by 4 | Viewed by 1980
Abstract
Enteroviruses (EVs) are medically important RNA viruses that cause a broad spectrum of human illnesses for which limited therapy exists. Although EVs have been shown to usurp the cellular recycling process of autophagy for pro-viral functions, the precise manner by which this is [...] Read more.
Enteroviruses (EVs) are medically important RNA viruses that cause a broad spectrum of human illnesses for which limited therapy exists. Although EVs have been shown to usurp the cellular recycling process of autophagy for pro-viral functions, the precise manner by which this is accomplished remains to be elucidated. In the current manuscript, we sought to address the mechanism by which EVs subvert the autophagy pathway using Coxsackievirus B3 (CVB3) as a model. We showed that CVB3 infection selectively degrades the autophagy cysteine protease ATG4A but not other isoforms. Exogenous expression of an N-terminally Flag-labeled ATG4A demonstrated the emergence of a 43-kDa cleavage fragment following CVB3 infection. Furthermore, bioinformatics analysis coupled with site-directed mutagenesis and in vitro cleavage assays revealed that CVB3 protease 2A cleaves ATG4A before glycine 374. Using a combination of genetic silencing and overexpression studies, we demonstrated a novel pro-viral function for the autophagy protease ATG4A. Additionally, cleavage of ATG4A was associated with a loss of autophagy function of the truncated cleavage fragment. Collectively, our study identified ATG4A as a novel substrate of CVB3 protease, leading to disrupted host cellular function and sheds further light on viral mechanisms of autophagy dysregulation. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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24 pages, 4005 KiB  
Article
Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation
by Kerry Dust, Michael Carpenter, Julie Chih-yu Chen, Chris Grant, Stuart McCorrister, Garret R. Westmacott and Alberto Severini
Viruses 2022, 14(8), 1764; https://doi.org/10.3390/v14081764 - 12 Aug 2022
Cited by 5 | Viewed by 2113
Abstract
The high-risk human papillomaviruses are oncogenic viruses associated with almost all cases of cervical carcinomas, and increasing numbers of anal, and oral cancers. Two oncogenic HPV proteins, E6 and E7, are capable of immortalizing keratinocytes and are required for HPV associated cell transformation. [...] Read more.
The high-risk human papillomaviruses are oncogenic viruses associated with almost all cases of cervical carcinomas, and increasing numbers of anal, and oral cancers. Two oncogenic HPV proteins, E6 and E7, are capable of immortalizing keratinocytes and are required for HPV associated cell transformation. Currently, the influence of these oncoproteins on the global regulation of the host proteome is not well defined. Liquid chromatography coupled with quantitative tandem mass spectrometry using isobaric-tagged peptides was used to investigate the effects of the HPV16 oncoproteins E6 and E7 on protein levels in human neonatal keratinocytes (HEKn). Pathway and gene ontology enrichment analyses revealed that the cells expressing the HPV oncoproteins have elevated levels of proteins related to interferon response, inflammation and DNA damage response, while the proteins related to cell organization and epithelial development are downregulated. This study identifies dysregulated pathways and potential biomarkers associated with HPV oncoproteins in primary keratinocytes which may have therapeutic implications. Most notably, DNA damage response pathways, DNA replication, and interferon signaling pathways were affected in cells transduced with HPV16 E6 and E7 lentiviruses. Moreover, proteins associated with cell organization and differentiation were significantly downregulated in keratinocytes expressing HPV16 E6 + E7. High-risk HPV E6 and E7 oncoproteins are necessary for the HPV-associated transformation of keratinocytes. However their influence on the global dysregulation of keratinocyte proteome is not well documented. Here shotgun proteomics using TMT-labeling detected over 2500 significantly dysregulated proteins associated with E6 and E7 expression. Networks of proteins related to interferon response, inflammation and DNA damage repair pathways were altered. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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18 pages, 2876 KiB  
Article
Flavivirus Capsid Proteins Inhibit the Interferon Response
by Adriana M. Airo, Alberto Felix-Lopez, Valeria Mancinelli, Danyel Evseev, Joaquin Lopez-Orozco, Kathy Shire, Patrick Paszkowski, Lori Frappier, Katharine E. Magor and Tom C. Hobman
Viruses 2022, 14(5), 968; https://doi.org/10.3390/v14050968 - 5 May 2022
Cited by 7 | Viewed by 3065
Abstract
Zika virus (ZIKV) establishes persistent infections in multiple human tissues, a phenomenon that likely plays a role in its ability to cause congenital birth defects and neurological disease. Multiple nonstructural proteins encoded by ZIKV, in particular NS5, are known to suppress the interferon [...] Read more.
Zika virus (ZIKV) establishes persistent infections in multiple human tissues, a phenomenon that likely plays a role in its ability to cause congenital birth defects and neurological disease. Multiple nonstructural proteins encoded by ZIKV, in particular NS5, are known to suppress the interferon (IFN) response by attacking different steps in this critical antiviral pathway. Less well known are the potential roles of structural proteins in affecting the host immune response during ZIKV infection. Capsid proteins of flaviviruses are of particular interest because a pool of these viral proteins is targeted to the nuclei during infection and, as such, they have the potential to affect host cell gene expression. In this study, RNA-seq analyses revealed that capsid proteins from six different flaviviruses suppress expression of type I IFN and IFN-stimulated genes. Subsequent interactome and in vitro ubiquitination assays showed that ZIKV capsid protein binds to and prevents activating ubiquitination of RIG-I CARD domains by TRIM25, a host factor that is important for the induction arm of the IFN response. The other flavivirus capsid proteins also interacted with TRIM25, suggesting that these viral proteins may attenuate antiviral signaling pathways at very early stages of infection, potentially even before nonstructural proteins are produced. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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31 pages, 6215 KiB  
Article
Zika Virus Infection of Sertoli Cells Alters Protein Expression Involved in Activated Immune and Antiviral Response Pathways, Carbohydrate Metabolism and Cardiovascular Disease
by Mahamud-ur Rashid, Ying Lao, Victor Spicer and Kevin M. Coombs
Viruses 2022, 14(2), 377; https://doi.org/10.3390/v14020377 - 11 Feb 2022
Cited by 6 | Viewed by 2377
Abstract
Zika virus (ZIKV), a re-emerging virus, causes congenital brain abnormalities and Guillain–Barré syndrome. It is mainly transmitted by Aedes mosquitoes, but infections are also linked to sexual transmissions. Infectious ZIKV has been isolated, and viral RNA has been detected in semen over a [...] Read more.
Zika virus (ZIKV), a re-emerging virus, causes congenital brain abnormalities and Guillain–Barré syndrome. It is mainly transmitted by Aedes mosquitoes, but infections are also linked to sexual transmissions. Infectious ZIKV has been isolated, and viral RNA has been detected in semen over a year after the onset of initial symptoms, but the mode of long-term persistence is not yet understood. ZIKV can proliferate in human Sertoli cells (HSerC) for several weeks in vitro, suggesting that it might be a reservoir for persistent ZIKV infection. This study determined proteomic changes in HSerC during ZIKV infections by TMT-mass spectrometry analysis. Levels of 4416 unique Sertoli cell proteins were significantly altered at 3, 5, and 7 days after ZIKV infection. The significantly altered proteins include enzymes, transcription regulators, transporters, kinases, peptidases, transmembrane receptors, cytokines, ion channels, and growth factors. Many of these proteins are involved in pathways associated with antiviral response, antigen presentation, and immune cell activation. Several immune response pathway proteins were significantly activated during infection, e.g., interferon signaling, T cell receptor signaling, IL-8 signaling, and Th1 signaling. The altered protein levels were linked to predicted activation of immune response in HSerC, which was predicted to suppress ZIKV infection. ZIKV infection also affected the levels of critical regulators of gluconeogenesis and glycolysis pathways such as phosphoglycerate mutase, phosphoglycerate kinase, and enolase. Interestingly, many significantly altered proteins were associated with cardiac hypertrophy, which may induce heart failure in infected patients. In summary, our research contributes to a better understanding of ZIKV replication dynamics and infection in Sertoli cells. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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Review

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22 pages, 845 KiB  
Review
Promiscuous Inflammasomes: The False Dichotomy of RNA/DNA Virus-Induced Inflammasome Activation and Pyroptosis
by Hannah L. Wallace and Rodney S. Russell
Viruses 2022, 14(10), 2113; https://doi.org/10.3390/v14102113 - 23 Sep 2022
Cited by 9 | Viewed by 3334
Abstract
It is well-known that viruses activate various inflammasomes, which can initiate the programmed cell death pathway known as pyroptosis, subsequently leading to cell lysis and release of inflammatory cytokines IL-1β and IL-18. This pathway can be triggered by various sensors, including, but [...] Read more.
It is well-known that viruses activate various inflammasomes, which can initiate the programmed cell death pathway known as pyroptosis, subsequently leading to cell lysis and release of inflammatory cytokines IL-1β and IL-18. This pathway can be triggered by various sensors, including, but not limited to, NLRP3, AIM2, IFI16, RIG-I, and NLRC4. Many viruses are known either to activate or inhibit inflammasomes as a part of the innate immune response or as a mechanism of pathogenesis. Early research in the field of virus-induced pyroptosis suggested a dichotomy, with RNA viruses activating the NLRP3 inflammasome and DNA viruses activating the AIM2 inflammasome. More recent research has shown that this dichotomy may not be as distinct as once thought. It seems many viruses activate multiple inflammasome sensors. Here, we detail which viruses fit the dichotomy as well as many that appear to defy this clearly false dichotomy. It seems likely that most, if not all, viruses activate multiple inflammasome sensors, and future research should focus on expanding our understanding of inflammasome activation in a variety of tissue types as well as virus activation of multiple inflammasomes, challenging biases that stemmed from early literature in this field. Here, we review primarily research performed on human viruses but also include details regarding animal viruses whenever possible. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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7 pages, 7053 KiB  
Review
The Rise and Fall of SARS-CoV-2 Variants and Ongoing Diversification of Omicron
by Tanner Wiegand, Artem Nemudryi, Anna Nemudraia, Aidan McVey, Agusta Little, David N. Taylor, Seth T. Walk and Blake Wiedenheft
Viruses 2022, 14(9), 2009; https://doi.org/10.3390/v14092009 - 10 Sep 2022
Cited by 15 | Viewed by 4409
Abstract
In late December of 2019, high-throughput sequencing technologies enabled rapid identification of SARS-CoV-2 as the etiological agent of COVID-19, and global sequencing efforts are now a critical tool for monitoring the ongoing spread and evolution of this virus. Here, we provide a short [...] Read more.
In late December of 2019, high-throughput sequencing technologies enabled rapid identification of SARS-CoV-2 as the etiological agent of COVID-19, and global sequencing efforts are now a critical tool for monitoring the ongoing spread and evolution of this virus. Here, we provide a short retrospective analysis of SARS-CoV-2 variants by analyzing a subset (n = 97,437) of all publicly available SARS-CoV-2 genomes (n = ~11.9 million) that were randomly selected but equally distributed over the course of the pandemic. We plot the appearance of new variants of concern (VOCs) over time and show that the mutation rates in Omicron (BA.1) and Omicron sub-lineages (BA.2–BA.5) are significantly elevated compared to previously identified SARS-CoV-2 variants. Mutations in Omicron are primarily restricted to the spike and nucleocapsid proteins, while 24 other viral proteins—including those involved in SARS-CoV-2 replication—are generally conserved. Collectively, this suggests that the genetic distinction of Omicron primarily arose from selective pressures on the spike, and that the fidelity of replication of this variant has not been altered. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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