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Editorial

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3 pages, 170 KiB

Open AccessEditorial

Virus–Host Cell Interactions

by Thomas Hoenen and Allison Groseth

Cells 2022, 11(5), 804; https://doi.org/10.3390/cells11050804 - 25 Feb 2022

Cited by 11 | Viewed by 2257

Abstract

As obligate intracellular parasites, viruses are intimately interconnected with their host cells [...] Full article

(This article belongs to the Special Issue Virus — Host Cell Interactions)

Research

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20 pages, 3184 KiB

Open AccessArticle

Interferon-Induced HERC5 Inhibits Ebola Virus Particle Production and Is Antagonized by Ebola Glycoprotein

by Ermela Paparisto, Nina R. Hunt, Daniel S. Labach, Macon D. Coleman, Eric J. Di Gravio, Mackenzie J. Dodge, Nicole J. Friesen, Marceline Côté, Andreas Müller, Thomas Hoenen and Stephen D. Barr

Cells 2021, 10(9), 2399; https://doi.org/10.3390/cells10092399 - 13 Sep 2021

Cited by 3 | Viewed by 3469

Abstract

Survival following Ebola virus (EBOV) infection correlates with the ability to mount an early and robust interferon (IFN) response. The host IFN-induced proteins that contribute to controlling EBOV replication are not fully known. Among the top genes with the strongest early increases in [...] Read more.

Survival following Ebola virus (EBOV) infection correlates with the ability to mount an early and robust interferon (IFN) response. The host IFN-induced proteins that contribute to controlling EBOV replication are not fully known. Among the top genes with the strongest early increases in expression after infection in vivo is IFN-induced HERC5. Using a transcription- and replication-competent VLP system, we showed that HERC5 inhibits EBOV virus-like particle (VLP) replication by depleting EBOV mRNAs. The HERC5 RCC1-like domain was necessary and sufficient for this inhibition and did not require zinc finger antiviral protein (ZAP). Moreover, we showed that EBOV (Zaire) glycoprotein (GP) but not Marburg virus GP antagonized HERC5 early during infection. Our data identify a novel ‘protagonist–antagonistic’ relationship between HERC5 and GP in the early stages of EBOV infection that could be exploited for the development of novel antiviral therapeutics. Full article

(This article belongs to the Special Issue Virus — Host Cell Interactions)

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25 pages, 2637 KiB

Open AccessArticle

The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry

by Jared Kirui, Yara Abidine, Annasara Lenman, Koushikul Islam, Yong-Dae Gwon, Lisa Lasswitz, Magnus Evander, Marta Bally and Gisa Gerold

Cells 2021, 10(7), 1828; https://doi.org/10.3390/cells10071828 - 20 Jul 2021

Cited by 19 | Viewed by 4871

Abstract

Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain [...] Read more.

Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood. The phosphatidylserine-dependent receptors, T-cell immunoglobulin and mucin domain 1 (TIM-1) and Axl receptor tyrosine kinase (Axl), are transmembrane proteins that can serve as entry factors for enveloped viruses. Previous studies used pseudoviruses to delineate the role of TIM-1 and Axl in CHIKV entry. Conversely, here, we use the authentic CHIKV and cells ectopically expressing TIM-1 or Axl and demonstrate a role for TIM-1 in CHIKV infection. To further characterize TIM-1-dependent CHIKV infection, we generated cells expressing domain mutants of TIM-1. We show that point mutations in the phosphatidylserine binding site of TIM-1 lead to reduced cell binding, entry, and infection of CHIKV. Ectopic expression of TIM-1 renders immortalized keratinocytes permissive to CHIKV, whereas silencing of endogenously expressed TIM-1 in human hepatoma cells reduces CHIKV infection. Altogether, our findings indicate that, unlike Axl, TIM-1 readily promotes the productive entry of authentic CHIKV into target cells. Full article

(This article belongs to the Special Issue Virus — Host Cell Interactions)

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14 pages, 4293 KiB

Open AccessArticle

Nipah Virus Efficiently Replicates in Human Smooth Muscle Cells without Cytopathic Effect

by Blair L. DeBuysscher, Dana P. Scott, Rebecca Rosenke, Victoria Wahl, Heinz Feldmann and Joseph Prescott

Cells 2021, 10(6), 1319; https://doi.org/10.3390/cells10061319 - 25 May 2021

Cited by 4 | Viewed by 3198

Abstract

Nipah virus (NiV) is a highly pathogenic zoonotic virus with a broad species tropism, originating in pteropid bats. Human outbreaks of NiV disease occur almost annually, often with high case-fatality rates. The specific events that lead to pathogenesis are not well defined, but [...] Read more.

Nipah virus (NiV) is a highly pathogenic zoonotic virus with a broad species tropism, originating in pteropid bats. Human outbreaks of NiV disease occur almost annually, often with high case-fatality rates. The specific events that lead to pathogenesis are not well defined, but the disease has both respiratory and encephalitic components, with relapsing encephalitis occurring in some cases more than a year after initial infection. Several cell types are targets of NiV, dictated by the expression of the ephrin-B2/3 ligand on the cell’s outer membrane, which interact with the NiV surface proteins. Vascular endothelial cells (ECs) are major targets of infection. Cytopathic effects (CPE), characterized by syncytia formation and cell death, and an ensuing vasculitis, are a major feature of the disease. Smooth muscle cells (SMCs) of the tunica media that line small blood vessels are infected in humans and animal models of NiV disease, although pathology or histologic changes associated with antigen-positive SMCs have not been reported. To gain an understanding of the possible contributions that SMCs might have in the development of NiV disease, we investigated the susceptibility and potential cytopathogenic changes of human SMCs to NiV infection in vitro. SMCs were permissive for NiV infection and resulted in high titers and prolonged NiV production, despite a lack of cytopathogenicity, and in the absence of detectable ephrin-B2/3. These results indicate that SMC might be important contributors to disease by producing progeny NiV during an infection, without suffering cytopathogenic consequences. Full article

(This article belongs to the Special Issue Virus — Host Cell Interactions)

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19 pages, 2081 KiB

Open AccessArticle

Dysregulated Host Responses Underlie 2009 Pandemic Influenza-Methicillin Resistant Staphylococcus aureus Coinfection Pathogenesis at the Alveolar-Capillary Barrier

by Michaela E. Nickol, Sarah M. Lyle, Brendan Dennehy and Jason Kindrachuk

Cells 2020, 9(11), 2472; https://doi.org/10.3390/cells9112472 - 13 Nov 2020

Cited by 3 | Viewed by 2532

Abstract

Influenza viruses are a continual public health concern resulting in 3–5 million severe infections annually despite intense vaccination campaigns and messaging. Secondary bacterial infections, including Staphylococcus aureus, result in increased morbidity and mortality during seasonal epidemics and pandemics. While coinfections can result [...] Read more.

Influenza viruses are a continual public health concern resulting in 3–5 million severe infections annually despite intense vaccination campaigns and messaging. Secondary bacterial infections, including Staphylococcus aureus, result in increased morbidity and mortality during seasonal epidemics and pandemics. While coinfections can result in deleterious pathologic consequences, including alveolar-capillary barrier disruption, the underlying mechanisms are poorly understood. We have characterized host- and pathogen-centric mechanisms contributing to influenza-bacterial coinfections in a primary cell coculture model of the alveolar-capillary barrier. Using 2009 pandemic influenza (pH1N1) and methicillin-resistant S. aureus (MRSA), we demonstrate that coinfection resulted in dysregulated barrier function. Preinfection with pH1N1 resulted in modulation of adhesion- and invasion-associated MRSA virulence factors during lag phase bacterial replication. Host response modulation in coinfected alveolar epithelial cells were primarily related to TLR- and inflammatory response-mediated cell signaling events. While less extensive in cocultured endothelial cells, coinfection resulted in changes to cellular stress response- and TLR-related signaling events. Analysis of cytokine expression suggested that cytokine secretion might play an important role in coinfection pathogenesis. Taken together, we demonstrate that coinfection pathogenesis is related to complex host- and pathogen-mediated events impacting both epithelial and endothelial cell regulation at the alveolar-capillary barrier. Full article

(This article belongs to the Special Issue Virus — Host Cell Interactions)

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Review

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16 pages, 3000 KiB

Open AccessReview

Ultrastructural Features of Membranous Replication Organelles Induced by Positive-Stranded RNA Viruses

by Van Nguyen-Dinh and Eva Herker

Cells 2021, 10(9), 2407; https://doi.org/10.3390/cells10092407 - 13 Sep 2021

Cited by 9 | Viewed by 4953

Abstract

All intracellular pathogens critically depend on host cell organelles and metabolites for successful infection and replication. One hallmark of positive-strand RNA viruses is to induce alterations of the (endo)membrane system in order to shield their double-stranded RNA replication intermediates from detection by the [...] Read more.

All intracellular pathogens critically depend on host cell organelles and metabolites for successful infection and replication. One hallmark of positive-strand RNA viruses is to induce alterations of the (endo)membrane system in order to shield their double-stranded RNA replication intermediates from detection by the host cell’s surveillance systems. This spatial seclusion also allows for accruing host and viral factors and building blocks required for efficient replication of the genome and prevents access of antiviral effectors. Even though the principle is iterated by almost all positive-strand RNA viruses infecting plants and animals, the specific structure and the organellar source of membranes differs. Here, we discuss the characteristic ultrastructural features of the virus-induced membranous replication organelles in plant and animal cells and the scientific progress gained by advanced microscopy methods. Full article

(This article belongs to the Special Issue Virus — Host Cell Interactions)

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23 pages, 2780 KiB

Open AccessFeature PaperReview

How Influenza Virus Uses Host Cell Pathways during Uncoating

by Etori Aguiar Moreira, Yohei Yamauchi and Patrick Matthias

Cells 2021, 10(7), 1722; https://doi.org/10.3390/cells10071722 - 08 Jul 2021

Cited by 19 | Viewed by 7703

Abstract

Influenza is a zoonotic respiratory disease of major public health interest due to its pandemic potential, and a threat to animals and the human population. The influenza A virus genome consists of eight single-stranded RNA segments sequestered within a protein capsid and a [...] Read more.

Influenza is a zoonotic respiratory disease of major public health interest due to its pandemic potential, and a threat to animals and the human population. The influenza A virus genome consists of eight single-stranded RNA segments sequestered within a protein capsid and a lipid bilayer envelope. During host cell entry, cellular cues contribute to viral conformational changes that promote critical events such as fusion with late endosomes, capsid uncoating and viral genome release into the cytosol. In this focused review, we concisely describe the virus infection cycle and highlight the recent findings of host cell pathways and cytosolic proteins that assist influenza uncoating during host cell entry. Full article

(This article belongs to the Special Issue Virus — Host Cell Interactions)

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22 pages, 2495 KiB

Open AccessReview

New Perspectives on the Biogenesis of Viral Inclusion Bodies in Negative-Sense RNA Virus Infections

by Olga Dolnik, Gesche K. Gerresheim and Nadine Biedenkopf

Cells 2021, 10(6), 1460; https://doi.org/10.3390/cells10061460 - 10 Jun 2021

Cited by 25 | Viewed by 7546

Abstract

Infections by negative strand RNA viruses (NSVs) induce the formation of viral inclusion bodies (IBs) in the host cell that segregate viral as well as cellular proteins to enable efficient viral replication. The induction of those membrane-less viral compartments leads inevitably to structural [...] Read more.

Infections by negative strand RNA viruses (NSVs) induce the formation of viral inclusion bodies (IBs) in the host cell that segregate viral as well as cellular proteins to enable efficient viral replication. The induction of those membrane-less viral compartments leads inevitably to structural remodeling of the cellular architecture. Recent studies suggested that viral IBs have properties of biomolecular condensates (or liquid organelles), as have previously been shown for other membrane-less cellular compartments like stress granules or P-bodies. Biomolecular condensates are highly dynamic structures formed by liquid-liquid phase separation (LLPS). Key drivers for LLPS in cells are multivalent protein:protein and protein:RNA interactions leading to specialized areas in the cell that recruit molecules with similar properties, while other non-similar molecules are excluded. These typical features of cellular biomolecular condensates are also a common characteristic in the biogenesis of viral inclusion bodies. Viral IBs are predominantly induced by the expression of the viral nucleoprotein (N, NP) and phosphoprotein (P); both are characterized by a special protein architecture containing multiple disordered regions and RNA-binding domains that contribute to different protein functions. P keeps N soluble after expression to allow a concerted binding of N to the viral RNA. This results in the encapsidation of the viral genome by N, while P acts additionally as a cofactor for the viral polymerase, enabling viral transcription and replication. Here, we will review the formation and function of those viral inclusion bodies upon infection with NSVs with respect to their nature as biomolecular condensates. Full article

(This article belongs to the Special Issue Virus — Host Cell Interactions)

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17 pages, 2472 KiB

Open AccessReview

Complex Roles of Neutrophils during Arboviral Infections

by Abenaya Muralidharan and St Patrick Reid

Cells 2021, 10(6), 1324; https://doi.org/10.3390/cells10061324 - 26 May 2021

Cited by 7 | Viewed by 4078

Abstract

Arboviruses are known to cause large-scale epidemics in many parts of the world. These arthropod-borne viruses are a large group consisting of viruses from a wide range of families. The ability of their vector to enhance viral pathogenesis and transmission makes the development [...] Read more.

Arboviruses are known to cause large-scale epidemics in many parts of the world. These arthropod-borne viruses are a large group consisting of viruses from a wide range of families. The ability of their vector to enhance viral pathogenesis and transmission makes the development of treatments against these viruses challenging. Neutrophils are generally the first leukocytes to be recruited to a site of infection, playing a major role in regulating inflammation and, as a result, viral replication and dissemination. However, the underlying mechanisms through which neutrophils control the progression of inflammation and disease remain to be fully understood. In this review, we highlight the major findings from recent years regarding the role of neutrophils during arboviral infections. We discuss the complex nature of neutrophils in mediating not only protection, but also augmenting disease pathology. Better understanding of neutrophil pathways involved in effective protection against arboviral infections can help identify potential targets for therapeutics. Full article

(This article belongs to the Special Issue Virus — Host Cell Interactions)

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12 pages, 666 KiB

Open AccessFeature PaperReview

Post-Transcriptional Regulation of Viral RNA through Epitranscriptional Modification

by David G. Courtney

Cells 2021, 10(5), 1129; https://doi.org/10.3390/cells10051129 - 07 May 2021

Cited by 24 | Viewed by 4188

Abstract

The field of mRNA modifications has been steadily growing in recent years as technologies have improved and the importance of these residues became clear. However, a subfield has also arisen, specifically focused on how these modifications affect viral RNA, with the possibility that [...] Read more.

The field of mRNA modifications has been steadily growing in recent years as technologies have improved and the importance of these residues became clear. However, a subfield has also arisen, specifically focused on how these modifications affect viral RNA, with the possibility that viruses can also be used as a model to best determine the role that these modifications play on cellular mRNAs. First, virologists focused on the most abundant internal mRNA modification, m⁶A, mapping this modification and elucidating its effects on the RNA of a wide range of RNA and DNA viruses. Next, less common RNA modifications including m⁵C, Nm and ac⁴C were investigated and also found to be present on viral RNA. It now appears that viral RNA is littered with a multitude of RNA modifications. In biological systems that are under constant evolutionary pressure to out compete both the host as well as newly arising viral mutants, it poses an interesting question about what evolutionary benefit these modifications provide as it seems evident, at least to this author, that these modifications have been selected for. In this review, I discuss how RNA modifications are identified on viral RNA and the roles that have now been uncovered for these modifications in regard to viral replication. Finally, I propose some interesting avenues of research that may shed further light on the exact role that these modifications play in viral replication. Full article

(This article belongs to the Special Issue Virus — Host Cell Interactions)

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