scholarly journals The Manifold Roles of Sphingolipids in Viral Infections

2021 ◽  
Vol 12 ◽  
Author(s):  
Elita Avota ◽  
Jochen Bodem ◽  
Janice Chithelen ◽  
Putri Mandasari ◽  
Niklas Beyersdorf ◽  
...  
Keyword(s):  
Measles Virus ◽  
Influenza A ◽  
Ebola Virus ◽  
Viral Infections ◽  
Virus Assembly ◽  
Sphingolipid Metabolism ◽  
Targeted Interventions ◽  
Antiviral Therapies ◽  
Essential Components ◽  
Endosomal Membranes

Sphingolipids are essential components of eukaryotic cells. In this review, we want to exemplarily illustrate what is known about the interactions of sphingolipids with various viruses at different steps of their replication cycles. This includes structural interactions during entry at the plasma membrane or endosomal membranes, early interactions leading to sphingolipid-mediated signal transduction, interactions with internal membranes and lipids during replication, and interactions during virus assembly and budding. Targeted interventions in sphingolipid metabolism – as far as they can be tolerated by cells and organisms – may open novel possibilities to support antiviral therapies. Human immunodeficiency virus type 1 (HIV-1) infections have intensively been studied, but for other viral infections, such as influenza A virus (IAV), measles virus (MV), hepatitis C virus (HCV), dengue virus, Ebola virus, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), investigations are still in their beginnings. As many inhibitors of sphingolipid metabolism are already in clinical use against other diseases, repurposing studies for applications in some viral infections appear to be a promising approach.

Sphingolipids in viral infection

2015 ◽  
Vol 396 (6-7) ◽  
pp. 585-595 ◽  
Author(s):  
Jürgen Schneider-Schaulies ◽  
Sibylle Schneider-Schaulies
Keyword(s):  
Measles Virus ◽  
Influenza A ◽  
Sindbis Virus ◽  
Intracellular Transport ◽  
Ebola Virus ◽  
Surface Expression ◽  
Sphingolipid Metabolism ◽  
C Protein ◽  
Protein Receptors ◽  
Niemann Pick

Abstract Viruses exploit membranes and their components such as sphingolipids in all steps of their life cycle including attachment and membrane fusion, intracellular transport, replication, protein sorting and budding. Examples for sphingolipid-dependent virus entry are found for: human immunodeficiency virus (HIV), which besides its protein receptors also interacts with glycosphingolipids (GSLs); rhinovirus, which promotes the formation of ceramide-enriched platforms and endocytosis; or measles virus (MV), which induces the surface expression of its own receptor CD150 via activation of sphingomyelinases (SMases). While SMase activation was implicated in Ebola virus (EBOV) attachment, the virus utilizes the cholesterol transporter Niemann-Pick C protein 1 (NPC1) as ‘intracellular’ entry receptor after uptake into endosomes. Differential activities of SMases also affect the intracellular milieu required for virus replication. Sindbis virus (SINV), for example, replicates better in cells lacking acid SMase (ASMase). Defined lipid compositions of viral assembly and budding sites influence virus release and infectivity, as found for hepatitis C virus (HCV) or HIV. And finally, viruses manipulate cellular signaling and the sphingolipid metabolism to their advantage, as for example influenza A virus (IAV), which activates sphingosine kinase 1 and the transcription factor NF-κB.

The comparative biochemistry of viruses and humans: an evolutionary path towards autoimmunity

2019 ◽  
Vol 400 (5) ◽  
pp. 629-638 ◽  
Author(s):  
Darja Kanduc
Keyword(s):  
Measles Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Sequence Similarity ◽  
Eukaryotic Cell ◽  
Point Of View ◽  
Peptide Sequence ◽  
Human Viruses ◽  
Archaeal Ancestor ◽  
Borna Disease

Abstract Analyses of the peptide sharing between five common human viruses (Borna disease virus, influenza A virus, measles virus, mumps virus and rubella virus) and the human proteome highlight a massive viral vs. human peptide overlap that is mathematically unexpected. Evolutionarily, the data underscore a strict relationship between viruses and the origin of eukaryotic cells. Indeed, according to the viral eukaryogenesis hypothesis and in light of the endosymbiotic theory, the first eukaryotic cell (our lineage) originated as a consortium consisting of an archaeal ancestor of the eukaryotic cytoplasm, a bacterial ancestor of the mitochondria and a viral ancestor of the nucleus. From a pathologic point of view, the peptide sequence similarity between viruses and humans may provide a molecular platform for autoimmune crossreactions during immune responses following viral infections/immunizations.

scholarly journals Reduced Nucleoprotein availability impairs negative-sense RNA virus replication and promotes host recognition

2021 ◽  
Author(s):  
Benjamin E. Nilsson-Payant ◽  
Daniel Blanco-Melo ◽  
Skyler Uhl ◽  
Beatriz Escudero-Pérez ◽  
Silke Olschewski ◽  
...  
Keyword(s):  
Host Response ◽  
Measles Virus ◽  
Influenza A ◽  
Ebola Virus ◽  
Rna Viruses ◽  
Viral Rna ◽  
Genome Replication ◽  
Replication Machinery ◽  
Molecular Patterns ◽  
Negative Sense

Negative-sense RNA viruses (NSVs) rely on prepackaged viral RNA-dependent RNA polymerases (RdRp) to replicate and transcribe their viral genomes. Their replication machinery consists of an RdRp bound to viral RNA which is wound around a nucleoprotein (NP) scaffold, forming a viral ribonucleoprotein complex. NSV NP is known to regulate transcription and replication of genomic RNA, however its role in maintaining and protecting the viral genetic material is unknown. Here, we exploited host microRNA expression to target NP of influenza A virus and Sendai virus to ascertain how this would impact genomic levels and the host response to infection. We find that in addition to inducing a drastic decrease in genome replication, the antiviral host response in the absence of NP is dramatically enhanced. Additionally, our data shows that insufficient levels of NP prevent the replication machinery of these NSVs to process full-length genomes, resulting in aberrant replication products which form pathogen-associated molecular patterns in the process. These dynamics facilitate immune recognition by cellular pattern recognition receptors leading to a strong host antiviral response. Moreover, we observe that the consequences of limiting NP levels are universal amongst NSVs including Ebola virus, Lassa virus and Measles virus. Overall, these results provide new insights into viral genome replication of negative-sense RNA viruses and highlight novel avenues towards developing effective antiviral strategies, adjuvants, and/or live-attenuated vaccines. IMPORTANCE Negative-sense RNA viruses comprise some of the most important known human pathogens, including influenza A virus, measles virus and Ebola virus. These viruses possess RNA genomes that are unreadable to the host as they require specific viral RNA dependent RNA polymerases in conjunction with other viral proteins such as nucleoprotein to be replicated and transcribed. As this process generates a significant amount of pathogen-associated molecular patterns, this phylum of viruses can result in a robust induction of the intrinsic host cellular response. To circumvent these defenses, these viruses form tightly regulated ribonucleoprotein replication complexes in order to protect their genomes from detection and to prevent excessive aberrant replication. Here we demonstrate the balance that negative-sense RNA viruses must achieve to both replicate efficiently and to avoid induction of the host defenses.

scholarly journals Defective Assembly of Influenza A Virus due to a Mutation in the Polymerase Subunit PA

2006 ◽  
Vol 80 (1) ◽  
pp. 252-261 ◽  
Author(s):  
John F. Regan ◽  
Yuying Liang ◽  
Tristram G. Parslow
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Virus Assembly ◽  
Functional Characterization ◽  
Genomic Rna ◽  
Viral Mrnas ◽  
Virus Particles ◽  
Essential Components ◽  
Viral Genomic Rna

ABSTRACT The RNA-dependent RNA polymerase of influenza A virus is composed of three subunits that together synthesize all viral mRNAs and also replicate the viral genomic RNA segments (vRNAs) through intermediates known as cRNAs. Here we describe functional characterization of 16 site-directed mutants of one polymerase subunit, termed PA. In accord with earlier studies, these mutants exhibited diverse, mainly quantitative impairments in expressing one or more classes of viral RNA, with associated infectivity defects of varying severity. One PA mutant, however, targeting residues 507 and 508, caused only modest perturbations of RNA expression yet completely eliminated the formation of plaque-forming virus. Polymerases incorporating this mutant, designated J10, proved capable of synthesizing translationally active mRNAs and of replicating diverse cRNA or vRNA templates at levels compatible with viral infectivity. Both the mutant protein and its RNA products were appropriately localized in the cytoplasm, where influenza virus assembly occurs. Nevertheless, J10 failed to generate infectious particles from cells in a plasmid-based influenza virus assembly assay, and hemagglutinating material from the supernatants of such cells contained little or no nuclease-resistant genomic RNA. These findings suggest that PA has a previously unrecognized role in assembly or release of influenza virus virions, perhaps influencing core structure or the packaging of vRNAs or other essential components into nascent influenza virus particles.

scholarly journals Transcriptome Analyses Implicate Endogenous Retroviruses Involved in the Host Antiviral Immune System through the Interferon Pathway

2021 ◽  
Author(s):  
Miao Wang ◽  
Liying Wang ◽  
Haizhou Liu ◽  
Jianjun Chen ◽  
Di Liu
Keyword(s):  
Transcriptional Activation ◽  
Measles Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Endogenous Retroviruses ◽  
Influenza B Virus ◽  
Influenza B ◽  
Published Data ◽  
Virus Infections ◽  
Antiviral Immune Response

AbstractHuman endogenous retroviruses (HERVs) are the remains of ancient retroviruses that invaded our ancestors’ germline cell and were integrated into the genome. The expression of HERVs has always been a cause for concern because of its association with various cancers and diseases. However, few previous studies have focused on specific activation of HERVs by viral infections. Our previous study has shown that dengue virus type 2 (DENV-2) infection induces the transcription of a large number of abnormal HERVs loci; therefore, the purpose of this study was to explore the relationship between exogenous viral infection and HERV activation further. In this study, we retrieved and reanalyzed published data on 21 transcriptomes of human cells infected with various viruses. We found that infection with different viruses could induce transcriptional activation of HERV loci. Through the comparative analysis of all viral datasets, we identified 43 key HERV loci that were up-regulated by DENV-2, influenza A virus, influenza B virus, Zika virus, measles virus, and West Nile virus infections. Furthermore, the neighboring genes of these HERVs were simultaneously up-regulated, and almost all such neighboring genes were interferon-stimulated genes (ISGs), which are enriched in the host’s antiviral immune response pathways. Our data supported the hypothesis that activation of HERVs, probably via an interferon-mediated mechanism, plays an important role in innate immunity against viral infections.

scholarly journals Favipiravir in Therapy of Viral Infections

2021 ◽  
Vol 10 (2) ◽  
pp. 273
Author(s):  
Ryta Łagocka ◽  
Violetta Dziedziejko ◽  
Patrycja Kłos ◽  
Andrzej Pawlik
Keyword(s):  
Ebola Virus ◽  
Viral Infections ◽  
Virus Disease ◽  
Antiviral Drug ◽  
Competitive Inhibitor ◽  
Mechanisms Of Action ◽  
Pharmacokinetic Parameters ◽  
Rna Dependent Rna Polymerase ◽  
Antiviral Therapies ◽  
Transcription And Replication

Favipiravir (FPV) is a novel antiviral drug acting as a competitive inhibitor of RNA-dependent RNA polymerase (RdRp), preventing viral transcription and replication. FPV was approved in Japan in 2014 for therapy of influenza unresponsive to standard antiviral therapies. FPV was also used in the therapy of Ebola virus disease (EVD) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this review, we discuss the mechanisms of action, pharmacokinetic parameters, toxicity, and adverse effects of FPV, as well as clinical studies evaluating the use of FPV in the therapy of influenza virus (IV) infection, EVD, and SARS-CoV-2 infection, along with its effectiveness in treating other human RNA infections.

scholarly journals Viral Pandemics of the Last Four Decades: Pathophysiology, Health Impacts and Perspectives

2020 ◽  
Vol 17 (24) ◽  
pp. 9411
Author(s):  
Shubhadeep Roychoudhury ◽  
Anandan Das ◽  
Pallav Sengupta ◽  
Sulagna Dutta ◽  
Shatabhisha Roychoudhury ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Influenza A ◽  
Ebola Virus ◽  
Viral Infections ◽  
H1n1 Influenza ◽  
Dipeptidyl Peptidase 4 ◽  
Invasion Mechanism ◽  
Hemagglutinin Protein ◽  
Gender Based ◽  
The Uk

The last four decades has witnessed some of the deadliest viral pandemics with far-reaching consequences. These include the Human Immunodeficiency Virus (HIV) (1981), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) (2002), Influenza A virus subtype H1N1 (A/H1N1) (2009), Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (2012), Ebola virus (2013) and the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (2019-present). Age- and gender-based characterizations suggest that SARS-CoV-2 resembles SARS-CoV and MERS-CoV with regard to higher fatality rates in males, and in the older population with comorbidities. The invasion-mechanism of SARS-CoV-2 and SARS-CoV, involves binding of its spike protein with angiotensin-converting enzyme 2 (ACE2) receptors; MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4), whereas H1N1 influenza is equipped with hemagglutinin protein. The viral infections-mediated immunomodulation, and progressive inflammatory state may affect the functions of several other organs. Although no effective commercial vaccine is available for any of the viruses, those against SARS-CoV-2 are being developed at an unprecedented speed. Until now, only Pfizer/BioNTech’s vaccine has received temporary authorization from the UK Medicines and Healthcare products Regulatory Agency. Given the frequent emergence of viral pandemics in the 21st century, proper understanding of their characteristics and modes of action are essential to address the immediate and long-term health consequences.

Implication of the proprotein convertases furin, PC5 and PC7 in the cleavage of surface glycoproteins of Hong Kong, Ebola and respiratory syncytial viruses: a comparative analysis with fluorogenic peptides

2001 ◽  
Vol 353 (3) ◽  
pp. 537-545 ◽  
Author(s):  
Ajoy BASAK ◽  
Mei ZHONG ◽  
Jon S. MUNZER ◽  
Michel CHRÉTIEN ◽  
Nabil G. SEIDAH
Keyword(s):  
Hong Kong ◽  
Influenza A ◽  
Ebola Virus ◽  
Rank Order ◽  
Kinetic Studies ◽  
Fold Increase ◽  
Similar Efficacy ◽  
Proprotein Convertases ◽  
Antiviral Therapies ◽  
Syncytial Virus

Fluorogenic peptides encompassing the processing sites of envelope glycoproteins of the infectious influenza A Hong Kong virus (HKV), Ebola virus (EBOV) and respiratory syncytial virus (RSV) were tested for cleavage by soluble recombinants of the proprotein convertases furin, PC5 and PC7. Kinetic studies with these intramolecularly quenched fluorogenic peptides revealed selective cleavages at the physiological dibasic sites. The HKV peptide is cleaved by both furin and PC5 with similar efficacy; in comparison, PC7 cleaves this substrate poorly. In contrast with the basic tetrapeptide insertion within the haemagglutinin sequence of HKV, two other dipeptide insertions revealed a poorer cleavage with a similar rank order of potency. These results demonstrate that the N-terminal RERR insertion to the wild-type avian RKKR↓ sequence is functionally significant, and suggest that the approx. 5-fold increase in cleavage efficacy contributes to the high infectivity of the H5N1 virus subtype. With regard to RSV peptide processing, PC7 is twice as effective as PC5 and furin. The EBOV peptide was processed with similar efficiency by the three enzymes. Our observations that all of these cleavages can be effectively inhibited by a plant andrographolide derivative at 250µM or less might aid in the design of potent convertase inhibitors as alternative antiviral therapies.

scholarly journals Prevalence of laboratory markers of human respiratory viruses in monkeys of Adler primate center

2022 ◽  
Vol 66 (6) ◽  
pp. 425-433
Author(s):  
L. I. Korzaya ◽  
D. I. Dogadov ◽  
A. M. Goncharenko ◽  
A. A. Karlsen ◽  
K. K. Kyuregyan ◽  
...  
Keyword(s):  
Virus Type ◽  
Measles Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Respiratory Viruses ◽  
Serum Samples ◽  
Recent Infection ◽  
Strict Adherence ◽  
Anubis Baboons ◽  
Type 3

Introduction. The relevance of studying the circulation of human respiratory viruses among laboratory primates is associated with the need to test vaccines and antiviral drugs against these infections on monkeys.The aim of this work was to study the prevalence of serological and molecular markers of human respiratory viral infections in laboratory primates born at the Adler Primate Center and in imported monkeys.Material and methods. Blood serum samples (n = 1971) and lung autopsy material (n = 26) were obtained from different monkey species. These samples were tested for the presence of serological markers of measles, parainfluenza (PI) types 1, 2, 3, influenza A and B, respiratory syncytial (RS) and adenovirus infections using enzyme immunoassay (ELISA). Detection of RS virus, metapneumovirus, PI virus types 1–4, rhinovirus, coronavirus, and adenoviruses B, C, E and bocavirus nucleic acids in this material was performed by reverse transcription polymerase chain reaction (RT-PCR).Results and discussion. The overall prevalence of antibodies (Abs) among all monkeys was low and amounted 11.3% (95% CI: 9.2–13.7%, n = 811) for measles virus, 8.9% (95% CI: 6.2–12.2%, n = 381) for PI type 3 virus, 2.5% (95% CI: 0.8–5.6%, n = 204) for PI type 1 virus, and 7.7% (95% CI: 3.8–13.7%, n = 130) for adenoviruses. When testing 26 autopsy lung samples from monkeys of different species that died from pneumonia, 2 samples from Anubis baboons (Papio аnubis) were positive for of parainfluenza virus type 3 RNA.Conclusion. Our data suggest the importance of the strict adherence to the terms of quarantine and mandatory testing of monkey sera for the presence of IgM antibodies to the measles virus that indicate the recent infection. The role of PI virus type 3 in the pathology of the respiratory tract in Anubis baboons has been established.

scholarly journals S-palmitoylation and sterol interactions mediate antiviral specificity of IFITM isoforms

2021 ◽  
Author(s):  
Tandrila Das ◽  
Xinglin Yang ◽  
Hwayoung Lee ◽  
Emma Garst ◽  
Estefania Valencia ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Influenza A ◽  
Ebola Virus ◽  
Viral Infections ◽  
Specific Activity ◽  
Cholesterol Homeostasis ◽  
Host Susceptibility ◽  
Nuclear Magnetic Resonance Analysis ◽  
Resonance Analysis

Abstract Interferon-induced transmembrane proteins (IFITM1, 2 and 3) are important antiviral proteins that are active against many viruses, including influenza A virus (IAV), dengue virus (DENV), Ebola virus (EBOV), Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus (SARS-CoV). IFITMs exhibit isoform-specific activity, but their distinct mechanisms of action and regulation are unclear. Since S-palmitoylation and cholesterol homeostasis are crucial for viral infections, we investigated IFITM interactions with cholesterol by molecular dynamic stimulations, nuclear magnetic resonance analysis in vitro and photoaffinity crosslinking in mammalian cells. These studies suggest that cholesterol can alter the conformation of IFITMs in membrane bilayers and directly interact with S-palmitoylated IFITMs in cells. Notably, we discovered that the S-palmitoylation levels regulate differential IFITM isoform interactions with cholesterol in mammalian cells and specificity of antiviral activity towards IAV, SARS-CoV-2 and EBOV. Our studies suggest that modulation of IFITM S-palmitoylation levels and cholesterol interaction may influence host susceptibility to different viruses.

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