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Cell Biology of Viral Infections
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Cell Biology of Viral Infections

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (15 August 2020) | Viewed by 112452

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Pierre-Yves Lozach

E-Mail Website
Guest Editor
CellNetworks—Cluster of Excellence and Center for Integrative Infectious Diseases Research (CIID), Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
Interests: amyloids; arbovirus; cell biology of virus entry; viral virulence factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viruses are rather small infectious agents that replicate and amplify in a wide range of hosts, including pro- and eukaryotes. Many cause severe human diseases—sometimes fatal—and represent a global threat to public health, as exemplified by the recent outbreaks of Ebola virus and the lasting problem created by the human immunodeficiency virus worldwide. Viruses exhibit an important diversity in the degree of severity of the diseases they cause. It undoubtedly reflects the large variety of molecular and cellular processes they subvert, or with which they interfere, in host cells for infectious entry, viral replication, and spread. In this Special Issue of Cells, I would like to include both review papers and research articles that together can not only provide a glance into the latest research in the cell biology of viral infections but also highlight the major achievements in the field of virus–host cell interactions made in recent years. Studies covering all aspects of virus life cycles and interactions between viruses and host cells are welcome, which also include novel technological approaches. With this Special Issue, I aim to offer a space for enthusiastic discussions on future research directions on virus–host cell interactions and promote some areas that are understudied or emerging.

Dr. Pierre-Yves Lozach
Guest Editor

Manuscript Submission Information

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Keywords

  • cell death
  • cellular receptor
  • degradative pathways
  • innate immune response
  • intracellular trafficking
  • DNA/RNA organization and synthesis
  • membrane fusion
  • signaling pathways
  • virus
  • virus–host cell interactions

Published Papers (23 papers)

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Editorial

Jump to: Research, Review, Other

6 pages, 352 KiB  
Editorial
Cell Biology of Viral Infections
by Pierre-Yves Lozach
Cells 2020, 9(11), 2431; https://doi.org/10.3390/cells9112431 - 07 Nov 2020
Cited by 10 | Viewed by 3678
Abstract
Viruses exhibit an elegant simplicity, as they are so basic, but so frightening. Although only a few are life threatening, they have substantial implications for human health and the economy, as exemplified by the ongoing coronavirus pandemic. Viruses are rather small infectious agents [...] Read more.
Viruses exhibit an elegant simplicity, as they are so basic, but so frightening. Although only a few are life threatening, they have substantial implications for human health and the economy, as exemplified by the ongoing coronavirus pandemic. Viruses are rather small infectious agents found in all types of life forms, from animals and plants to prokaryotes and archaebacteria. They are obligate intracellular parasites, and as such, subvert many molecular and cellular processes of the host cell to ensure their own replication, amplification, and subsequent spread. This special issue addresses the cell biology of viral infections based on a collection of original research articles, communications, opinions, and reviews on various aspects of virus-host cell interactions. Together, these articles not only provide a glance into the latest research on the cell biology of viral infections, but also include novel technological developments. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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Research

Jump to: Editorial, Review, Other

23 pages, 2794 KiB  
Article
Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity
by Francisco J. Zapatero-Belinchón, Rina Ötjengerdes, Julie Sheldon, Benjamin Schulte, Belén Carriquí-Madroñal, Graham Brogden, Laura M. Arroyo-Fernández, Florian W. R. Vondran, Benjamin Maasoumy, Thomas von Hahn and Gisa Gerold
Cells 2021, 10(7), 1626; https://doi.org/10.3390/cells10071626 - 29 Jun 2021
Cited by 6 | Viewed by 2735
Abstract
The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very-low-density lipoprotein (VLDL) secretory pathway. Hence, medications [...] Read more.
The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very-low-density lipoprotein (VLDL) secretory pathway. Hence, medications that interfere with the lipid metabolism of the cell, such as statins, may affect HCV infection. Here, we study the interplay between lipoprotein receptors, lipid homeostasis, and HCV infection by genetic and pharmacological interventions. We found that individual ablation of the lipoprotein receptors SR-B1 and LDLr did not drastically affect HCV entry, replication, or infection, but double lipoprotein receptor knock-outs significantly reduced HCV infection. Furthermore, we could show that this effect was neither due to altered expression of additional HCV entry factors nor caused by changes in cellular cholesterol content. Strikingly, whereas lipid-lowering drugs such as simvastatin or fenofibrate did not affect HCV entry or infection of immortalized hepatoma cells expressing SR-B1 and/or LDLr or primary human hepatocytes, ablation of these receptors rendered cells more susceptible to these drugs. Finally, we observed no significant differences between statin users and control groups with regards to HCV viral load in a cohort of HCV infected patients before and during HCV antiviral treatment. Interestingly, statin treatment, which blocks the mevalonate pathway leading to decreased cholesterol levels, was associated with mild but appreciable lower levels of liver damage markers before HCV therapy. Overall, our findings confirm the role of lipid homeostasis in HCV infection and highlight the importance of the mevalonate pathway in the HCV replication cycle. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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15 pages, 2763 KiB  
Communication
Development of Feline Ileum- and Colon-Derived Organoids and Their Potential Use to Support Feline Coronavirus Infection
by Gergely Tekes, Rosina Ehmann, Steeve Boulant and Megan L. Stanifer
Cells 2020, 9(9), 2085; https://doi.org/10.3390/cells9092085 - 12 Sep 2020
Cited by 18 | Viewed by 3954
Abstract
Feline coronaviruses (FCoVs) infect both wild and domestic cat populations world-wide. FCoVs present as two main biotypes: the mild feline enteric coronavirus (FECV) and the fatal feline infectious peritonitis virus (FIPV). FIPV develops through mutations from FECV during a persistence infection. So far, [...] Read more.
Feline coronaviruses (FCoVs) infect both wild and domestic cat populations world-wide. FCoVs present as two main biotypes: the mild feline enteric coronavirus (FECV) and the fatal feline infectious peritonitis virus (FIPV). FIPV develops through mutations from FECV during a persistence infection. So far, the molecular mechanism of FECV-persistence and contributing factors for FIPV development may not be studied, since field FECV isolates do not grow in available cell culture models. In this work, we aimed at establishing feline ileum and colon organoids that allow the propagation of field FECVs. We have determined the best methods to isolate, culture and passage feline ileum and colon organoids. Importantly, we have demonstrated using GFP-expressing recombinant field FECV that colon organoids are able to support infection of FECV, which were unable to infect traditional feline cell culture models. These organoids in combination with recombinant FECVs can now open the door to unravel the molecular mechanisms by which FECV can persist in the gut for a longer period of time and how transition to FIPV is achieved. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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20 pages, 4676 KiB  
Article
Importance of Endocytosis for the Biological Activity of Cedar Virus Fusion Protein
by Kerstin Fischer, Martin H. Groschup and Sandra Diederich
Cells 2020, 9(9), 2054; https://doi.org/10.3390/cells9092054 - 08 Sep 2020
Cited by 5 | Viewed by 2913
Abstract
Endocytosis plays a particular role in the proteolytic activation of highly pathogenic henipaviruses Hendra (HeV) and Nipah virus (NiV) fusion (F) protein precursors. These proteins require endocytic uptake from the cell surface to be cleaved by cellular proteases within the endosomal compartment, followed [...] Read more.
Endocytosis plays a particular role in the proteolytic activation of highly pathogenic henipaviruses Hendra (HeV) and Nipah virus (NiV) fusion (F) protein precursors. These proteins require endocytic uptake from the cell surface to be cleaved by cellular proteases within the endosomal compartment, followed by recycling to the plasma membrane for incorporation into budding virions or mediation of cell-cell fusion. This internalization largely depends on a tyrosine-based consensus motif for endocytosis present in the cytoplasmic tail of HeV and NiV F. Given the large number of tyrosine residues present in the F protein cytoplasmic domain of Cedar virus (CedV), a closely related but low pathogenic henipavirus, we aimed to investigate whether CedV F protein undergoes signal-mediated endocytosis from the cell surface controlled by tyrosine-based motifs present in its cytoplasmic tail and whether endocytosis is relevant for its biological activity. Therefore, tyrosine-based signals were mutated, and mutations were assessed for their effect on F cell surface expression, endocytosis, and biological activity. A membrane-proximal YXXΦ motif and a C-terminal di-tyrosine motif are of particular importance for cell surface expression and endocytosis rate. Furthermore, our data strongly indicate the pivotal role of endocytosis for the biological activity of the CedV F protein. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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22 pages, 2319 KiB  
Article
A Broad-Spectrum Antiviral Peptide Blocks Infection of Viruses by Binding to Phosphatidylserine in the Viral Envelope
by Rutger D. Luteijn, Patrique Praest, Frank Thiele, Saravanan Manikam Sadasivam, Katrin Singethan, Jan W. Drijfhout, Christian Bach, Steffen Matthijn de Boer, Robert J. Lebbink, Sha Tao, Markus Helfer, Nina C. Bach, Ulrike Protzer, Ana I. Costa, J. Antoinette Killian, Ingo Drexler and Emmanuel J. H. J. Wiertz
Cells 2020, 9(9), 1989; https://doi.org/10.3390/cells9091989 - 29 Aug 2020
Cited by 12 | Viewed by 3422
Abstract
The ongoing threat of viral infections and the emergence of antiviral drug resistance warrants a ceaseless search for new antiviral compounds. Broadly-inhibiting compounds that act on elements shared by many viruses are promising antiviral candidates. Here, we identify a peptide derived from the [...] Read more.
The ongoing threat of viral infections and the emergence of antiviral drug resistance warrants a ceaseless search for new antiviral compounds. Broadly-inhibiting compounds that act on elements shared by many viruses are promising antiviral candidates. Here, we identify a peptide derived from the cowpox virus protein CPXV012 as a broad-spectrum antiviral peptide. We found that CPXV012 peptide hampers infection by a multitude of clinically and economically important enveloped viruses, including poxviruses, herpes simplex virus-1, hepatitis B virus, HIV-1, and Rift Valley fever virus. Infections with non-enveloped viruses such as Coxsackie B3 virus and adenovirus are not affected. The results furthermore suggest that viral particles are neutralized by direct interactions with CPXV012 peptide and that this cationic peptide may specifically bind to and disrupt membranes composed of the anionic phospholipid phosphatidylserine, an important component of many viral membranes. The combined results strongly suggest that CPXV012 peptide inhibits virus infections by direct interactions with phosphatidylserine in the viral envelope. These results reiterate the potential of cationic peptides as broadly-acting virus inhibitors. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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14 pages, 1919 KiB  
Article
A New ERAP2/Iso3 Isoform Expression Is Triggered by Different Microbial Stimuli in Human Cells. Could It Play a Role in the Modulation of SARS-CoV-2 Infection?
by Irma Saulle, Claudia Vanetti, Sara Goglia, Chiara Vicentini, Enrico Tombetti, Micaela Garziano, Mario Clerici and Mara Biasin
Cells 2020, 9(9), 1951; https://doi.org/10.3390/cells9091951 - 24 Aug 2020
Cited by 25 | Viewed by 3527
Abstract
Following influenza infection, rs2248374-G ERAP2 expressing cells may transcribe an alternative spliced isoform: ERAP2/Iso3. This variant, unlike ERAP2-wt, is unable to trim peptides to be loaded on MHC class I molecules, but it can still dimerize with both ERAP2-wt and ERAP1-wt, thus contributing [...] Read more.
Following influenza infection, rs2248374-G ERAP2 expressing cells may transcribe an alternative spliced isoform: ERAP2/Iso3. This variant, unlike ERAP2-wt, is unable to trim peptides to be loaded on MHC class I molecules, but it can still dimerize with both ERAP2-wt and ERAP1-wt, thus contributing to profiling an alternative cellular immune-peptidome. In order to verify if the expression of ERAP2/Iso3 may be induced by other pathogens, PBMCs and MDMs isolated from 20 healthy subjects were stimulated with flu, LPS, CMV, HIV-AT-2, SARS-CoV-2 antigens to analyze its mRNA and protein expression. In parallel, Calu3 cell lines and PBMCs were in vitro infected with growing doses of SARS-CoV-2 (0.5, 5, 1000 MOI) and HIV-1BAL (0.1, 1, and 10 ng p24 HIV-1Bal/1 × 106 PBMCs) viruses, respectively. Results showed that: (1) ERAP2/Iso3 mRNA expression can be prompted by many pathogens and it is coupled with the modulation of several determinants (cytokines, interferon-stimulated genes, activation/inhibition markers, antigen-presentation elements) orchestrating the anti-microbial immune response (Quantigene); (2) ERAP2/Iso3 mRNA is translated into a protein (western blot); (3) ERAP2/Iso3 mRNA expression is sensitive to SARS-CoV-2 and HIV-1 concentration. Considering the key role played by ERAPs in antigen processing and presentation, it is conceivable that these enzymes may be potential targets and modulators of the pathogenicity of infectious diseases and further analyses are needed to define the role played by the different isoforms. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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15 pages, 2436 KiB  
Article
Ebola Virus Nucleocapsid-Like Structures Utilize Arp2/3 Signaling for Intracellular Long-Distance Transport
by Katharina Grikscheit, Olga Dolnik, Yuki Takamatsu, Ana Raquel Pereira and Stephan Becker
Cells 2020, 9(7), 1728; https://doi.org/10.3390/cells9071728 - 19 Jul 2020
Cited by 7 | Viewed by 3755
Abstract
The intracellular transport of nucleocapsids of the highly pathogenic Marburg, as well as Ebola virus (MARV, EBOV), represents a critical step during the viral life cycle. Intriguingly, a population of these nucleocapsids is distributed over long distances in a directed and polar fashion. [...] Read more.
The intracellular transport of nucleocapsids of the highly pathogenic Marburg, as well as Ebola virus (MARV, EBOV), represents a critical step during the viral life cycle. Intriguingly, a population of these nucleocapsids is distributed over long distances in a directed and polar fashion. Recently, it has been demonstrated that the intracellular transport of filoviral nucleocapsids depends on actin polymerization. While it was shown that EBOV requires Arp2/3-dependent actin dynamics, the details of how the virus exploits host actin signaling during intracellular transport are largely unknown. Here, we apply a minimalistic transfection system to follow the nucleocapsid-like structures (NCLS) in living cells, which can be used to robustly quantify NCLS transport in live cell imaging experiments. Furthermore, in cells co-expressing LifeAct, a marker for actin dynamics, NCLS transport is accompanied by pulsative actin tails appearing on the rear end of NCLS. These actin tails can also be preserved in fixed cells, and can be visualized via high resolution imaging using STORM in transfected, as well as EBOV infected, cells. The application of inhibitory drugs and siRNA depletion against actin regulators indicated that EBOV NCLS utilize the canonical Arp2/3-Wave1-Rac1 pathway for long-distance transport in cells. These findings highlight the relevance of the regulation of actin polymerization during directed EBOV nucleocapsid transport in human cells. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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19 pages, 6792 KiB  
Article
The RNA Replication Site of Tula Orthohantavirus Resides within a Remodelled Golgi Network
by Katherine A. Davies, Benjamin Chadwick, Roger Hewson, Juan Fontana, Jamel Mankouri and John N. Barr
Cells 2020, 9(7), 1569; https://doi.org/10.3390/cells9071569 - 27 Jun 2020
Cited by 8 | Viewed by 3766
Abstract
The family Hantaviridae within the Bunyavirales order comprises tri-segmented negative sense RNA viruses, many of which are rodent-borne emerging pathogens associated with fatal human disease. In contrast, hantavirus infection of corresponding rodent hosts results in inapparent or latent infections, which can be recapitulated [...] Read more.
The family Hantaviridae within the Bunyavirales order comprises tri-segmented negative sense RNA viruses, many of which are rodent-borne emerging pathogens associated with fatal human disease. In contrast, hantavirus infection of corresponding rodent hosts results in inapparent or latent infections, which can be recapitulated in cultured cells that become persistently infected. In this study, we used Tula virus (TULV) to investigate the location of hantavirus replication during early, peak and persistent phases of infection, over a 30-day time course. Using immunofluorescent (IF) microscopy, we showed that the TULV nucleocapsid protein (NP) is distributed within both punctate and filamentous structures, with the latter increasing in size as the infection progresses. Transmission electron microscopy of TULV-infected cell sections revealed these filamentous structures comprised aligned clusters of filament bundles. The filamentous NP-associated structures increasingly co-localized with the Golgi and with the stress granule marker TIA-1 over the infection time course, suggesting a redistribution of these cellular organelles. The analysis of the intracellular distribution of TULV RNAs using fluorescent in-situ hybridization revealed that both genomic and mRNAs co-localized with Golgi-associated filamentous compartments that were positive for TIA. These results show that TULV induces a dramatic reorganization of the intracellular environment, including the establishment of TULV RNA synthesis factories in re-modelled Golgi compartments. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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15 pages, 9130 KiB  
Article
The Cellular Protein CAD is Recruited into Ebola Virus Inclusion Bodies by the Nucleoprotein NP to Facilitate Genome Replication and Transcription
by Janine Brandt, Lisa Wendt, Bianca S. Bodmer, Thomas C. Mettenleiter and Thomas Hoenen
Cells 2020, 9(5), 1126; https://doi.org/10.3390/cells9051126 - 01 May 2020
Cited by 17 | Viewed by 3825
Abstract
Ebola virus (EBOV) is a zoonotic pathogen causing severe hemorrhagic fevers in humans and non-human primates with high case fatality rates. In recent years, the number and extent of outbreaks has increased, highlighting the importance of better understanding the molecular aspects of EBOV [...] Read more.
Ebola virus (EBOV) is a zoonotic pathogen causing severe hemorrhagic fevers in humans and non-human primates with high case fatality rates. In recent years, the number and extent of outbreaks has increased, highlighting the importance of better understanding the molecular aspects of EBOV infection and host cell interactions to control this virus more efficiently. Many viruses, including EBOV, have been shown to recruit host proteins for different viral processes. Based on a genome-wide siRNA screen, we recently identified the cellular host factor carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) as being involved in EBOV RNA synthesis. However, mechanistic details of how this host factor plays a role in the EBOV life cycle remain elusive. In this study, we analyzed the functional and molecular interactions between EBOV and CAD. To this end, we used siRNA knockdowns in combination with various reverse genetics-based life cycle modelling systems and additionally performed co-immunoprecipitation and co-immunofluorescence assays to investigate the influence of CAD on individual aspects of the EBOV life cycle and to characterize the interactions of CAD with viral proteins. Following this approach, we could demonstrate that CAD directly interacts with the EBOV nucleoprotein NP, and that NP is sufficient to recruit CAD into inclusion bodies dependent on the glutaminase (GLN) domain of CAD. Further, siRNA knockdown experiments indicated that CAD is important for both viral genome replication and transcription, while substrate rescue experiments showed that the function of CAD in pyrimidine synthesis is indeed required for those processes. Together, this suggests that NP recruits CAD into inclusion bodies via its GLN domain in order to provide pyrimidines for EBOV genome replication and transcription. These results define a novel mechanism by which EBOV hijacks host cell pathways in order to facilitate genome replication and transcription and provide a further basis for the development of host-directed broad-spectrum antivirals. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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20 pages, 14998 KiB  
Article
Astrocyte Infection during Rabies Encephalitis Depends on the Virus Strain and Infection Route as Demonstrated by Novel Quantitative 3D Analysis of Cell Tropism
by Madlin Potratz, Luca Zaeck, Michael Christen, Verena te Kamp, Antonia Klein, Tobias Nolden, Conrad M. Freuling, Thomas Müller and Stefan Finke
Cells 2020, 9(2), 412; https://doi.org/10.3390/cells9020412 - 11 Feb 2020
Cited by 26 | Viewed by 6161
Abstract
Although conventional immunohistochemistry for neurotropic rabies virus (RABV) usually shows high preference for neurons, non-neuronal cells are also potential targets, and abortive astrocyte infection is considered a main trigger of innate immunity in the CNS. While in vitro studies indicated differences between field [...] Read more.
Although conventional immunohistochemistry for neurotropic rabies virus (RABV) usually shows high preference for neurons, non-neuronal cells are also potential targets, and abortive astrocyte infection is considered a main trigger of innate immunity in the CNS. While in vitro studies indicated differences between field and less virulent lab-adapted RABVs, a systematic, quantitative comparison of astrocyte tropism in vivo is lacking. Here, solvent-based tissue clearing was used to measure RABV cell tropism in infected brains. Immunofluorescence analysis of 1 mm-thick tissue slices enabled 3D-segmentation and quantification of astrocyte and neuron infection frequencies. Comparison of three highly virulent field virus clones from fox, dog, and raccoon with three lab-adapted strains revealed remarkable differences in the ability to infect astrocytes in vivo. While all viruses and infection routes led to neuron infection frequencies between 7–19%, striking differences appeared for astrocytes. Whereas astrocyte infection by field viruses was detected independent of the inoculation route (8–27%), only one lab-adapted strain infected astrocytes route-dependently [0% after intramuscular (i.m.) and 13% after intracerebral (i.c.) inoculation]. Two lab-adapted vaccine viruses lacked astrocyte infection altogether (0%, i.c. and i.m.). This suggests a model in which the ability to establish productive astrocyte infection in vivo functionally distinguishes field and attenuated lab RABV strains. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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20 pages, 22758 KiB  
Article
The Ebola Virus Nucleoprotein Recruits the Nuclear RNA Export Factor NXF1 into Inclusion Bodies to Facilitate Viral Protein Expression
by Lisa Wendt, Janine Brandt, Bianca S. Bodmer, Sven Reiche, Marie Luisa Schmidt, Shelby Traeger and Thomas Hoenen
Cells 2020, 9(1), 187; https://doi.org/10.3390/cells9010187 - 11 Jan 2020
Cited by 25 | Viewed by 5397
Abstract
Ebola virus (EBOV) causes severe outbreaks of viral hemorrhagic fever in humans. While virus-host interactions are promising targets for antivirals, there is only limited knowledge regarding the interactions of EBOV with cellular host factors. Recently, we performed a genome-wide siRNA screen that identified [...] Read more.
Ebola virus (EBOV) causes severe outbreaks of viral hemorrhagic fever in humans. While virus-host interactions are promising targets for antivirals, there is only limited knowledge regarding the interactions of EBOV with cellular host factors. Recently, we performed a genome-wide siRNA screen that identified the nuclear RNA export factor 1 (NXF1) as an important host factor for the EBOV life cycle. NXF1 is a major component of the nuclear mRNA export pathway that is usurped by many viruses whose life cycles include nuclear stages. However, the role of NXF1 in the life cycle of EBOV, a virus replicating in cytoplasmic inclusion bodies, remains unknown. In order to better understand the role of NXF1 in the EBOV life cycle, we performed a combination of co-immunoprecipitation and double immunofluorescence assays to characterize the interactions of NXF1 with viral proteins and RNAs. Additionally, using siRNA-mediated knockdown of NXF1 together with functional assays, we analyzed the role of NXF1 in individual aspects of the virus life cycle. With this approach we identified the EBOV nucleoprotein (NP) as a viral interaction partner of NXF1. Further studies revealed that NP interacts with the RNA-binding domain of NXF1 and competes with RNA for this interaction. Co-localization studies showed that RNA binding-deficient, but not wildtype NXF1, accumulates in NP-derived inclusion bodies, and knockdown experiments demonstrated that NXF1 is necessary for viral protein expression, but not for viral RNA synthesis. Finally, our results showed that NXF1 interacts with viral mRNAs, but not with viral genomic RNAs. Based on these results we suggest a model whereby NXF1 is recruited into inclusion bodies to promote the export of viral mRNA:NXF1 complexes from these sites. This would represent a novel function for NXF1 in the life cycle of cytoplasmically replicating viruses, and may provide a basis for new therapeutic approaches against EBOV, and possibly other emerging viruses. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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20 pages, 4991 KiB  
Article
Fluorescent TAP as a Platform for Virus-Induced Degradation of the Antigenic Peptide Transporter
by Magda Wąchalska, Małgorzata Graul, Patrique Praest, Rutger D. Luteijn, Aleksandra W. Babnis, Emmanuel J. H. J. Wiertz, Krystyna Bieńkowska-Szewczyk and Andrea D. Lipińska
Cells 2019, 8(12), 1590; https://doi.org/10.3390/cells8121590 - 07 Dec 2019
Cited by 6 | Viewed by 4563
Abstract
Transporter associated with antigen processing (TAP), a key player in the major histocompatibility complex class I-restricted antigen presentation, makes an attractive target for viruses that aim to escape the immune system. Mechanisms of TAP inhibition vary among virus species. Bovine herpesvirus 1 (BoHV-1) [...] Read more.
Transporter associated with antigen processing (TAP), a key player in the major histocompatibility complex class I-restricted antigen presentation, makes an attractive target for viruses that aim to escape the immune system. Mechanisms of TAP inhibition vary among virus species. Bovine herpesvirus 1 (BoHV-1) is unique in its ability to target TAP for proteasomal degradation following conformational arrest by the UL49.5 gene product. The exact mechanism of TAP removal still requires elucidation. For this purpose, a TAP-GFP (green fluorescent protein) fusion protein is instrumental, yet GFP-tagging may affect UL49.5-induced degradation. Therefore, we constructed a series of TAP-GFP variants using various linkers to obtain an optimal cellular fluorescent TAP platform. Mel JuSo (MJS) cells with CRISPR/Cas9 TAP1 or TAP2 knockouts were reconstituted with TAP-GFP constructs. Our results point towards a critical role of GFP localization on fluorescent properties of the fusion proteins and, in concert with the type of a linker, on the susceptibility to virally-induced inhibition and degradation. The fluorescent TAP platform was also used to re-evaluate TAP stability in the presence of other known viral TAP inhibitors, among which only UL49.5 was able to reduce TAP levels. Finally, we provide evidence that BoHV-1 UL49.5-induced TAP removal is p97-dependent, which indicates its degradation via endoplasmic reticulum-associated degradation (ERAD). Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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21 pages, 5710 KiB  
Article
The Host Factor Erlin-1 is Required for Efficient Hepatitis C Virus Infection
by Christina Whitten-Bauer, Josan Chung, Andoni Gómez-Moreno, Pilar Gomollón-Zueco, Michael D. Huber, Larry Gerace and Urtzi Garaigorta
Cells 2019, 8(12), 1555; https://doi.org/10.3390/cells8121555 - 02 Dec 2019
Cited by 9 | Viewed by 3222
Abstract
Development of hepatitis C virus (HCV) infection cell culture systems has permitted the identification of cellular factors that regulate the HCV life cycle. Some of these cellular factors affect steps in the viral life cycle that are tightly associated with intracellular membranes derived [...] Read more.
Development of hepatitis C virus (HCV) infection cell culture systems has permitted the identification of cellular factors that regulate the HCV life cycle. Some of these cellular factors affect steps in the viral life cycle that are tightly associated with intracellular membranes derived from the endoplasmic reticulum (ER). Here, we describe the discovery of erlin-1 protein as a cellular factor that regulates HCV infection. Erlin-1 is a cholesterol-binding protein located in detergent-resistant membranes within the ER. It is implicated in cholesterol homeostasis and the ER-associated degradation pathway. Silencing of erlin-1 protein expression by siRNA led to decreased infection efficiency characterized by reduction in intracellular RNA accumulation, HCV protein expression and virus production. Mechanistic studies revealed that erlin-1 protein is required early in the infection, downstream of cell entry and primary translation, specifically to initiate RNA replication, and later in the infection to support infectious virus production. This study identifies erlin-1 protein as an important cellular factor regulating HCV infection. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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18 pages, 6296 KiB  
Article
The Combination of IFN β and TNF Induces an Antiviral and Immunoregulatory Program via Non-Canonical Pathways Involving STAT2 and IRF9
by Mélissa K. Mariani, Pouria Dasmeh, Audray Fortin, Elise Caron, Mario Kalamujic, Alexander N. Harrison, Diana I. Hotea, Dacquin M. Kasumba, Sandra L. Cervantes-Ortiz, Espérance Mukawera, Adrian W. R. Serohijos and Nathalie Grandvaux
Cells 2019, 8(8), 919; https://doi.org/10.3390/cells8080919 - 17 Aug 2019
Cited by 12 | Viewed by 5482
Abstract
Interferon (IFN) β and Tumor Necrosis Factor (TNF) are key players in immunity against viruses. Compelling evidence has shown that the antiviral and inflammatory transcriptional response induced by IFNβ is reprogrammed by crosstalk with TNF. IFNβ mainly induces interferon-stimulated genes by the Janus [...] Read more.
Interferon (IFN) β and Tumor Necrosis Factor (TNF) are key players in immunity against viruses. Compelling evidence has shown that the antiviral and inflammatory transcriptional response induced by IFNβ is reprogrammed by crosstalk with TNF. IFNβ mainly induces interferon-stimulated genes by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway involving the canonical ISGF3 transcriptional complex, composed of STAT1, STAT2, and IRF9. The signaling pathways engaged downstream of the combination of IFNβ and TNF remain elusive, but previous observations suggested the existence of a response independent of STAT1. Here, using genome-wide transcriptional analysis by RNASeq, we observed a broad antiviral and immunoregulatory response initiated in the absence of STAT1 upon IFNβ and TNF costimulation. Additional stratification of this transcriptional response revealed that STAT2 and IRF9 mediate the expression of a wide spectrum of genes. While a subset of genes was regulated by the concerted action of STAT2 and IRF9, other gene sets were independently regulated by STAT2 or IRF9. Collectively, our data supports a model in which STAT2 and IRF9 act through non-canonical parallel pathways to regulate distinct pool of antiviral and immunoregulatory genes in conditions with elevated levels of both IFNβ and TNF. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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22 pages, 4963 KiB  
Article
Teratogenic Rubella Virus Alters the Endodermal Differentiation Capacity of Human Induced Pluripotent Stem Cells
by Nicole C. Bilz, Edith Willscher, Hans Binder, Janik Böhnke, Megan L. Stanifer, Denise Hübner, Steeve Boulant, Uwe G. Liebert and Claudia Claus
Cells 2019, 8(8), 870; https://doi.org/10.3390/cells8080870 - 10 Aug 2019
Cited by 13 | Viewed by 5309
Abstract
The study of congenital virus infections in humans requires suitable ex vivo platforms for the species-specific events during embryonal development. A prominent example for these infections is rubella virus (RV) which most commonly leads to defects in ear, heart, and eye development. We [...] Read more.
The study of congenital virus infections in humans requires suitable ex vivo platforms for the species-specific events during embryonal development. A prominent example for these infections is rubella virus (RV) which most commonly leads to defects in ear, heart, and eye development. We applied teratogenic RV to human induced pluripotent stem cells (iPSCs) followed by differentiation into cells of the three embryonic lineages (ecto-, meso-, and endoderm) as a cell culture model for blastocyst- and gastrulation-like stages. In the presence of RV, lineage-specific differentiation markers were expressed, indicating that lineage identity was maintained. However, portrait analysis of the transcriptomic expression signatures of all samples revealed that mock- and RV-infected endodermal cells were less related to each other than their ecto- and mesodermal counterparts. Markers for definitive endoderm were increased during RV infection. Profound alterations of the epigenetic landscape including the expression level of components of the chromatin remodeling complexes and an induction of type III interferons were found, especially after endodermal differentiation of RV-infected iPSCs. Moreover, the eye field transcription factors RAX and SIX3 and components of the gene set vasculogenesis were identified as dysregulated transcripts. Although iPSC morphology was maintained, the formation of embryoid bodies as three-dimensional cell aggregates and as such cellular adhesion capacity was impaired during RV infection. The correlation of the molecular alterations induced by RV during differentiation of iPSCs with the clinical signs of congenital rubella syndrome suggests mechanisms of viral impairment of human development. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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Review

Jump to: Editorial, Research, Other

24 pages, 1932 KiB  
Review
Infection of Mammals and Mosquitoes by Alphaviruses: Involvement of Cell Death
by Lucie Cappuccio and Carine Maisse
Cells 2020, 9(12), 2612; https://doi.org/10.3390/cells9122612 - 05 Dec 2020
Cited by 4 | Viewed by 2759
Abstract
Alphaviruses, such as the chikungunya virus, are emerging and re-emerging viruses that pose a global public health threat. They are transmitted by blood-feeding arthropods, mainly mosquitoes, to humans and animals. Although alphaviruses cause debilitating diseases in mammalian hosts, it appears that they have [...] Read more.
Alphaviruses, such as the chikungunya virus, are emerging and re-emerging viruses that pose a global public health threat. They are transmitted by blood-feeding arthropods, mainly mosquitoes, to humans and animals. Although alphaviruses cause debilitating diseases in mammalian hosts, it appears that they have no pathological effect on the mosquito vector. Alphavirus/host interactions are increasingly studied at cellular and molecular levels. While it seems clear that apoptosis plays a key role in some human pathologies, the role of cell death in determining the outcome of infections in mosquitoes remains to be fully understood. Here, we review the current knowledge on alphavirus-induced regulated cell death in hosts and vectors and the possible role they play in determining tolerance or resistance of mosquitoes. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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30 pages, 2142 KiB  
Review
“Repair Me if You Can”: Membrane Damage, Response, and Control from the Viral Perspective
by Coralie F. Daussy and Harald Wodrich
Cells 2020, 9(9), 2042; https://doi.org/10.3390/cells9092042 - 07 Sep 2020
Cited by 19 | Viewed by 4301
Abstract
Cells are constantly challenged by pathogens (bacteria, virus, and fungi), and protein aggregates or chemicals, which can provoke membrane damage at the plasma membrane or within the endo-lysosomal compartments. Detection of endo-lysosomal rupture depends on a family of sugar-binding lectins, known as galectins, [...] Read more.
Cells are constantly challenged by pathogens (bacteria, virus, and fungi), and protein aggregates or chemicals, which can provoke membrane damage at the plasma membrane or within the endo-lysosomal compartments. Detection of endo-lysosomal rupture depends on a family of sugar-binding lectins, known as galectins, which sense the abnormal exposure of glycans to the cytoplasm upon membrane damage. Galectins in conjunction with other factors orchestrate specific membrane damage responses such as the recruitment of the endosomal sorting complex required for transport (ESCRT) machinery to either repair damaged membranes or the activation of autophagy to remove membrane remnants. If not controlled, membrane damage causes the release of harmful components including protons, reactive oxygen species, or cathepsins that will elicit inflammation. In this review, we provide an overview of current knowledge on membrane damage and cellular responses. In particular, we focus on the endo-lysosomal damage triggered by non-enveloped viruses (such as adenovirus) and discuss viral strategies to control the cellular membrane damage response. Finally, we debate the link between autophagy and inflammation in this context and discuss the possibility that virus induced autophagy upon entry limits inflammation. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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14 pages, 1535 KiB  
Review
On the Host Side of the Hepatitis E Virus Life Cycle
by Noémie Oechslin, Darius Moradpour and Jérôme Gouttenoire
Cells 2020, 9(5), 1294; https://doi.org/10.3390/cells9051294 - 22 May 2020
Cited by 17 | Viewed by 4508
Abstract
Hepatitis E virus (HEV) infection is one of the most common causes of acute hepatitis in the world. HEV is an enterically transmitted positive-strand RNA virus found as a non-enveloped particle in bile as well as stool and as a quasi-enveloped particle in [...] Read more.
Hepatitis E virus (HEV) infection is one of the most common causes of acute hepatitis in the world. HEV is an enterically transmitted positive-strand RNA virus found as a non-enveloped particle in bile as well as stool and as a quasi-enveloped particle in blood. Current understanding of the molecular mechanisms and host factors involved in productive HEV infection is incomplete, but recently developed model systems have facilitated rapid progress in this area. Here, we provide an overview of the HEV life cycle with a focus on the host factors required for viral entry, RNA replication, assembly and release. Further developments of HEV model systems and novel technologies should yield a broader picture in the future. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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17 pages, 3677 KiB  
Review
Environmental Restrictions: A New Concept Governing HIV-1 Spread Emerging from Integrated Experimental-Computational Analysis of Tissue-Like 3D Cultures
by Samy Sid Ahmed, Nils Bundgaard, Frederik Graw and Oliver T. Fackler
Cells 2020, 9(5), 1112; https://doi.org/10.3390/cells9051112 - 30 Apr 2020
Cited by 8 | Viewed by 3280
Abstract
HIV-1 can use cell-free and cell-associated transmission modes to infect new target cells, but how the virus spreads in the infected host remains to be determined. We recently established 3D collagen cultures to study HIV-1 spread in tissue-like environments and applied iterative cycles [...] Read more.
HIV-1 can use cell-free and cell-associated transmission modes to infect new target cells, but how the virus spreads in the infected host remains to be determined. We recently established 3D collagen cultures to study HIV-1 spread in tissue-like environments and applied iterative cycles of experimentation and computation to develop a first in silico model to describe the dynamics of HIV-1 spread in complex tissue. These analyses (i) revealed that 3D collagen environments restrict cell-free HIV-1 infection but promote cell-associated virus transmission and (ii) defined that cell densities in tissue dictate the efficacy of these transmission modes for virus spread. In this review, we discuss, in the context of the current literature, the implications of this study for our understanding of HIV-1 spread in vivo, which aspects of in vivo physiology this integrated experimental–computational analysis takes into account, and how it can be further improved experimentally and in silico. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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12 pages, 810 KiB  
Review
Activation of the PI3K-AKT Pathway by Old World Alphaviruses
by Eline Van Huizen and Gerald M. McInerney
Cells 2020, 9(4), 970; https://doi.org/10.3390/cells9040970 - 15 Apr 2020
Cited by 20 | Viewed by 6675
Abstract
Alphaviruses can infect a broad range of vertebrate hosts, including birds, horses, primates, and humans, in which infection can lead to rash, fever, encephalitis, and arthralgia or arthritis. They are most often transmitted by mosquitoes in which they establish persistent, asymptomatic infections. Currently, [...] Read more.
Alphaviruses can infect a broad range of vertebrate hosts, including birds, horses, primates, and humans, in which infection can lead to rash, fever, encephalitis, and arthralgia or arthritis. They are most often transmitted by mosquitoes in which they establish persistent, asymptomatic infections. Currently, there are no vaccines or antiviral therapies for any alphavirus. Several Old World alphaviruses, including Semliki Forest virus, Ross River virus and chikungunya virus, activate or hyperactivate the phosphatidylinositol-3-kinase (PI3K)-AKT pathway in vertebrate cells, potentially influencing many cellular processes, including survival, proliferation, metabolism and autophagy. Inhibition of PI3K or AKT inhibits replication of several alphaviruses either in vitro or in vivo, indicating the importance for viral replication. In this review, we discuss what is known about the mechanism(s) of activation of the pathway during infection and describe those effects of PI3K-AKT activation which could be of advantage to the alphaviruses. Such knowledge may be useful for the identification and development of therapies. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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26 pages, 3760 KiB  
Review
Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy
by Hong-My Nguyen, Kirsten Guz-Montgomery and Dipongkor Saha
Cells 2020, 9(2), 400; https://doi.org/10.3390/cells9020400 - 10 Feb 2020
Cited by 56 | Viewed by 8895
Abstract
Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). [...] Read more.
Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). IL-12 is a potent anti-cancer agent that promotes T-helper 1 (Th1) differentiation, facilitates T-cell-mediated killing of cancer cells, and inhibits tumor angiogenesis. Despite success in preclinical models, systemic IL-12 therapy is associated with significant toxicity in humans. Therefore, to utilize the therapeutic potential of IL-12 in OV-based cancer therapy, 25 different IL-12 expressing OVs (OV-IL12s) have been genetically engineered for local IL-12 production and tested preclinically in various cancer models. Among OV-IL12s, oncolytic herpes simplex virus encoding IL-12 (OHSV-IL12) is the furthest along in the clinic. IL-12 expression locally in the tumors avoids systemic toxicity while inducing an efficient anti-tumor immunity and synergizes with anti-angiogenic drugs or immunomodulators without compromising safety. Despite the rapidly rising interest, there are no current reviews on OV-IL12s that exploit their potential efficacy and safety to translate into human subjects. In this article, we will discuss safety, tumor-specificity, and anti-tumor immune/anti-angiogenic effects of OHSV-IL12 as mono- and combination-therapies. In addition to OHSV-IL12 viruses, we will also review other IL-12-expressing OVs and their application in cancer therapy. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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13 pages, 1473 KiB  
Review
Host Calcium Channels and Pumps in Viral Infections
by Xingjuan Chen, Ruiyuan Cao and Wu Zhong
Cells 2020, 9(1), 94; https://doi.org/10.3390/cells9010094 - 30 Dec 2019
Cited by 88 | Viewed by 12118
Abstract
Ca2+ is essential for virus entry, viral gene replication, virion maturation, and release. The alteration of host cells Ca2+ homeostasis is one of the strategies that viruses use to modulate host cells signal transduction mechanisms in their favor. Host calcium-permeable channels [...] Read more.
Ca2+ is essential for virus entry, viral gene replication, virion maturation, and release. The alteration of host cells Ca2+ homeostasis is one of the strategies that viruses use to modulate host cells signal transduction mechanisms in their favor. Host calcium-permeable channels and pumps (including voltage-gated calcium channels, store-operated channels, receptor-operated channels, transient receptor potential ion channels, and Ca2+-ATPase) mediate Ca2+ across the plasma membrane or subcellular organelles, modulating intracellular free Ca2+. Therefore, these Ca2+ channels or pumps present important aspects of viral pathogenesis and virus–host interaction. It has been reported that viruses hijack host calcium channels or pumps, disturbing the cellular homeostatic balance of Ca2+. Such a disturbance benefits virus lifecycles while inducing host cells’ morbidity. Evidence has emerged that pharmacologically targeting the calcium channel or calcium release from the endoplasmic reticulum (ER) can obstruct virus lifecycles. Impeding virus-induced abnormal intracellular Ca2+ homeostasis is becoming a useful strategy in the development of potent antiviral drugs. In this present review, the recent identified cellular calcium channels and pumps as targets for virus attack are emphasized. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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Other

15 pages, 1058 KiB  
Opinion
Coronaviruses: Is Sialic Acid a Gate to the Eye of Cytokine Storm? From the Entry to the Effects
by Przemyslaw Wielgat, Karol Rogowski, Katarzyna Godlewska and Halina Car
Cells 2020, 9(9), 1963; https://doi.org/10.3390/cells9091963 - 25 Aug 2020
Cited by 34 | Viewed by 6771
Abstract
Coronaviruses (CoVs) are a diverse family of the enveloped human and animal viruses reported as causative agents for respiratory and intestinal infections. The high pathogenic potential of human CoVs, including SARS-CoV, MERS-CoV and SARS-CoV-2, is closely related to the invasion mechanisms underlying the [...] Read more.
Coronaviruses (CoVs) are a diverse family of the enveloped human and animal viruses reported as causative agents for respiratory and intestinal infections. The high pathogenic potential of human CoVs, including SARS-CoV, MERS-CoV and SARS-CoV-2, is closely related to the invasion mechanisms underlying the attachment and entry of viral particles to the host cells. There is increasing evidence that sialylated compounds of cellular glycocalyx can serve as an important factor in the mechanism of CoVs infection. Additionally, the sialic acid-mediated cross-reactivity with the host immune lectins is known to exert the immune response of different intensity in selected pathological stages. Here, we focus on the last findings in the field of glycobiology in the context of the role of sialic acid in tissue tropism, viral entry kinetics and immune regulation in the CoVs infections. Full article
(This article belongs to the Special Issue Cell Biology of Viral Infections)
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