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2.
Nucleic Acids Res ; 49(17): e102, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1594917

ABSTRACT

Rapidly evolving RNA viruses continuously produce minority haplotypes that can become dominant if they are drug-resistant or can better evade the immune system. Therefore, early detection and identification of minority viral haplotypes may help to promptly adjust the patient's treatment plan preventing potential disease complications. Minority haplotypes can be identified using next-generation sequencing, but sequencing noise hinders accurate identification. The elimination of sequencing noise is a non-trivial task that still remains open. Here we propose CliqueSNV based on extracting pairs of statistically linked mutations from noisy reads. This effectively reduces sequencing noise and enables identifying minority haplotypes with the frequency below the sequencing error rate. We comparatively assess the performance of CliqueSNV using an in vitro mixture of nine haplotypes that were derived from the mutation profile of an existing HIV patient. We show that CliqueSNV can accurately assemble viral haplotypes with frequencies as low as 0.1% and maintains consistent performance across short and long bases sequencing platforms.


Subject(s)
Algorithms , Computational Biology/methods , Haplotypes , High-Throughput Nucleotide Sequencing/methods , RNA Virus Infections/diagnosis , RNA Viruses/genetics , COVID-19/diagnosis , COVID-19/virology , Gene Frequency , HIV Infections/diagnosis , HIV Infections/virology , HIV-1/genetics , Humans , Mutation , Polymorphism, Single Nucleotide , RNA Virus Infections/virology , Reproducibility of Results , SARS-CoV-2/genetics , Sensitivity and Specificity
3.
PLoS Comput Biol ; 17(10): e1008874, 2021 10.
Article in English | MEDLINE | ID: covidwho-1484838

ABSTRACT

Respiratory viruses present major public health challenges, as evidenced by the 1918 Spanish Flu, the 1957 H2N2, 1968 H3N2, and 2009 H1N1 influenza pandemics, and the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Severe RNA virus respiratory infections often correlate with high viral load and excessive inflammation. Understanding the dynamics of the innate immune response and its manifestations at the cell and tissue levels is vital to understanding the mechanisms of immunopathology and to developing strain-independent treatments. Here, we present a novel spatialized multicellular computational model of RNA virus infection and the type-I interferon-mediated antiviral response that it induces within lung epithelial cells. The model is built using the CompuCell3D multicellular simulation environment and is parameterized using data from influenza virus-infected cell cultures. Consistent with experimental observations, it exhibits either linear radial growth of viral plaques or arrested plaque growth depending on the local concentration of type I interferons. The model suggests that modifying the activity of signaling molecules in the JAK/STAT pathway or altering the ratio of the diffusion lengths of interferon and virus in the cell culture could lead to plaque growth arrest. The dependence of plaque growth arrest on diffusion lengths highlights the importance of developing validated spatial models of cytokine signaling and the need for in vitro measurement of these diffusion coefficients. Sensitivity analyses under conditions leading to continuous or arrested plaque growth found that plaque growth is more sensitive to variations of most parameters and more likely to have identifiable model parameters when conditions lead to plaque arrest. This result suggests that cytokine assay measurements may be most informative under conditions leading to arrested plaque growth. The model is easy to extend to include SARS-CoV-2-specific mechanisms or to use as a component in models linking epithelial cell signaling to systemic immune models.


Subject(s)
Host-Pathogen Interactions/immunology , Interferons , RNA Virus Infections , RNA Viruses , Virus Replication , Cells, Cultured , Computational Biology , Epithelial Cells/immunology , Humans , Immunity, Innate/immunology , Interferons/immunology , Interferons/metabolism , Lung/cytology , Lung/immunology , Models, Biological , RNA Virus Infections/immunology , RNA Virus Infections/virology , RNA Viruses/immunology , RNA Viruses/physiology , Virus Replication/immunology , Virus Replication/physiology
4.
Viruses ; 13(9)2021 09 21.
Article in English | MEDLINE | ID: covidwho-1427003

ABSTRACT

The error rate displayed during template copying to produce viral RNA progeny is a biologically relevant parameter of the replication complexes of viruses. It has consequences for virus-host interactions, and it represents the first step in the diversification of viruses in nature. Measurements during infections and with purified viral polymerases indicate that mutation rates for RNA viruses are in the range of 10-3 to 10-6 copying errors per nucleotide incorporated into the nascent RNA product. Although viruses are thought to exploit high error rates for adaptation to changing environments, some of them possess misincorporation correcting activities. One of them is a proofreading-repair 3' to 5' exonuclease present in coronaviruses that may decrease the error rate during replication. Here we review experimental evidence and models of information maintenance that explain why elevated mutation rates have been preserved during the evolution of RNA (and some DNA) viruses. The models also offer an interpretation of why error correction mechanisms have evolved to maintain the stability of genetic information carried out by large viral RNA genomes such as the coronaviruses.


Subject(s)
Genome, Viral , Mutation , RNA Virus Infections/virology , RNA Viruses/genetics , RNA, Viral , Animals , Biological Evolution , Coronavirus/genetics , Exonucleases/metabolism , Genetic Variation , Humans , Mutation Rate , Virus Replication
5.
J Microbiol Biotechnol ; 31(8): 1088-1097, 2021 Aug 28.
Article in English | MEDLINE | ID: covidwho-1399433

ABSTRACT

Grouper nervous necrosis virus (GNNV) infection causes mass grouper mortality, leading to substantial economic loss in Taiwan. Traditional methods of controlling GNNV infections involve the challenge of controlling disinfectant doses; low doses are ineffective, whereas high doses may cause environmental damage. Identifying potential methods to safely control GNNV infection to prevent viral outbreaks is essential. We engineered a virus-binding bacterium expressing a myxovirus resistance (Mx) protein on its surface for GNNV removal from phosphate-buffered saline (PBS), thus increasing the survival of grouper fin (GF-1) cells. We fused the grouper Mx protein (which recognizes and binds to the coat protein of GNNV) to the C-terminus of outer membrane lipoprotein A (lpp-Mx) and to the N-terminus of a bacterial autotransporter adhesin (Mx-AIDA); these constructs were expressed on the surfaces of Escherichia coli BL21 (BL21/lpp-Mx and BL21/Mx-AIDA). We examined bacterial surface expression capacity and GNNV binding activity through enzyme-linked immunosorbent assay; we also evaluated the GNNV removal efficacy of the bacteria and viral cytotoxicity after bacterial adsorption treatment. Although both constructs were successfully expressed, only BL21/lpp-Mx exhibited GNNV binding activity; BL21/lpp-Mx cells removed GNNV and protected GF-1 cells from GNNV infection more efficiently. Moreover, salinity affected the GNNV removal efficacy of BL21/lpp-Mx. Thus, our GNNV-binding bacterium is an efficient microparticle for removing GNNV from 10‰ brackish water and for preventing GNNV infection in groupers.


Subject(s)
Bacteria/metabolism , Fish Diseases/prevention & control , Fish Proteins/metabolism , Myxovirus Resistance Proteins/metabolism , RNA Virus Infections/veterinary , Animals , Antiviral Agents/metabolism , Bacteria/genetics , Bass , Cell Line , Cell Membrane/metabolism , Cell Surface Display Techniques , Cell Survival , Fish Diseases/virology , Fish Proteins/genetics , Myxovirus Resistance Proteins/genetics , Nodaviridae/isolation & purification , Nodaviridae/metabolism , RNA Virus Infections/prevention & control , RNA Virus Infections/virology , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Salinity , Virus Attachment
6.
Viruses ; 13(6)2021 05 21.
Article in English | MEDLINE | ID: covidwho-1359299

ABSTRACT

Viral RNAs contain the information needed to synthesize their own proteins, to replicate, and to spread to susceptible cells. However, due to their reduced coding capacity RNA viruses rely on host cells to complete their multiplication cycle. This is largely achieved by the concerted action of regulatory structural elements on viral RNAs and a subset of host proteins, whose dedicated function across all stages of the infection steps is critical to complete the viral cycle. Importantly, not only the RNA sequence but also the RNA architecture imposed by the presence of specific structural domains mediates the interaction with host RNA-binding proteins (RBPs), ultimately affecting virus multiplication and spreading. In marked difference with other biological systems, the genome of positive strand RNA viruses is also the mRNA. Here we focus on distinct types of positive strand RNA viruses that differ in the regulatory elements used to promote translation of the viral RNA, as well as in the mechanisms used to evade the series of events connected to antiviral response, including translation shutoff induced in infected cells, assembly of stress granules, and trafficking stress.


Subject(s)
Host-Pathogen Interactions , RNA Viruses/physiology , RNA, Viral/genetics , RNA, Viral/metabolism , RNA-Binding Proteins/metabolism , Response Elements , Biological Transport , Cytoplasmic Granules/metabolism , Gene Expression Regulation, Viral , Humans , Protein Biosynthesis , RNA Virus Infections/metabolism , RNA Virus Infections/virology , RNA, Viral/chemistry , Stress, Physiological , Transport Vesicles/metabolism , Virus Replication
7.
Science ; 373(6551): 231-236, 2021 07 09.
Article in English | MEDLINE | ID: covidwho-1304152

ABSTRACT

In mammals, early resistance to viruses relies on interferons, which protect differentiated cells but not stem cells from viral replication. Many other organisms rely instead on RNA interference (RNAi) mediated by a specialized Dicer protein that cleaves viral double-stranded RNA. Whether RNAi also contributes to mammalian antiviral immunity remains controversial. We identified an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses-including Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-by dicing viral double-stranded RNA to orchestrate antiviral RNAi. Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity, in which different cell-intrinsic antiviral pathways can be tailored to the differentiation status of cells.


Subject(s)
DEAD-box RNA Helicases/genetics , DEAD-box RNA Helicases/metabolism , RNA Interference , RNA Viruses/physiology , RNA, Viral/metabolism , Ribonuclease III/genetics , Ribonuclease III/metabolism , Stem Cells/enzymology , Stem Cells/virology , Alternative Splicing , Animals , Brain/enzymology , Brain/virology , Cell Line , DEAD-box RNA Helicases/chemistry , Humans , Immunity, Innate , Isoenzymes/chemistry , Isoenzymes/genetics , Isoenzymes/metabolism , Mice , Organoids/enzymology , Organoids/virology , RNA Virus Infections/enzymology , RNA Virus Infections/immunology , RNA Virus Infections/virology , RNA Viruses/genetics , RNA Viruses/immunology , RNA, Double-Stranded/metabolism , RNA, Small Interfering/metabolism , Ribonuclease III/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Virus Replication , Zika Virus/genetics , Zika Virus/immunology , Zika Virus/physiology , Zika Virus Infection/enzymology , Zika Virus Infection/immunology , Zika Virus Infection/virology
8.
Front Immunol ; 11: 573583, 2020.
Article in English | MEDLINE | ID: covidwho-1226976

ABSTRACT

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.


Subject(s)
Adaptive Immunity , Complement Activation , Complement System Proteins/immunology , Immunity, Innate , RNA Virus Infections/virology , RNA Viruses/pathogenicity , Animals , Complement System Proteins/genetics , Complement System Proteins/metabolism , Evolution, Molecular , Gene Expression Regulation, Viral , Host-Pathogen Interactions , Humans , RNA Virus Infections/genetics , RNA Virus Infections/immunology , RNA Virus Infections/mortality , RNA Viruses/genetics , RNA Viruses/immunology , Severity of Illness Index
9.
Viruses ; 13(4)2021 04 13.
Article in English | MEDLINE | ID: covidwho-1187061

ABSTRACT

RNA viruses cause a wide range of human diseases that are associated with high mortality and morbidity. In the past decades, the rise of genetic-based screening methods and high-throughput sequencing approaches allowed the uncovering of unique and elusive aspects of RNA virus replication and pathogenesis at an unprecedented scale. However, viruses often hijack critical host functions or trigger pathological dysfunctions, perturbing cellular proteostasis, macromolecular complex organization or stoichiometry, and post-translational modifications. Such effects require the monitoring of proteins and proteoforms both on a global scale and at the structural level. Mass spectrometry (MS) has recently emerged as an important component of the RNA virus biology toolbox, with its potential to shed light on critical aspects of virus-host perturbations and streamline the identification of antiviral targets. Moreover, multiple novel MS tools are available to study the structure of large protein complexes, providing detailed information on the exact stoichiometry of cellular and viral protein complexes and critical mechanistic insights into their functions. Here, we review top-down and bottom-up mass spectrometry-based approaches in RNA virus biology with a special focus on the most recent developments in characterizing host responses, and their translational implications to identify novel tractable antiviral targets.


Subject(s)
Proteomics/methods , RNA Virus Infections , RNA Viruses , Tandem Mass Spectrometry/methods , Host Microbial Interactions , Humans , RNA Virus Infections/immunology , RNA Virus Infections/virology , RNA Viruses/immunology , RNA Viruses/physiology , Virus Replication
10.
Int J Mol Sci ; 22(1)2020 Dec 30.
Article in English | MEDLINE | ID: covidwho-1006614

ABSTRACT

Being opportunistic intracellular pathogens, viruses are dependent on the host for their replication. They hijack host cellular machinery for their replication and survival by targeting crucial cellular physiological pathways, including transcription, translation, immune pathways, and apoptosis. Immediately after translation, the host and viral proteins undergo a process called post-translational modification (PTM). PTMs of proteins involves the attachment of small proteins, carbohydrates/lipids, or chemical groups to the proteins and are crucial for the proteins' functioning. During viral infection, host proteins utilize PTMs to control the virus replication, using strategies like activating immune response pathways, inhibiting viral protein synthesis, and ultimately eliminating the virus from the host. PTM of viral proteins increases solubility, enhances antigenicity and virulence properties. However, RNA viruses are devoid of enzymes capable of introducing PTMs to their proteins. Hence, they utilize the host PTM machinery to promote their survival. Proteins from viruses belonging to the family: Togaviridae, Flaviviridae, Retroviridae, and Coronaviridae such as chikungunya, dengue, zika, HIV, and coronavirus are a few that are well-known to be modified. This review discusses various host and virus-mediated PTMs that play a role in the outcome during the infection.


Subject(s)
Protein Processing, Post-Translational , RNA Virus Infections/enzymology , RNA Virus Infections/virology , RNA Viruses/metabolism , RNA Viruses/pathogenicity , Viral Proteins/metabolism , Acetylation , Chikungunya virus/metabolism , Coronavirus/metabolism , Coronavirus/pathogenicity , Cytopathogenic Effect, Viral , Glycosylation , HIV/metabolism , HIV/pathogenicity , Host Microbial Interactions , Humans , Phosphorylation , RNA Virus Infections/immunology , RNA Virus Infections/metabolism , RNA Viruses/immunology , Ubiquitination , Virus Replication/physiology , Zika Virus/metabolism , Zika Virus/pathogenicity
11.
Cell Rep Med ; 2(4): 100245, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1155662

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and variants has led to significant mortality. We recently reported that an RNA-targeting CRISPR-Cas13 system, called prophylactic antiviral CRISPR in human cells (PAC-MAN), offered an antiviral strategy against SARS-CoV-2 and influenza A virus. Here, we expand in silico analysis to use PAC-MAN to target a broad spectrum of human- or livestock-infectious RNA viruses with high specificity, coverage, and predicted efficiency. Our analysis reveals that a minimal set of 14 CRISPR RNAs (crRNAs) is able to target >90% of human-infectious viruses across 10 RNA virus families. We predict that a set of 5 experimentally validated crRNAs can target new SARS-CoV-2 variant sequences with zero mismatches. We also build an online resource (crispr-pacman.stanford.edu) to support community use of CRISPR-Cas13 for broad-spectrum RNA virus targeting. Our work provides a new bioinformatic resource for using CRISPR-Cas13 to target diverse RNA viruses to facilitate the development of CRISPR-based antivirals.


Subject(s)
CRISPR-Cas Systems/genetics , RNA Viruses/genetics , RNA, Guide/metabolism , COVID-19/pathology , COVID-19/virology , Humans , RNA Virus Infections/pathology , RNA Virus Infections/virology , RNA Viruses/isolation & purification , RNA, Viral/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Species Specificity
12.
Sci Rep ; 11(1): 3209, 2021 02 05.
Article in English | MEDLINE | ID: covidwho-1065951

ABSTRACT

Viral co-infections occur in COVID-19 patients, potentially impacting disease progression and severity. However, there is currently no dedicated method to identify viral co-infections in patient RNA-seq data. We developed PACIFIC, a deep-learning algorithm that accurately detects SARS-CoV-2 and other common RNA respiratory viruses from RNA-seq data. Using in silico data, PACIFIC recovers the presence and relative concentrations of viruses with > 99% precision and recall. PACIFIC accurately detects SARS-CoV-2 and other viral infections in 63 independent in vitro cell culture and patient datasets. PACIFIC is an end-to-end tool that enables the systematic monitoring of viral infections in the current global pandemic.


Subject(s)
COVID-19/diagnosis , Coinfection/diagnosis , Deep Learning , RNA Virus Infections/diagnosis , RNA Viruses/isolation & purification , SARS-CoV-2/isolation & purification , COVID-19 Testing , Coinfection/virology , Coronaviridae/isolation & purification , Humans , Metapneumovirus/classification , Metapneumovirus/isolation & purification , Neural Networks, Computer , Orthomyxoviridae/classification , Orthomyxoviridae/isolation & purification , RNA Virus Infections/virology , RNA Viruses/classification , RNA-Seq , Rhinovirus/classification , Rhinovirus/isolation & purification , SARS-CoV-2/classification , Sensitivity and Specificity
13.
Viruses ; 12(12)2020 12 10.
Article in English | MEDLINE | ID: covidwho-969583

ABSTRACT

Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathways and disturbance in interactions between cellular HSP70 complex and viral proteins, illustrating the supportive role of HSP70 on many RNA viruses across virus families. Collectively, this strategy identifies new small molecule inhibitors with broad antiviral activity against pathogenic RNA viruses, but also uncovers novel virus biology urgently needed for design of new antiviral therapies.


Subject(s)
Antiviral Agents/pharmacology , Host-Pathogen Interactions/drug effects , RNA Viruses/drug effects , Virus Replication/drug effects , Animals , Cell Line , Ebolavirus/drug effects , Ebolavirus/physiology , HSP70 Heat-Shock Proteins/metabolism , Hemorrhagic Fever Virus, Crimean-Congo/drug effects , Hemorrhagic Fever Virus, Crimean-Congo/physiology , Humans , Protein Binding/drug effects , Protein Stability , Proteome/drug effects , Proteostasis/drug effects , RNA Virus Infections/metabolism , RNA Virus Infections/virology , RNA Viruses/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Small Molecule Libraries/pharmacology , Viral Proteins/metabolism
14.
J Proteome Res ; 19(11): 4259-4274, 2020 11 06.
Article in English | MEDLINE | ID: covidwho-960274

ABSTRACT

Emerging and re-emerging infectious diseases due to RNA viruses cause major negative consequences for the quality of life, public health, and overall economic development. Most of the RNA viruses causing illnesses in humans are of zoonotic origin. Zoonotic viruses can directly be transferred from animals to humans through adaptation, followed by human-to-human transmission, such as in human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and, more recently, SARS coronavirus 2 (SARS-CoV-2), or they can be transferred through insects or vectors, as in the case of Crimean-Congo hemorrhagic fever virus (CCHFV), Zika virus (ZIKV), and dengue virus (DENV). At the present, there are no vaccines or antiviral compounds against most of these viruses. Because proteins possess a vast array of functions in all known biological systems, proteomics-based strategies can provide important insights into the investigation of disease pathogenesis and the identification of promising antiviral drug targets during an epidemic or pandemic. Mass spectrometry technology has provided the capacity required for the precise identification and the sensitive and high-throughput analysis of proteins on a large scale and has contributed greatly to unravelling key protein-protein interactions, discovering signaling networks, and understanding disease mechanisms. In this Review, we present an account of quantitative proteomics and its application in some prominent recent examples of emerging and re-emerging RNA virus diseases like HIV-1, CCHFV, ZIKV, and DENV, with more detail with respect to coronaviruses (MERS-CoV and SARS-CoV) as well as the recent SARS-CoV-2 pandemic.


Subject(s)
Communicable Diseases, Emerging , Proteomics , RNA Virus Infections , Animals , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Communicable Diseases, Emerging/diagnosis , Communicable Diseases, Emerging/therapy , Communicable Diseases, Emerging/virology , Coronavirus Infections/diagnosis , Humans , Pandemics , Pneumonia, Viral , RNA Virus Infections/diagnosis , RNA Virus Infections/therapy , RNA Virus Infections/virology , RNA Viruses
15.
Viruses ; 12(4)2020 03 31.
Article in English | MEDLINE | ID: covidwho-820253

ABSTRACT

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.


Subject(s)
ADP-Ribosylation/immunology , RNA Viruses/immunology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/immunology , Adenosine Diphosphate Ribose/metabolism , Cytoplasmic Granules/immunology , Cytoplasmic Granules/virology , Humans , Interferons/immunology , Mutation , Poly(ADP-ribose) Polymerases/immunology , Protein Domains , RNA Virus Infections/immunology , RNA Virus Infections/metabolism , RNA Virus Infections/virology , RNA Viruses/classification , RNA Viruses/genetics , RNA Viruses/metabolism , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Virus Replication
16.
Sci Rep ; 10(1): 4746, 2020 03 16.
Article in English | MEDLINE | ID: covidwho-740043

ABSTRACT

Ginkgolic acids (GA) are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; and potential rescue of amyloid-ß (Aß) induced synaptic impairment. GA was also reported to have activity against Escherichia coli and Staphylococcus aureus. Several mechanisms for this activity have been suggested including: SUMOylation inhibition; blocking formation of the E1-SUMO intermediate; inhibition of fatty acid synthase; non-specific SIRT inhibition; and activation of protein phosphatase type-2C. Here we report that GA inhibits Herpes simplex virus type 1 (HSV-1) by inhibition of both fusion and viral protein synthesis. Additionally, we report that GA inhibits human cytomegalovirus (HCMV) genome replication and Zika virus (ZIKV) infection of normal human astrocytes (NHA). We show a broad spectrum of fusion inhibition by GA of all three classes of fusion proteins including HIV, Ebola virus (EBOV), influenza A virus (IAV) and Epstein Barr virus (EBV). In addition, we show inhibition of a non-enveloped adenovirus. Our experiments suggest that GA inhibits virion entry by blocking the initial fusion event. Data showing inhibition of HSV-1 and CMV replication, when GA is administered post-infection, suggest a possible secondary mechanism targeting protein and DNA synthesis. Thus, in light of the strong effect of GA on viral infection, even after the infection begins, it may potentially be used to treat acute infections (e.g. Coronavirus, EBOV, ZIKV, IAV and measles), and also topically for the successful treatment of active lesions (e.g. HSV-1, HSV-2 and varicella-zoster virus (VZV)).


Subject(s)
Antiviral Agents/pharmacology , DNA Virus Infections/metabolism , DNA Viruses/drug effects , RNA Virus Infections/metabolism , RNA Viruses/drug effects , Salicylates/pharmacology , Viral Envelope Proteins/antagonists & inhibitors , Viral Fusion Proteins/antagonists & inhibitors , Animals , Astrocytes/metabolism , Chlorocebus aethiops , DNA Replication/drug effects , DNA Virus Infections/virology , DNA Viruses/genetics , DNA, Viral/genetics , HEK293 Cells , Humans , RNA Virus Infections/virology , RNA Viruses/genetics , Vero Cells , Viral Envelope Proteins/biosynthesis , Viral Fusion Proteins/biosynthesis , Virion/drug effects , Virus Internalization/drug effects , Virus Replication/drug effects
18.
J Infect Dis ; 221(6): 882-889, 2020 03 02.
Article in English | MEDLINE | ID: covidwho-27190

ABSTRACT

BACKGROUND: Virus infections result in a range of clinical outcomes for the host, from asymptomatic to severe or even lethal disease. Despite global efforts to prevent and treat virus infections to limit morbidity and mortality, the continued emergence and re-emergence of new outbreaks as well as common infections such as influenza persist as a health threat. Challenges to the prevention of severe disease after virus infection include both a paucity of protective vaccines as well as the early identification of individuals with the highest risk that may require supportive treatment. METHODS: We completed a screen of mice from the Collaborative Cross (CC) that we infected with influenza, severe acute respiratory syndrome-coronavirus, and West Nile virus. RESULTS: The CC mice exhibited a range of disease manifestations upon infections, and we used this natural variation to identify strains with mortality after infection and strains exhibiting no mortality. We then used comprehensive preinfection immunophenotyping to identify global baseline immune correlates of protection from mortality to virus infection. CONCLUSIONS: These data suggest that immune phenotypes might be leveraged to identify humans at highest risk of adverse clinical outcomes upon infection, who may most benefit from intensive clinical interventions, in addition to providing insight for rational vaccine design.


Subject(s)
Mortality , RNA Virus Infections/immunology , RNA Virus Infections/mortality , Animals , Collaborative Cross Mice , Cytokines/metabolism , Disease Models, Animal , Female , Humans , Influenza A virus/immunology , Influenza, Human , Male , Mice , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/mortality , RNA , RNA Virus Infections/virology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/mortality , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Viral Vaccines/immunology , West Nile Fever/immunology , West Nile Fever/mortality , West Nile virus/immunology
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