scholarly journals Virus Population Bottlenecks: What Are They Telling Us?

2020 ◽  
Author(s):  
Feng Qu ◽  
Limin Zheng ◽  
Shaoyan Zhang ◽  
Rong Sun ◽  
Jason Slot
Keyword(s):  
Rna Virus ◽  
Viral Population ◽  
Dependent Manner ◽  
Population Bottlenecks ◽  
Replication Proteins ◽  
Concentration Dependent Manner ◽  
Beneficial Mutations ◽  
Viral Genomes ◽  
Infected Cells ◽  
New Hypothesis

Stringent, stochastic viral population bottlenecks have been observed in the infections of many 5 viruses, but exactly how and why they occur is unclear. A critical review of recent literature prompts us 6 to propose a new hypothesis, designated Isolate, Amplify, and Select (IAS), that satisfactorily explains 7 the bottlenecks in single-stranded, positive sense (+) RNA virus infections. This new hypothesis 8 postulates that, unlike those in free-living organisms, the viral population bottlenecks are imposed by 9 viruses themselves, inside the infected cells, through virus-encoded bottleneck-enforcing proteins 10 (BNEPs) that function in a concentration-dependent manner. Most BNEPs are directly translated from 11 the (+) RNA genomes of invading viruses, so that if numerous virions of the same virus invade a cell 12 simultaneously, the bottleneck-ready concentration of BNEPs would be reached sufficiently early to 13 arrest nearly all internalized viral genomes. As a result, in these cells very few (as few as one) viral 14 genomes escape from the bottlenecks stochastically to initiate viral reproduction. Repetition of this 15 process in successively infected cells ensures the progeny genomes in each cell descend from the same 16 parental genome(s), hence isolating different mutant genomes in separate cells. This isolation precludes 17 mutant viral genomes encoding defective replication proteins from exploiting the complementing 18 proteins synthesized by sister genomes, leading to the prompt elimination of such mutants. Conversely, 19 the IAS model ensures replication proteins with beneficial mutations exclusively amplify the viral 20 genomes that harbor the very mutations. Reiteration of this process in consecutively infected cells 21 enriches such beneficial mutations in the virus pool. In conclusion, the IAS hypothesis provides a 22 compelling evolutionary model for population bottlenecks of (+) RNA viruses.

scholarly journals Bottleneck, Isolate, Amplify, Select (BIAS) as a Mechanistic Framework for Intracellular Population Dynamics of Positive Sense RNA Viruses

2020 ◽  
Author(s):  
Feng Qu ◽  
Limin Zheng ◽  
Shaoyan Zhang ◽  
Rong Sun ◽  
Jason Slot ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Virus Disease ◽  
Dependent Manner ◽  
Population Bottlenecks ◽  
Concentration Dependent Manner ◽  
Beneficial Mutations ◽  
Phenotypic Differences ◽  
Viral Genomes ◽  
Positive Sense ◽  
Infected Cells

Many positive sense RNA viruses, especially those infecting plants, are known to experience stringent, stochastic population bottlenecks inside the cells they invade, but exactly how and why these populations become bottlenecked are unclear. A model proposed ten years ago advocates that such bottlenecks are evolutionarily favored because they cause the isolation of individual viral variants in separate cells. Such isolation in turn allows the viral variants to manifest the phenotypic differences they encode. Recently published observations lend mechanistic support to this model, and prompt us to refine the model with novel molecular details. The refined model, designated Bottleneck, Isolate, Amplify, Select (BIAS), postulates that these viruses impose population bottlenecks on themselves by encoding bottleneck-enforcing proteins (BNEPs) that function in a concentration-dependent manner. In cells simultaneously invaded by numerous virions of the same virus, BNEPs reach the bottleneck-ready concentration sufficiently early to arrest nearly all internalized viral genomes. As a result, very few (as few as one) viral genomes stochastically escape to initiate reproduction. Repetition of this process in successively infected cells isolate viral genomes with different mutations in separate cells. This isolation prevents mutant viruses encoding defective viral proteins from hitchhiking on sister genome-encoded products, leading to the swift purging of such mutants. Importantly, genome isolation also ensures viral genomes harboring beneficial mutations accrue the cognate benefit exclusively to themselves, leading to the fixation of such beneficial mutations. Further interrogation of the BIAS hypothesis promises to deepen our understanding of virus evolution, and inspire new solutions to virus disease mitigation.

scholarly journals Bottleneck, Isolate, Amplify, Select (BIAS) as a mechanistic framework for intracellular population dynamics of positive-sense RNA viruses

2020 ◽  
Vol 6 (2) ◽  
Author(s):  
Feng Qu ◽  
Limin Zheng ◽  
Shaoyan Zhang ◽  
Rong Sun ◽  
Jason Slot ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Virus Disease ◽  
Dependent Manner ◽  
Population Bottlenecks ◽  
Concentration Dependent Manner ◽  
Beneficial Mutations ◽  
Phenotypic Differences ◽  
Viral Genomes ◽  
Positive Sense ◽  
Infected Cells

Abstract Many positive-sense RNA viruses, especially those infecting plants, are known to experience stringent, stochastic population bottlenecks inside the cells they invade, but exactly how and why these populations become bottlenecked are unclear. A model proposed ten years ago advocates that such bottlenecks are evolutionarily favored because they cause the isolation of individual viral variants in separate cells. Such isolation in turn allows the viral variants to manifest the phenotypic differences they encode. Recently published observations lend mechanistic support to this model and prompt us to refine the model with novel molecular details. The refined model, designated Bottleneck, Isolate, Amplify, Select (BIAS), postulates that these viruses impose population bottlenecks on themselves by encoding bottleneck-enforcing proteins (BNEPs) that function in a concentration-dependent manner. In cells simultaneously invaded by numerous virions of the same virus, BNEPs reach the bottleneck-ready concentration sufficiently early to arrest nearly all internalized viral genomes. As a result, very few (as few as one) viral genomes stochastically escape to initiate reproduction. Repetition of this process in successively infected cells isolates viral genomes with different mutations in separate cells. This isolation prevents mutant viruses encoding defective viral proteins from hitchhiking on sister genome-encoded products, leading to the swift purging of such mutants. Importantly, genome isolation also ensures viral genomes harboring beneficial mutations accrue the cognate benefit exclusively to themselves, leading to the fixation of such beneficial mutations. Further interrogation of the BIAS hypothesis promises to deepen our understanding of virus evolution and inspire new solutions to virus disease mitigation.

scholarly journals The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1062
Author(s):  
Victoria Callahan ◽  
Seth Hawks ◽  
Matthew A. Crawford ◽  
Caitlin W. Lehman ◽  
Holly A. Morrison ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Virus ◽  
Pulmonary Complications ◽  
Lung Epithelial Cells ◽  
Dependent Manner ◽  
Akt Inhibitor ◽  
Inflammatory Chemokines ◽  
Inflammatory State ◽  
Infected Cells ◽  
Ifn Γ

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a ‘cytokine storm.’ In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation.

scholarly journals Coxsackieviruses Undergo Intercellular Transmission as Pools of Sibling Viral Genomes Associated to Membranes

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 120
Author(s):  
Juan-Vicente Bou ◽  
Ron Geller ◽  
Rafael Sanjuán
Keyword(s):  
Genetic Variants ◽  
Social Evolution ◽  
Viral Population ◽  
Multiplicity Of Infection ◽  
Defective Interfering Particles ◽  
Viral Genomes ◽  
Viral Particles ◽  
A Cell ◽  
Infected Cells ◽  
Population Sequence

Some viruses are released from cells as pools of membrane-associated virions. By increasing the multiplicity of infection, this type of collective dispersal could favor viral cooperation, but also the emergence of cheater-like viruses, such as defective interfering particles. To better understand this process, we examined the genetic diversity of membrane-associated coxsackievirus infectious units. We found that infected cells released large membranous structures containing 8–21 infectious particles on average, including vesicles. However, in most cases (62–93%), these structures did not promote the co-transmission of different viral genetic variants present in a cell. Furthermore, collective dispersal had no effect on viral population sequence diversity. Our results indicate that membrane-associated collective infectious units typically contain viral particles derived from the same parental genome. Hence, if cooperation occurred, it should probably involve sibling viral particles rather than different variants. As shown by social evolution theory, cooperation among siblings should be robust against cheater invasion.

scholarly journals Live-cell observation of cytosolic HIV-1 assembly onset reveals RNA-interacting Gag oligomers

2015 ◽  
Vol 210 (4) ◽  
pp. 629-646 ◽  
Author(s):  
Jelle Hendrix ◽  
Viola Baumgärtel ◽  
Waldemar Schrimpf ◽  
Sergey Ivanchenko ◽  
Michelle A. Digman ◽  
...  
Keyword(s):  
Live Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Gag Polyprotein ◽  
Viral Particles ◽  
Infected Cells ◽  
Retroviral Replication ◽  
Gag Assembly ◽  
Reduced Mobility ◽  
Hiv 1

Assembly of the Gag polyprotein into new viral particles in infected cells is a crucial step in the retroviral replication cycle. Currently, little is known about the onset of assembly in the cytosol. In this paper, we analyzed the cytosolic HIV-1 Gag fraction in real time in live cells using advanced fluctuation imaging methods and thereby provide detailed insights into the complex relationship between cytosolic Gag mobility, stoichiometry, and interactions. We show that Gag diffuses as a monomer on the subsecond timescale with severely reduced mobility. Reduction of mobility is associated with basic residues in its nucleocapsid (NC) domain, whereas capsid (CA) and matrix (MA) domains do not contribute significantly. Strikingly, another diffusive Gag species was observed on the seconds timescale that oligomerized in a concentration-dependent manner. Both NC- and CA-mediated interactions strongly assist this process. Our results reveal potential nucleation steps of cytosolic Gag fractions before membrane-assisted Gag assembly.

scholarly journals Inhibition of Nipah Virus by Defective Interfering Particles

2020 ◽  
Vol 221 (Supplement_4) ◽  
pp. S460-S470 ◽  
Author(s):  
Stephen R Welch ◽  
Natasha L Tilston ◽  
Michael K Lo ◽  
Shannon L M Whitmer ◽  
Jessica R Harmon ◽  
...  
Keyword(s):  
Rna Virus ◽  
Nipah Virus ◽  
Vero Cells ◽  
Viral Population ◽  
Alternative Source ◽  
Highly Pathogenic ◽  
Defective Interfering Particles ◽  
Viral Genomes ◽  
Antiviral Control

Abstract The error-prone nature of RNA-dependent RNA polymerases drives the diversity of RNA virus populations. Arising within this diversity is a subset of defective viral genomes that retain replication competency, termed defective interfering (DI) genomes. These defects are caused by aberrant viral polymerase reinitiation on the same viral RNA template (deletion DI species) or the nascent RNA strand (copyback DI species). DI genomes have previously been shown to alter the dynamics of a viral population by interfering with normal virus replication and/or by stimulating the innate immune response. In this study, we investigated the ability of artificially produced DI genomes to inhibit Nipah virus (NiV), a highly pathogenic biosafety level 4 paramyxovirus. High multiplicity of infection passaging of both NiV clinical isolates and recombinant NiV in Vero cells generated an extensive DI population from which individual DIs were identified using next-generation sequencing techniques. Assays were established to generate and purify both naturally occurring and in silico-designed DIs as fully encapsidated, infectious virus-like particles termed defective interfering particles (DIPs). We demonstrate that several of these NiV DIP candidates reduced NiV titers by up to 4 logs in vitro. These data represent a proof-of-principle that a therapeutic application of DIPs to combat NiV infections may be an alternative source of antiviral control for this disease.

scholarly journals Inhibition of glycoprotein oligosaccharide processing in vitro and in influenza-virus-infected cells by α-d-mannopyranosylmethyl-p-nitrophenyltriazene

1988 ◽  
Vol 255 (3) ◽  
pp. 991-998 ◽  
Author(s):  
W McDowell ◽  
A Tlusty ◽  
R Rott ◽  
J N BeMiller ◽  
J A Bohn ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Rat Liver ◽  
Biological Activities ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Oligosaccharide Processing ◽  
Viral Glycoproteins ◽  
Embryo Cells ◽  
Infected Cells

The effects of alpha-D-mannopyranosylmethyl-p-nitrophenyltriazene (MMNT) on mannosidases involved in asparagine-linked oligosaccharide processing were investigated. MMNT was found to inhibit the activity of rat liver Golgi alpha-mannosidase I in a concentration-dependent manner (50% inhibition with 0.18 mM-MMNT), whereas rat liver endoplasmic-reticulum alpha-mannosidase appeared to be resistant (less than 5% inhibition at 1 mM-MMNT). Jack-bean alpha-mannosidase was also sensitive to inhibition by MMNT (50% inhibition with 0.32 mM-MMNT). Treatment of influenza-virus-infected chick-embryo cells with 1 mM-MMNT led to a decrease in the formation of complex-type asparagine-linked oligosaccharides and an accumulation of high-mannose-type oligosaccharides with the composition Man8(GlcNAc)2 and Man7(GlcNAc)2 on the viral glycoproteins. The biological activities of influenza-virus haemagglutinin and neuraminidase synthesized in the presence of 1 mM-MMNT remained unchanged, but the virus was less infectious than the control.

scholarly journals Intra-Population Competition during Adaptation to Increased Temperature in an RNA Bacteriophage

2021 ◽  
Vol 22 (13) ◽  
pp. 6815
Author(s):  
María Arribas ◽  
Ester Lázaro
Keyword(s):  
Large Population ◽  
Error Rates ◽  
Viral Population ◽  
Population Bottlenecks ◽  
Beneficial Mutations ◽  
The Family ◽  
Rapid Changes ◽  
Occasional Occurrence ◽  
Population Sizes ◽  
Population Competition

Evolution of RNA bacteriophages of the family Leviviridae is governed by the high error rates of their RNA-dependent RNA polymerases. This fact, together with their large population sizes, leads to the generation of highly heterogeneous populations that adapt rapidly to most changes in the environment. Throughout adaptation, the different mutants that make up a viral population compete with each other in a non-trivial process in which their selective values change over time due to the generation of new mutations. In this work we have characterised the intra-population dynamics of a well-studied levivirus, Qβ, when it is propagated at a higher-than-optimal temperature. Our results show that adapting populations experienced rapid changes that involved the ascent of particular genotypes and the loss of some beneficial mutations of early generation. Artificially reconstructed populations, containing a fraction of the diversity present in actual populations, fixed mutations more rapidly, illustrating how population bottlenecks may guide the adaptive pathways. The conclusion is that, when the availability of beneficial mutations under a particular selective condition is elevated, the final outcome of adaptation depends more on the occasional occurrence of population bottlenecks and how mutations combine in genomes than on the selective value of particular mutations.

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 Leaked genomic and mitochondrial DNA contribute to the host response to noroviruses in a STING-dependent manner

2021 ◽  
Author(s):  
Aminu S. Jahun ◽  
Frederic Sorgeloos ◽  
Yasmin Chaudhry ◽  
Sabastine E. Arthur ◽  
Myra Hosmillo ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Rna Viruses ◽  
Rna Virus ◽  
List Type ◽  
Dependent Manner ◽  
Dna Viruses ◽  
Molecular Pattern ◽  
Infectious Gastroenteritis ◽  
Infected Cells ◽  
Sting Pathway

AbstractThe cGAS-STING pathway is central to the IFN response against DNA viruses. However, recent studies are increasingly demonstrating its role in the restriction of some RNA viruses. Here we show that the cGAS-STING pathway also contributes to the IFN response against noroviruses, positive-sense single-stranded RNA viruses that are now one of the most common causes of infectious gastroenteritis world-wide. We show a significant reduction in IFN-β induction and a corresponding increase in viral replication in norovirus-infected cells following STING inhibition, knockdown or deletion. Upstream of STING, we show that cells lacking either cGAS or IFI16 also have severely impaired IFN responses. Further, we demonstrate that immunostimulatory host genome-derived DNA, and to a lesser extent mitochondrial DNA, accumulate in the cytosol of norovirus-infected cells. And lastly, overexpression of the viral NS4 protein was sufficient to drive the accumulation of cytosolic DNA. Together, our data elucidate a role for cGAS, IFI16 and STING in the restriction of noroviruses, and demonstrate for the first time the utility of host genomic DNA as a damage-associated molecular pattern in cells infected with an RNA virus.HighlightscGAS, IFI16 and STING are required for a robust IFN response against norovirusesNuclear and mitochondrial DNA accumulate in the cytosols of infected cellsViral NS4 mediates accumulation of cytosolic DNA

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