scholarly journals Replication defective viral genomes exploit a cellular pro-survival mechanism to establish paramyxovirus persistence

2017 ◽  
Author(s):  
Jie Xu ◽  
Yan Sun ◽  
Yize Li ◽  
Gordon Ruthel ◽  
Susan R. Weiss ◽  
...  
Keyword(s):  
Cell Fate ◽  
Sendai Virus ◽  
Rna Virus ◽  
Viral Persistence ◽  
Virus Infections ◽  
Viral Genomes ◽  
Persistent Infections ◽  
Infected Cells ◽  
Syncytial Virus ◽  
Survival Effect

ABSTRACTReplication defective viral genomes (DVGs) generated during virus replication are the primary triggers of antiviral immunity in many RNA virus infections. However, DVGs can also facilitate viral persistence. Why and how these two opposing functions of DVGs are achieved remain unknown. Here we report that during Sendai and respiratory syncytial virus infections DVGs selectively protect a subpopulation of cells from death and promote the establishment of persistent infections. We find that during Sendai virus infection this phenotype results from DVGs stimulating a MAVS-mediated TNF response that drives apoptosis of highly infected cells while extending the survival of cells enriched in DVGs. The pro-survival effect of TNF depends on the activity of the TNFR2/TRAF1 pathway that is regulated by MAVS signaling. These results identify TNF as a pivotal factor in determining cell fate during a viral infection and delineate a MAVS/TNFR2-mediated mechanism that drives the persistence of otherwise acute viruses.

scholarly journals Formation and Function of Liquid-Like Viral Factories in Negative-Sense Single-Stranded RNA Virus Infections

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 126
Author(s):  
Justin M. Su ◽  
Maxwell Z. Wilson ◽  
Charles E. Samuel ◽  
Dzwokai Ma
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Host Responses ◽  
Future Research ◽  
Virus Infections ◽  
Infected Cells ◽  
And Function ◽  
Negative Sense ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) represents a major physiochemical principle to organize intracellular membrane-less structures. Studies with non-segmented negative-sense (NNS) RNA viruses have uncovered a key role of LLPS in the formation of viral inclusion bodies (IBs), sites of viral protein concentration in the cytoplasm of infected cells. These studies further reveal the structural and functional complexity of viral IB factories and provide a foundation for their future research. Herein, we review the literature leading to the discovery of LLPS-driven formation of IBs in NNS RNA virus-infected cells and the identification of viral scaffold components involved, and then outline important questions and challenges for IB assembly and disassembly. We discuss the functional implications of LLPS in the life cycle of NNS RNA viruses and host responses to infection. Finally, we speculate on the potential mechanisms underlying IB maturation, a phenomenon relevant to many human diseases.

scholarly journals Type III interferons disrupt the lung epithelial barrier upon viral recognition

2020 ◽  
Author(s):  
Achille Broggi ◽  
Sreya Ghosh ◽  
Benedetta Sposito ◽  
Roberto Spreafico ◽  
Fabio Balzarini ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infections ◽  
Rna Virus ◽  
Virus Infections ◽  
Highly Pathogenic ◽  
Type Iii ◽  
Lung Epithelial ◽  
Syncytial Virus ◽  
Tract Infections ◽  
Viral Recognition

AbstractLower respiratory tract infections are a leading cause of mortality driven by infectious agents. RNA viruses such as influenza virus, respiratory syncytial virus and the new pandemic coronavirus SARS-CoV-2 can be highly pathogenic. Clinical and experimental evidence indicate that most severe and lethal cases do not depend on the viral burden and are, instead, characterized by an aberrant immune response. In this work we assessed how the innate immune response contributes to the pathogenesis of RNA virus infections. We demonstrate that type III interferons produced by dendritic cells in the lung in response to viral recognition cause barrier damage and compromise the host tissue tolerance. In particular, type III interferons inhibit tissue repair and lung epithelial cell proliferation, causing susceptibility to lethal bacterial superinfections. Overall, our data give a strong mandate to rethink the pathophysiological roles of this group of interferons and their possible use in the clinical practice against endemic as well as emerging viral infections.

scholarly journals Antiviral Role of Plant-Encoded RNA-Dependent RNA Polymerases Revisited with Deep Sequencing of Small Interfering RNAs of Virus Origin

2010 ◽  
Vol 23 (10) ◽  
pp. 1248-1252 ◽  
Author(s):  
Feng Qu
Keyword(s):  
Rna Virus ◽  
Rna Polymerases ◽  
Viral Rna ◽  
Antiviral Defense ◽  
Small Interfering Rnas ◽  
Virus Infections ◽  
Virus Origin ◽  
Infected Cells ◽  
Sequencing Platforms ◽  
Rna Accumulation

Several recent studies profiled virus-specific small interfering RNAs (vsRNAs) using next generation sequencing platforms and compellingly implicated plant-encoded RNA-dependent RNA polymerases (RDR) in vsRNA biogenesis and vsRNA-mediated antiviral defense. Specifically, both RDR1 and RDR6 were found to contribute to the accumulation of vsRNAs in virus-infected cells. While RDR1 was responsible for the majority of vsRNAs in plants infected with three different viruses, RDR6 acted as a surrogate when RDR1 function was disrupted. Mechanistically, vsRNAs associated with RDR1 mostly mapped to viral RNA regions close to the 5′ ends, whereas those associated with RDR6 mapped to more 3′ regions and appeared to be dependent on higher viral RNA concentrations. Knocking out both RDR1 and RDR6 led to drastically diminished vsRNA levels concomitant with enhanced viral RNA accumulation. In conclusion, these studies established that RDR1 and RDR6 function synergistically to contain RNA virus infections through the RNA silencing–based antiviral defense.

scholarly journals Cellular La Protein Shields Nonsegmented Negative-Strand RNA Viral Leader RNA from RIG-I and Enhances Virus Growth by Diverse Mechanisms

2008 ◽  
Vol 82 (16) ◽  
pp. 7977-7987 ◽  
Author(s):  
Vira Bitko ◽  
Alla Musiyenko ◽  
Mark A. Bayfield ◽  
Richard J. Maraia ◽  
Sailen Barik
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Sendai Virus ◽  
Rna Virus ◽  
Cellular Protein ◽  
Rna Recognition Motif ◽  
Type I ◽  
Virus Growth ◽  
Negative Strand ◽  
Syncytial Virus

ABSTRACT The La antigen (SS-B) associates with a wide variety of cellular and viral RNAs to affect gene expression in multiple systems. We show that La is the major cellular protein found to be associated with the abundant 44-nucleotide viral leader RNA (leRNA) early after infection with respiratory syncytial virus (RSV), a nonsegmented negative-strand RNA virus. Consistent with this, La redistributes from the nucleus to the cytoplasm in RSV-infected cells. Upon RNA interference knockdown of La, leRNA is redirected to associate with the RNA-binding protein RIG-I, a known activator of interferon (IFN) gene expression, and this is accompanied by the early induction of IFN mRNA. These results suggest that La shields leRNA from RIG-I, abrogating the early viral activation of type I IFN. We mapped the leRNA binding function to RNA recognition motif 1 of La and showed that while wild-type La greatly enhanced RSV growth, a La mutant defective in RSV leRNA binding also did not support RSV growth. Comparative studies of RSV and Sendai virus and the use of IFN-negative Vero cells indicated that La supports the growth of nonsegmented negative-strand RNA viruses by both IFN suppression and a potentially novel IFN-independent mechanism.

scholarly journals Discovery of divided RdRp sequences and a hitherto unknown genomic complexity in fungal viruses

2020 ◽  
Author(s):  
Yuto Chiba ◽  
Sayoko Oiki ◽  
Takashi Yaguchi ◽  
Syun-Ichi Urayama ◽  
Daisuke Hagiwara
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Single Gene ◽  
Virus Infections ◽  
Independent Manner ◽  
Viral Genomes ◽  
Genomic Complexity ◽  
True Diversity ◽  
Genomic Regions ◽  
Fungal Viruses

Abstract By identifying variations in viral RNA genomes, cutting-edge metagenome technology has potential to reshape current concepts about the evolution of RNA viruses. This technology, however, cannot process low-homology genomic regions properly, leaving the true diversity of RNA viruses unappreciated. To overcome this technological limitation, we applied an advanced method, Fragmented and Primer-Ligated Double-stranded (ds) RNA Sequencing (FLDS), to screen RNA viruses from 155 fungal isolates, which allowed us to obtain complete viral genomes in a homology-independent manner. We created a high-quality catalog of 19 RNA viruses (12 viral species) that infect Aspergillus isolates. Among them, nine viruses were not detectable by the conventional methodology involving agarose gel electrophoresis of dsRNA, a hallmark of RNA virus infections. Segmented genome structures were determined in 42% of the viruses. Some RNA viruses had novel genome architectures; one contained a dual methyltransferase domain and another had a separated RNA-dependent RNA polymerase (RdRp) gene. A virus from a different fungal taxon (Pyricularia) had an RdRp sequence that was separated on different segments, suggesting that a divided RdRp is widely present among fungal viruses, despite the belief that all RNA viruses encode RdRp as a single gene. These findings illustrate the previously hidden diversity and evolution of RNA viruses, and prompt reconsideration of the structural plasticity of RdRp.

scholarly journals Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Brian Webster ◽  
Scott W Werneke ◽  
Biljana Zafirova ◽  
Sébastien This ◽  
Séverin Coléon ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cell ◽  
Rna Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Virus Infections ◽  
Antiviral Responses ◽  
Infected Cells ◽  
Interferon Responses

Type I interferon (IFN-I) responses are critical for the control of RNA virus infections, however, many viruses, including Dengue (DENV) and Chikungunya (CHIKV) virus, do not directly activate plasmacytoid dendritic cells (pDCs), robust IFN-I producing cells. Herein, we demonstrated that DENV and CHIKV infected cells are sensed by pDCs, indirectly, resulting in selective IRF7 activation and IFN-I production, in the absence of other inflammatory cytokine responses. To elucidate pDC immunomodulatory functions, we developed a mouse model in which IRF7 signaling is restricted to pDC. Despite undetectable levels of IFN-I protein, pDC-restricted IRF7 signaling controlled both viruses and was sufficient to protect mice from lethal CHIKV infection. Early pDC IRF7-signaling resulted in amplification of downstream antiviral responses, including an accelerated natural killer (NK) cell-mediated type II IFN response. These studies revealed the dominant, yet indirect role of pDC IRF7-signaling in directing both type I and II IFN responses during arbovirus infections.

scholarly journals The Viral Polymerase Complex Mediates the Interaction of vRNPs with Recycling Endosomes During SeV Assembly

2020 ◽  
Author(s):  
Emmanuelle Genoyer ◽  
Katarzyna Kulej ◽  
Chuan Tien Hung ◽  
Patricia A. Thibault ◽  
Kristopher Azarm ◽  
...  
Keyword(s):  
Sendai Virus ◽  
Initial Step ◽  
Viral Proteins ◽  
Viral Polymerase ◽  
Recycling Endosomes ◽  
Viral Genomes ◽  
Parainfluenza Viruses ◽  
Infected Cells ◽  
Human Parainfluenza Viruses

ABSTRACTParamyxoviruses are negative sense single-stranded RNA viruses that comprise many important human and animal pathogens, including human parainfluenza viruses. These viruses bud from the plasma membrane of infected cells after the viral ribonucleoprotein complex (vRNP) is transported from the cytoplasm to the cell membrane via Rab11a-marked recycling endosomes. The viral proteins that are critical for mediating this important initial step in viral assembly are unknown. Here we use the model paramyxovirus, murine parainfluenza virus 1, or Sendai virus (SeV), to investigate the roles of viral proteins in Rab11a-driven virion assembly. We previously reported that infection with SeV containing high levels of copy-back defective viral genomes (DVGs) generates heterogenous populations of cells. Cells enriched in full-length virus produce viral particles containing standard or defective viral genomes, while cells enriched in DVGs do not, despite high levels of defective viral genome replication. Here we take advantage of this heterogenous cell phenotype to identify proteins that mediate interaction of vRNPs with Rab11a. We examine the role of matrix protein and nucleoprotein and determine that they are not sufficient to drive interaction of vRNPs with recycling endosomes. Using a combination of mass spectrometry and comparative protein abundance and localization in DVG- and FL-high cells, we identify viral polymerase complex components L and, specifically, its cofactor C proteins as interactors with Rab11a. We find that accumulation of these proteins within the cell is the defining feature that differentiates cells that proceed to viral egress from cells which remain in replication phases.IMPORTANCEParamyxoviruses are a family of viruses that include a number of pathogens with significant burdens on human health. Particularly, human parainfluenza viruses are an important cause of pneumonia and bronchiolitis in children for which there are no vaccines or direct acting antivirals. These cytoplasmic replicating viruses bud from the plasma membrane and coopt cellular endosomal recycling pathways to traffic viral ribonucleoprotein complexes from the cytoplasm to the membrane of infected cells. The viral proteins required for viral engagement with the recycling endosome pathway are still not known. Here we use the model paramyxovirus Sendai virus, or murine parainfluenza virus 1, to investigate the role of viral proteins in this initial step of viral assembly. We find that viral polymerase components large protein L and accessory C proteins are necessary for engagement with recycling endosomes. These findings are important in identifying viral proteins as potential targets for development of antivirals.

scholarly journals 4'-Fluorouridine is a broad-spectrum orally efficacious antiviral blocking respiratory syncytial virus and SARS-CoV-2 replication

2021 ◽  
Author(s):  
Julien Sourimant ◽  
Carolin Lieber ◽  
Megha Aggarwal ◽  
Robert Cox ◽  
Josef Wolf ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Broad Spectrum ◽  
Rna Virus ◽  
Oral Treatment ◽  
The Elderly ◽  
Virus Infections ◽  
Once Daily ◽  
Syncytial Virus ◽  
Well Differentiated

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and the elderly. We describe 4'-fluorouridine (4'-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and SARS-CoV-2 with high selectivity index in cells and well-differentiated human airway epithelia. Polymerase inhibition in in vitro RdRP assays established for RSV and SARS-CoV-2 revealed transcriptional pauses at positions i or i+3/4 post-incorporation. Once-daily oral treatment was highly efficacious at 5 mg/kg in RSV-infected mice or 20 mg/kg in ferrets infected with SARS-CoV-2 WA1/2020 or variant-of-concern (VoC) isolate CA/2020, initiated 24 or 12 hours after infection, respectively. These properties define 4'-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2 and related RNA virus infections.

scholarly journals The Morphology and Assembly of Respiratory Syncytial Virus Revealed by Cryo-Electron Tomography

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 446 ◽  
Author(s):  
Zunlong Ke ◽  
Rebecca Dillard ◽  
Tatiana Chirkova ◽  
Fredrick Leon ◽  
Christopher Stobart ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Electron Tomography ◽  
Rna Virus ◽  
3D Structure ◽  
Three Dimensional ◽  
The Elderly ◽  
Cryo Electron Tomography ◽  
Infected Cells ◽  
Syncytial Virus ◽  
Tract Disease

Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in young children. With repeat infections throughout life, it can also cause substantial disease in the elderly and in adults with compromised cardiac, pulmonary and immune systems. RSV is a pleomorphic enveloped RNA virus in the Pneumoviridae family. Recently, the three-dimensional (3D) structure of purified RSV particles has been elucidated, revealing three distinct morphological categories: spherical, asymmetric, and filamentous. However, the native 3D structure of RSV particles associated with or released from infected cells has yet to be investigated. In this study, we have established an optimized system for studying RSV structure by imaging RSV-infected cells on transmission electron microscopy (TEM) grids by cryo-electron tomography (cryo-ET). Our results demonstrate that RSV is filamentous across several virus strains and cell lines by cryo-ET, cryo-immuno EM, and thin section TEM techniques. The viral filament length varies from 0.5 to 12 μm and the average filament diameter is approximately 130 nm. Taking advantage of the whole cell tomography technique, we have resolved various stages of RSV assembly. Collectively, our results can facilitate the understanding of viral morphogenesis in RSV and other pleomorphic enveloped viruses.

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