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Frontiers in Immunology 2020Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses.... (Review)
Review
Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses. Among the major groups of viruses, RNA viruses contribute significantly to the global mortality and morbidity index associated with viral infection. Despite multiple routes of entry adopted by these viruses, facing complement is inevitable. The initial interaction with complement and the nature of this interaction play an important role in determining host resistance versus susceptibility to the viral infection. Many RNA viruses are potent activators of complement, often resulting in virus neutralization. Yet, another facet of virus-induced activation is the exacerbation in pathogenesis contributing to the overall morbidity. The severity in disease and death associated with RNA virus infections shows a tip in the scale favoring viruses. Growing evidence suggest that like their DNA counterparts, RNA viruses have co-evolved to master ingenious strategies to remarkably restrict complement. Modulation of host genes involved in antiviral responses contributed prominently to the adoption of unique strategies to keep complement at bay, which included either down regulation of activation components (C3, C4) or up regulation of complement regulatory proteins. All this hints at a possible "hijacking" of the cross-talk mechanism of the host immune system. Enveloped RNA viruses have a selective advantage of not only modulating the host responses but also recruiting membrane-associated regulators of complement activation (RCAs). This review aims to highlight the significant progress in the understanding of RNA virus-complement interactions.
Topics: Adaptive Immunity; Animals; Complement Activation; Complement System Proteins; Evolution, Molecular; Gene Expression Regulation, Viral; Host-Pathogen Interactions; Humans; Immunity, Innate; RNA Virus Infections; RNA Viruses; Severity of Illness Index
PubMed: 33133089
DOI: 10.3389/fimmu.2020.573583 -
Molecules (Basel, Switzerland) Dec 2018Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression... (Review)
Review
Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans.
Topics: Animals; Clinical Trials as Topic; Humans; RNA; RNA Viruses; Virus Replication
PubMed: 30551668
DOI: 10.3390/molecules23123310 -
Trends in Molecular Medicine Jan 2017microRNAs (miRNAs) are non-coding RNAs that regulate many processes within a cell by manipulating protein levels through direct binding to mRNA and influencing... (Review)
Review
microRNAs (miRNAs) are non-coding RNAs that regulate many processes within a cell by manipulating protein levels through direct binding to mRNA and influencing translation efficiency, or mRNA abundance. Recent evidence demonstrates that miRNAs can also affect RNA virus replication and pathogenesis through direct binding to the RNA virus genome or through virus-mediated changes in the host transcriptome. Here, we review the current knowledge on the interaction between RNA viruses and cellular miRNAs. We also discuss how cell and tissue-specific expression of miRNAs can directly affect viral pathogenesis. Understanding the role of cellular miRNAs during viral infection may lead to the identification of novel mechanisms to block RNA virus replication or cell-specific regulation of viral vector targeting.
Topics: Animals; Genome, Viral; Host-Pathogen Interactions; Humans; MicroRNAs; RNA Virus Infections; RNA Viruses; RNA, Viral; Transcriptome; Virus Replication
PubMed: 27989642
DOI: 10.1016/j.molmed.2016.11.003 -
Annual Review of Virology Sep 2018RNA viruses are unique in their evolutionary capacity, exhibiting high mutation rates and frequent recombination. They rapidly adapt to environmental changes, such as... (Review)
Review
RNA viruses are unique in their evolutionary capacity, exhibiting high mutation rates and frequent recombination. They rapidly adapt to environmental changes, such as shifts in immune pressure or pharmacological challenge. The evolution of RNA viruses has been brought into new focus with the recent developments of genetic and experimental tools to explore and manipulate the evolutionary dynamics of viral populations. These studies have uncovered new mechanisms that enable viruses to overcome evolutionary challenges in the environment and have emphasized the intimate relationship of viral populations with evolution. Here, we review some of the emerging viral and host mechanisms that underlie the evolution of RNA viruses. We also discuss new studies that demonstrate that the relationship between evolutionary dynamics and virus biology spans many spatial and temporal scales, affecting transmission dynamics within and between hosts as well as pathogenesis.
Topics: Adaptation, Biological; Biological Evolution; Host-Pathogen Interactions; Population Dynamics; RNA Viruses
PubMed: 30048219
DOI: 10.1146/annurev-virology-101416-041718 -
Advances in Virus Research 2022Reverse genetics is the prospective analysis of how genotype determines phenotype. In a typical experiment, a researcher alters a viral genome, then observes the...
Reverse genetics is the prospective analysis of how genotype determines phenotype. In a typical experiment, a researcher alters a viral genome, then observes the phenotypic outcome. Among RNA viruses, this approach was first applied to positive-strand RNA viruses in the mid-1970s and over nearly 50 years has become a powerful and widely used approach for dissecting the mechanisms of viral replication and pathogenesis. During this time the global health importance of two virus groups, flaviviruses (genus Flavivirus, family Flaviviridae) and betacoronaviruses (genus Betacoronavirus, subfamily Orthocoronavirinae, family Coronaviridae), have dramatically increased, yet these viruses have genomes that are technically challenging to manipulate. As a result, several new techniques have been developed to overcome these challenges. Here I briefly review key historical aspects of positive-strand RNA virus reverse genetics, describe some recent reverse genetic innovations, particularly as applied to flaviviruses and coronaviruses, and discuss their benefits and limitations within the larger context of rigorous genetic analysis.
Topics: Flavivirus; Genome, Viral; Positive-Strand RNA Viruses; RNA Viruses; Reverse Genetics; Virus Replication
PubMed: 35840179
DOI: 10.1016/bs.aivir.2022.03.001 -
Trends in Biotechnology Dec 2018CRISPR-Cas13a is an efficient RNA targeting and editing tool characterized recently in prokaryotes. This system can be recruited to engineer resistance against plant RNA... (Review)
Review
CRISPR-Cas13a is an efficient RNA targeting and editing tool characterized recently in prokaryotes. This system can be recruited to engineer resistance against plant RNA viruses and regulate gene expression. We discuss some important achievements in using the CRISPR-Cas13a system to confer resistance against plant RNA viruses.
Topics: CRISPR-Cas Systems; Disease Resistance; Gene Editing; Plant Diseases; Plant Viruses; Plants, Genetically Modified; RNA Viruses
PubMed: 29903474
DOI: 10.1016/j.tibtech.2018.05.005 -
Viruses Jul 2020Negative strand RNA viruses (NSVs) include many important human pathogens, such as influenza virus, Ebola virus, and rabies virus. One of the unique characteristics that... (Review)
Review
Negative strand RNA viruses (NSVs) include many important human pathogens, such as influenza virus, Ebola virus, and rabies virus. One of the unique characteristics that NSVs share is the assembly of the nucleocapsid and its role in viral RNA synthesis. In NSVs, the single strand RNA genome is encapsidated in the linear nucleocapsid throughout the viral replication cycle. Subunits of the nucleocapsid protein are parallelly aligned along the RNA genome that is sandwiched between two domains composed of conserved helix motifs. The viral RNA-dependent-RNA polymerase (vRdRp) must recognize the protein-RNA complex of the nucleocapsid and unveil the protected genomic RNA in order to initiate viral RNA synthesis. In addition, vRdRp must continuously translocate along the protein-RNA complex during elongation in viral RNA synthesis. This unique mechanism of viral RNA synthesis suggests that the nucleocapsid may play a regulatory role during NSV replication.
Topics: Genome, Viral; Models, Molecular; Negative-Sense RNA Viruses; Nucleocapsid; Nucleocapsid Proteins; Protein Conformation; Protein Folding; RNA, Viral; RNA-Dependent RNA Polymerase
PubMed: 32751700
DOI: 10.3390/v12080835 -
Viruses Mar 2020Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune... (Review)
Review
Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune responses to virus infection. ADP-ribose is covalently attached to target proteins by poly-ADP-ribose polymerases (PARPs), using nicotinamide adenine dinucleotide (NAD+) as a substrate. This modification can have a wide variety of effects on proteins including alteration of enzyme activity, protein-protein interactions, and protein stability. Several PARPs are induced by interferon (IFN) and are known to have antiviral properties, implicating ADP-ribosylation in the host defense response and suggesting that viral macrodomains may counter this response. Recent studies have demonstrated that viral macrodomains do counter the innate immune response by interfering with PARP-mediated antiviral defenses, stress granule formation, and pro-inflammatory cytokine production. Here, we will describe the known functions of the viral macrodomains and review recent literature demonstrating their roles in countering PARP-mediated antiviral responses.
Topics: ADP-Ribosylation; Adenosine Diphosphate Ribose; Cytoplasmic Granules; Humans; Interferons; Mutation; Poly(ADP-ribose) Polymerases; Protein Domains; RNA Virus Infections; RNA Viruses; Viral Nonstructural Proteins; Virus Replication
PubMed: 32244383
DOI: 10.3390/v12040384 -
Seminars in Cell & Developmental Biology May 2020Autophagy is an evolutionarily conserved process central to host metabolism. Among its major functions are conservation of energy during starvation, recycling... (Review)
Review
Autophagy is an evolutionarily conserved process central to host metabolism. Among its major functions are conservation of energy during starvation, recycling organelles, and turnover of long-lived proteins. Besides, autophagy plays a critical role in removing intracellular pathogens and very likely represents a primordial intrinsic cellular defence mechanism. More recent findings indicate that it has not only retained its ability to degrade intracellular pathogens, but also functions to augment and fine tune antiviral immune responses. Interestingly, viruses have also co-evolved strategies to manipulate this pathway and use it to their advantage. Particularly intriguing is infection-dependent activation of autophagy with positive stranded (+)RNA virus infections, which benefit from the pathway without succumbing to lysosomal degradation. In this review we summarise recent data on viral manipulation of autophagy, with a particular emphasis on +RNA viruses and highlight key unanswered questions in the field that we believe merit further attention.
Topics: Autophagy; Humans; RNA Viruses
PubMed: 31382014
DOI: 10.1016/j.semcdb.2019.07.013 -
International Journal of Molecular... Sep 2019RNA viruses are known to replicate by low fidelity polymerases and have high mutation rates whereby the resulting virus population tends to exist as a distribution of... (Review)
Review
RNA viruses are known to replicate by low fidelity polymerases and have high mutation rates whereby the resulting virus population tends to exist as a distribution of mutants. In this review, we aim to explore how genetic events such as spontaneous mutations could alter the genomic organization of RNA viruses in such a way that they impact virus replications and plaque morphology. The phenomenon of quasispecies within a viral population is also discussed to reflect virulence and its implications for RNA viruses. An understanding of how such events occur will provide further evidence about whether there are molecular determinants for plaque morphology of RNA viruses or whether different plaque phenotypes arise due to the presence of quasispecies within a population. Ultimately this review gives an insight into whether the intrinsically high error rates due to the low fidelity of RNA polymerases is responsible for the variation in plaque morphology and diversity in virulence. This can be a useful tool in characterizing mechanisms that facilitate virus adaptation and evolution.
Topics: Animals; DNA-Directed RNA Polymerases; Evolution, Molecular; Humans; Quasispecies; RNA Viruses; Viral Proteins; Virulence
PubMed: 31546962
DOI: 10.3390/ijms20184657