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1.
J Med Virol ; 93(11): 6116-6123, 2021 11.
Article in English | MEDLINE | ID: covidwho-1349155

ABSTRACT

Virus invasion activates the host's innate immune response, inducing the production of numerous cytokines and interferons to eliminate pathogens. Except for viral DNA/RNA, viral proteins are also targets of pattern recognition receptors. Membrane-bound receptors such as Toll-like receptor (TLR)1, TLR2, TLR4, TLR6, and TLR10 relate to the recognition of viral proteins. Distinct TLRs perform both protective and detrimental roles for a specific virus. Here, we review viral proteins serving as pathogen-associated molecular patterns and their corresponding TLRs. These viruses are all enveloped, including respiratory syncytial virus, hepatitis C virus, measles virus, herpesvirus human immunodeficiency virus, and coronavirus, and can encode proteins to activate innate immunity in a TLR-dependent way. The TLR-viral protein relationship plays an important role in innate immunity activation. A detailed understanding of their pathways contributes to a novel direction for vaccine development.


Subject(s)
Immunity, Innate , Pathogen-Associated Molecular Pattern Molecules/metabolism , Toll-Like Receptors/immunology , Toll-Like Receptors/metabolism , Viral Proteins/metabolism , Virus Diseases/immunology , Viruses/immunology , Animals , HIV/immunology , HIV/metabolism , HIV/pathogenicity , Hepacivirus/immunology , Hepacivirus/metabolism , Hepacivirus/pathogenicity , Herpesviridae/immunology , Herpesviridae/metabolism , Herpesviridae/pathogenicity , Humans , Measles virus/immunology , Measles virus/metabolism , Measles virus/pathogenicity , Pathogen-Associated Molecular Pattern Molecules/chemistry , Respiratory Syncytial Viruses/immunology , Respiratory Syncytial Viruses/metabolism , Respiratory Syncytial Viruses/pathogenicity , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Viral Proteins/chemistry , Virus Diseases/virology , Viruses/metabolism , Viruses/pathogenicity
4.
6.
Viruses ; 14(2)2022 02 14.
Article in English | MEDLINE | ID: covidwho-1715774

ABSTRACT

Virus-like particles resemble infectious virus particles in size, shape, and molecular composition; however, they fail to productively infect host cells. Historically, the presence of virus-like particles has been inferred from total particle counts by microscopy, and infectious particle counts or plaque-forming-units (PFUs) by plaque assay; the resulting ratio of particles-to-PFUs is often greater than one, easily 10 or 100, indicating that most particles are non-infectious. Despite their inability to hijack cells for their reproduction, virus-like particles and the defective genomes they carry can exhibit a broad range of behaviors: interference with normal virus growth during co-infections, cell killing, and activation or inhibition of innate immune signaling. In addition, some virus-like particles become productive as their multiplicities of infection increase, a sign of cooperation between particles. Here, we review established and emerging methods to count virus-like particles and characterize their biological functions. We take a critical look at evidence for defective interfering virus genomes in natural and clinical isolates, and we review their potential as antiviral therapeutics. In short, we highlight an urgent need to better understand how virus-like genomes and particles interact with intact functional viruses during co-infection of their hosts, and their impacts on the transmission, severity, and persistence of virus-associated diseases.


Subject(s)
Defective Viruses/physiology , Virion/physiology , Animals , Colony-Forming Units Assay , Genome, Viral , Humans , Microscopy, Electron, Transmission , Viral Plaque Assay , Virus Diseases/virology , Virus Replication
7.
Viruses ; 14(2)2022 02 01.
Article in English | MEDLINE | ID: covidwho-1715768

ABSTRACT

Viral diseases consistently pose a substantial economic and public health burden worldwide [...].


Subject(s)
Antiviral Agents/pharmacology , Virus Diseases/drug therapy , Humans , Virus Diseases/virology , Virus Physiological Phenomena , Viruses/classification , Viruses/drug effects , Viruses/genetics
8.
Cancer Treat Res Commun ; 31: 100537, 2022.
Article in English | MEDLINE | ID: covidwho-1693708

ABSTRACT

This overview describes the research of Nobutu Yamamoto (Philadelphia) concerning immunotherapy with GcMAF for patients with cancer and for patients infected with pathogenic envelope viruses. GcMAF (Group-specific component Macrophage-Activating Factor) is a mammalian protein with an incredible potency to directly activate macrophages. Since the late 1980s Yamamoto's investigations were published in numerous journals but in order to understand the details of his research, a minute survey of many of his patents was required. But even then, regrettably, a precise description of his experiments was sometimes lacking. This overview tries to summarize all of Yamamoto's research on GcMAF, as well as some selected more recent papers from other investigators, who tried to verify and/or reproduce Yamamoto's reports. In my opinion the most important result of the GcMAF research deserves widespread renewed attention: human GcMAF injections (100 ng per week, intramuscular or intravenous) can help to cure patients with a great variety of cancers as well as patients infected with pathogenic envelope viruses like the human immunodeficiency virus 1 (HIV-1), influenza, measles and rubella (and maybe also SARS-CoV-2). From Yamamoto's data it can be calculated that GcMAF is a near-stoichiometric activator of macrophages. Yamamoto monitored the progress of his immunotherapy via the serum level of an enzyme called nagalase (α-N-acetylgalactosaminidase activity at pH 6). I have extensively discussed the properties and potential catalytic site of this enzyme activity in an Appendix entitled: "Search for the potential active site of the latent α-N-acetylgalactosaminidase activity in the glycoproteins of some envelope viruses".


Subject(s)
Immunotherapy , Macrophage-Activating Factors , Neoplasms , Vitamin D-Binding Protein , Animals , Humans , Macrophage-Activating Factors/therapeutic use , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/virology , Virus Diseases/drug therapy , Virus Diseases/immunology , Virus Diseases/virology , Vitamin D-Binding Protein/therapeutic use , alpha-N-Acetylgalactosaminidase/immunology
11.
Microbiol Spectr ; 10(1): e0165521, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1673364

ABSTRACT

Although lessons have been learned from previous severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) outbreaks, the rapid evolution of the viruses means that future outbreaks of a much larger scale are possible, as shown by the current coronavirus disease 2019 (COVID-19) outbreak. Therefore, it is necessary to better understand the evolution of coronaviruses as well as viruses in general. This study reports a comparative analysis of the amino acid usage within several key viral families and genera that are prone to triggering outbreaks, including coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], SARS-CoV, MERS-CoV, human coronavirus-HKU1 [HCoV-HKU1], HCoV-OC43, HCoV-NL63, and HCoV-229E), influenza A (H1N1 and H3N2), flavivirus (dengue virus serotypes 1 to 4 and Zika) and ebolavirus (Zaire, Sudan, and Bundibugyo ebolavirus). Our analysis reveals that the distribution of amino acid usage in the viral genome is constrained to follow a linear order, and the distribution remains closely related to the viral species within the family or genus. This constraint can be adapted to predict viral mutations and future variants of concern. By studying previous SARS and MERS outbreaks, we have adapted this naturally occurring pattern to determine that although pangolin plays a role in the outbreak of COVID-19, it may not be the sole agent as an intermediate animal. In addition to this study, our findings contribute to the understanding of viral mutations for subsequent development of vaccines and toward developing a model to determine the source of the outbreak. IMPORTANCE This study reports a comparative analysis of amino acid usage within several key viral genera that are prone to triggering outbreaks. Interestingly, there is evidence that the amino acid usage within the viral genomes is not random but in a linear order.


Subject(s)
Coronavirus/genetics , Ebolavirus/genetics , Evolution, Molecular , Flavivirus/genetics , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H3N2 Subtype/genetics , Codon , Coronavirus/classification , Genome, Viral , Humans , Linear Models , Mutation , SARS-CoV-2/genetics , Virus Diseases/virology
12.
J Nanobiotechnology ; 20(1): 41, 2022 Jan 21.
Article in English | MEDLINE | ID: covidwho-1643157

ABSTRACT

Early detection of viral pathogens by DNA-sensors in clinical samples, contaminated foods, soil or water can dramatically improve clinical outcomes and reduce the socioeconomic impact of diseases such as COVID-19. Clustered regularly interspaced short palindromic repeat (CRISPR) and its associated protein Cas12a (previously known as CRISPR-Cpf1) technology is an innovative new-generation genomic engineering tool, also known as 'genetic scissors', that has demonstrated the accuracy and has recently been effectively applied as appropriate (E-CRISPR) DNA-sensor to detect the nucleic acid of interest. The CRISPR-Cas12a from Prevotella and Francisella 1 are guided by a short CRISPR RNA (gRNA). The unique simultaneous cis- and trans- DNA cleavage after target sequence recognition at the PAM site, sticky-end (5-7 bp) employment, and ssDNA/dsDNA hybrid cleavage strategies to manipulate the attractive nature of CRISPR-Cas12a are reviewed. DNA-sensors based on the CRISPR-Cas12a technology for rapid, robust, sensitive, inexpensive, and selective detection of virus DNA without additional sample purification, amplification, fluorescent-agent- and/or quencher-labeling are relevant and becoming increasingly important in industrial and medical applications. In addition, CRISPR-Cas12a system shows great potential in the field of E-CRISPR-based bioassay research technologies. Therefore, we are highlighting insights in this research direction.


Subject(s)
CRISPR-Cas Systems/physiology , DNA, Viral/isolation & purification , Nucleic Acid Amplification Techniques , Animals , Biosensing Techniques/methods , Biosensing Techniques/trends , COVID-19/virology , DNA, Viral/analysis , Environmental Pollutants/analysis , Environmental Pollutants/isolation & purification , Food Contamination/analysis , Humans , Molecular Typing/methods , Molecular Typing/trends , Nucleic Acid Amplification Techniques/methods , Nucleic Acid Amplification Techniques/trends , SARS-CoV-2/genetics , Virology/methods , Virology/trends , Virus Diseases/classification , Virus Diseases/diagnosis , Virus Diseases/virology
13.
J Neuroinflammation ; 19(1): 8, 2022 Jan 06.
Article in English | MEDLINE | ID: covidwho-1613238

ABSTRACT

BACKGROUND: The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to an ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model. METHODS: CD-1 mice received an intraperitoneal injection of R848 (200 µg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100 µL, 3 mg/kg in 5% dextrose) or 5% dextrose alone. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 h post-challenge to measure markers of peripheral and central inflammation by blood analysis, immunohistochemistry and qPCR. RESULTS: R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment. CONCLUSIONS: Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19.


Subject(s)
Benzamidines , Guanidines , Inflammation/drug therapy , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors , Toll-Like Receptor 7/immunology , Virus Diseases/drug therapy , Animals , Benzamidines/pharmacology , Benzamidines/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Guanidines/pharmacology , Guanidines/therapeutic use , Illness Behavior/drug effects , Imidazoles/administration & dosage , Imidazoles/immunology , Inflammation/metabolism , Inflammation/virology , Male , Mice , Serine Proteinase Inhibitors/pharmacology , Serine Proteinase Inhibitors/therapeutic use , Toll-Like Receptor 7/agonists , Virus Diseases/metabolism , Virus Diseases/virology
15.
PLoS One ; 16(12): e0261497, 2021.
Article in English | MEDLINE | ID: covidwho-1581739

ABSTRACT

Since the emergence of yellow fever in the Americas and the devastating 1918 influenza pandemic, biologists and clinicians have been drawn to human infecting viruses to understand their mechanisms of infection better and develop effective therapeutics against them. However, the complex molecular and cellular processes that these viruses use to infect and multiply in human cells have been a source of great concern for the scientific community since the discovery of the first human infecting virus. Viral disease outbreaks, such as the recent COVID-19 pandemic caused by a novel coronavirus, have claimed millions of lives and caused significant economic damage worldwide. In this study, we investigated the mechanisms of host-virus interaction and the molecular machinery involved in the pathogenesis of some common human viruses. We also performed a phylogenetic analysis of viral proteins involved in host-virus interaction to understand the changes in the sequence organization of these proteins during evolution for various strains of viruses to gain insights into the viral origin's evolutionary perspectives.


Subject(s)
Host-Pathogen Interactions , Phylogeny , Viral Proteins/genetics , Virus Diseases/virology , HIV Envelope Protein gp160/genetics , Humans
16.
Nat Microbiol ; 6(12): 1483-1492, 2021 12.
Article in English | MEDLINE | ID: covidwho-1550288

ABSTRACT

Better methods to predict and prevent the emergence of zoonotic viruses could support future efforts to reduce the risk of epidemics. We propose a network science framework for understanding and predicting human and animal susceptibility to viral infections. Related approaches have so far helped to identify basic biological rules that govern cross-species transmission and structure the global virome. We highlight ways to make modelling both accurate and actionable, and discuss the barriers that prevent researchers from translating viral ecology into public health policies that could prevent future pandemics.


Subject(s)
Host-Pathogen Interactions , Virus Diseases/virology , Virus Physiological Phenomena , Animals , Humans , Virus Diseases/physiopathology , Viruses/genetics , Zoonoses/physiopathology , Zoonoses/virology
17.
Viruses ; 13(12)2021 11 29.
Article in English | MEDLINE | ID: covidwho-1542801

ABSTRACT

Nestled within the Rocky Mountain National Forest, 114 scientists and students gathered at Colorado State University's Mountain Campus for this year's 21st annual Rocky Mountain National Virology Association meeting. This 3-day retreat consisted of 31 talks and 30 poster presentations discussing advances in research pertaining to viral and prion diseases. The keynote address provided a timely discussion on zoonotic coronaviruses, lessons learned, and the path forward towards predicting, preparing, and preventing future viral disease outbreaks. Other invited speakers discussed advances in SARS-CoV-2 surveillance, molecular interactions involved in flavivirus genome assembly, evaluation of ethnomedicines for their efficacy against infectious diseases, multi-omic analyses to define risk factors associated with long COVID, the role that interferon lambda plays in control of viral pathogenesis, cell-fusion-dependent pathogenesis of varicella zoster virus, and advances in the development of a vaccine platform against prion diseases. On behalf of the Rocky Mountain Virology Association, this report summarizes select presentations.


Subject(s)
Virology , Animals , Host-Pathogen Interactions , Humans , Pandemics/prevention & control , Prion Diseases/diagnosis , Prion Diseases/prevention & control , Prions/immunology , Prions/isolation & purification , Prions/pathogenicity , Vaccines , Virology/organization & administration , Virus Diseases/diagnosis , Virus Diseases/epidemiology , Virus Diseases/prevention & control , Virus Diseases/virology , Viruses/classification , Viruses/immunology , Viruses/isolation & purification , Viruses/pathogenicity
18.
Viruses ; 13(11)2021 10 20.
Article in English | MEDLINE | ID: covidwho-1538532

ABSTRACT

Over the course of human history, billions of people worldwide have been infected by various viruses. Despite rapid progress in the development of biomedical techniques, it is still a significant challenge to find promising new antiviral targets and drugs. In the past, antiviral drugs mainly targeted viral proteins when they were used as part of treatment strategies. Since the virus mutation rate is much faster than that of the host, such drugs feature drug resistance and narrow-spectrum antiviral problems. Therefore, the targeting of host molecules has gradually become an important area of research for the development of antiviral drugs. In recent years, rapid advances in high-throughput sequencing techniques have enabled numerous genetic studies (such as genome-wide association studies (GWAS), clustered regularly interspersed short palindromic repeats (CRISPR) screening, etc.) for human diseases, providing valuable genetic and evolutionary resources. Furthermore, it has been revealed that successful drug targets exhibit similar genetic and evolutionary features, which are of great value in identifying promising drug targets and discovering new drugs. Considering these developments, in this article the authors propose a host-targeted antiviral drug discovery strategy based on knowledge of genetics and evolution. We first comprehensively summarized the genetic, subcellular location, and evolutionary features of the human genes that have been successfully used as antiviral targets. Next, the summarized features were used to screen novel druggable antiviral targets and to find potential antiviral drugs, in an attempt to promote the discovery of new antiviral drugs.


Subject(s)
Antiviral Agents/pharmacology , Virus Diseases/virology , Viruses/drug effects , Viruses/genetics , Animals , Antiviral Agents/chemistry , Drug Discovery , Genome-Wide Association Study , Humans , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Diseases/drug therapy , Viruses/metabolism
19.
Viruses ; 13(11)2021 10 20.
Article in English | MEDLINE | ID: covidwho-1538529

ABSTRACT

Viruses are obligate parasites that depend on a host cell for replication and survival. Consequently, to fully understand the viral processes involved in infection and replication, it is fundamental to study them in the cellular context. Often, viral infections induce significant changes in the subcellular organization of the host cell due to the formation of viral factories, alteration of cell cytoskeleton and/or budding of newly formed particles. Accurate 3D mapping of organelle reorganization in infected cells can thus provide valuable information for both basic virus research and antiviral drug development. Among the available techniques for 3D cell imaging, cryo-soft X-ray tomography stands out for its large depth of view (allowing for 10 µm thick biological samples to be imaged without further thinning), its resolution (about 50 nm for tomographies, sufficient to detect viral particles), the minimal requirements for sample manipulation (can be used on frozen, unfixed and unstained whole cells) and the potential to be combined with other techniques (i.e., correlative fluorescence microscopy). In this review we describe the fundamentals of cryo-soft X-ray tomography, its sample requirements, its advantages and its limitations. To highlight the potential of this technique, examples of virus research performed at BL09-MISTRAL beamline in ALBA synchrotron are also presented.


Subject(s)
Tomography, X-Ray/methods , Virus Diseases/virology , Virus Physiological Phenomena , Animals , Antiviral Agents/pharmacology , Humans , Tomography, X-Ray/instrumentation , Virus Diseases/diagnostic imaging , Virus Diseases/drug therapy , Viruses/chemistry , Viruses/drug effects
20.
Biochem Soc Trans ; 49(6): 2527-2537, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1537346

ABSTRACT

The protein-membrane interactions that mediate viral infection occur via loosely ordered, transient assemblies, creating challenges for high-resolution structure determination. Computational methods and in particular molecular dynamics simulation have thus become important adjuncts for integrating experimental data, developing mechanistic models, and suggesting testable hypotheses regarding viral function. However, the large molecular scales of virus-host interaction also create challenges for detailed molecular simulation. For this reason, continuum membrane models have played a large historical role, although they have become less favored for high-resolution models of protein assemblies and lipid organization. Here, we review recent progress in the field, with an emphasis on the insight that has been gained using a mixture of coarse-grained and atomic-resolution molecular dynamics simulations. Based on successes and challenges to date, we suggest a multiresolution strategy that should yield the best mixture of computational efficiency and physical fidelity. This strategy may facilitate further simulations of viral entry by a broader range of viruses, helping illuminate the diversity of viral entry strategies and the essential common elements that can be targeted for antiviral therapies.


Subject(s)
Computational Biology/methods , Virus Internalization , Host-Pathogen Interactions , Molecular Dynamics Simulation , Virus Diseases/virology
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