scholarly journals Ethacridine inhibits SARS-CoV-2 by inactivating viral particles

2021 ◽  
Vol 17 (9) ◽  
pp. e1009898
Author(s):  
Xiaoquan Li ◽  
Peter Lidsky ◽  
Yinghong Xiao ◽  
Chien-Ting Wu ◽  
Miguel Garcia-Knight ◽  
...  
Keyword(s):  
Mode Of Action ◽  
High Throughput Screening ◽  
Cell Types ◽  
Host Cells ◽  
Main Mode ◽  
Distinct Mode ◽  
Human Nasal Epithelial Cells ◽  
Viral Particles ◽  
Potent Drug ◽  
Air Liquid Interface

The respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2. Here we report the discovery of ethacridine as a potent drug against SARS-CoV-2 (EC50 ~ 0.08 μM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescence assay. Plaque assays, RT-PCR and immunofluorescence imaging at various stages of viral infection demonstrate that the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Consistently, ethacridine is effective in various cell types, including primary human nasal epithelial cells that are cultured in an air-liquid interface. Taken together, our work identifies a promising, potent, and new use of the old drug via a distinct mode of action for inhibiting SARS-CoV-2.

scholarly journals Ethacridine inhibits SARS-CoV-2 by inactivating viral particles in cellular models

2020 ◽  
Author(s):  
Xiaoquan Li ◽  
Peter Lidsky ◽  
Yinghong Xiao ◽  
Chien-Ting Wu ◽  
Miguel Garcia-Knight ◽  
...  
Keyword(s):  
Mode Of Action ◽  
High Throughput Screening ◽  
Cell Types ◽  
The United States ◽  
Host Cells ◽  
Viral Agent ◽  
Main Mode ◽  
Cellular Models ◽  
Human Nasal Epithelial Cells ◽  
Viral Particles

AbstractSARS-CoV-2 is the coronavirus that causes the respiratory disease COVID-19, which is now the third-leading cause of death in the United States. The FDA has recently approved remdesivir, an inhibitor of SARS-CoV-2 replication, to treat COVID-19, though recent data from the WHO shows little to no benefit with use of this anti-viral agent. Here we report the discovery of ethacridine, a safe antiseptic use in humans, as a potent drug for use against SARS-CoV-2 (EC50 ~ 0.08 μM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescent assay. Interestingly, the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Indeed, ethacridine is effective in various cell types, including primary human nasal epithelial cells. Taken together, these data identify a promising, potent, and new use of the old drug possessing a distinct mode of action for inhibiting SARS-CoV-2.

High Voltage Electron Microscopy of Viral Inclusion Bodies

1980 ◽  
Vol 38 ◽  
pp. 486-487 ◽  
Author(s):  
H.M. Mazzone ◽  
W.F. Engler ◽  
G. Wray ◽  
A. Szirmae ◽  
J. Conroy ◽  
...  
Keyword(s):  
New York ◽  
Environmental Protection Agency ◽  
Inclusion Bodies ◽  
Host Cells ◽  
High Voltage Electron Microscopy ◽  
Voltage Electron ◽  
Viral Particles ◽  
Pest Insects ◽  
Viral Inclusion ◽  
Insect Gut

Viral inclusion bodies isolated from infected pest insects are being evaluated by the U.S. Dept. of Agriculture as biological insecticides against their hosts. Our research on these inclusion bodies constitutes part of an effort to support their approval by the Environmental Protection Agency as insect control agents. The inclusion bodies in this study are polyhedral in shape and contain rod-shaped viral particles. When ingested by pest insects, the inclusion bodies are broken down in the insect gut and release the viral particles which infect and multiply in the nuclei of host cells. These viruses are termed nucleopolyhedrosis viruses (NPV) and are representatives of the baculoviruses (Wildy, P. 1971 IN J.L. Melnick, ed., Monographs in Virology, vol. 5, S.Karger, New York).

scholarly journals SARS-CoV-2 Is Not Detected in the Cerebrospinal Fluid of Encephalopathic COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Dimitris G. Placantonakis ◽  
Maria Aguero-Rosenfeld ◽  
Abdallah Flaifel ◽  
John Colavito ◽  
Kenneth Inglima ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Viral Entry ◽  
Cell Types ◽  
Host Cells ◽  
Nasopharyngeal Swab ◽  
Rt Pcr ◽  
Neurologic Sequelae ◽  
Show Evidence ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

Neurologic manifestations of the novel coronavirus SARS-CoV-2 infection have received wide attention, but the mechanisms remain uncertain. Here, we describe computational data from public domain RNA-seq datasets and cerebrospinal fluid data from adult patients with severe COVID-19 pneumonia that suggest that SARS-CoV-2 infection of the central nervous system is unlikely. We found that the mRNAs encoding the ACE2 receptor and the TMPRSS2 transmembrane serine protease, both of which are required for viral entry into host cells, are minimally expressed in the major cell types of the brain. In addition, CSF samples from 13 adult encephalopathic COVID-19 patients diagnosed with the viral infection via nasopharyngeal swab RT-PCR did not show evidence for the virus. This particular finding is robust for two reasons. First, the RT-PCR diagnostic was validated for CSF studies using stringent criteria; and second, 61% of these patients had CSF testing within 1 week of a positive nasopharyngeal diagnostic test. We propose that neurologic sequelae of COVID-19 are not due to SARS-CoV-2 meningoencephalitis and that other etiologies are more likely mechanisms.

scholarly journals High-throughput screening of circRNAs reveals novel mechanisms of tuberous sclerosis complex-related renal angiomyolipoma

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Yang Zhao ◽  
Hao Guo ◽  
Wenda Wang ◽  
Guoyang Zheng ◽  
Zhan Wang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Regulatory Network ◽  
High Throughput Screening ◽  
Kidney Tissue ◽  
Cell Types ◽  
The Body ◽  
Differentially Expressed ◽  
Renal Angiomyolipoma

Abstract Objective Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease characterized by lesions throughout the body. Our previous study showed the abnormal up-regulation of miRNAs plays an important part in the pathogenesis of TSC-related renal angiomyolipoma (TSC-RAML). circRNAs were known as important regulators of miRNA, but little is known about the circRNAs in TSC-RAMLs. Methods Microarray chips and RNA sequencing were used to identify the circRNAs and mRNAs that were differently expressed between the TSC-RAML and normal kidney tissue. A competitive endogenous RNA (ceRNA) regulatory network was constructed to reveal the regulation of miRNAs and mRNAs by the circRNAs. The biological functions of circRNA and mRNA were analyzed by pathway analysis. Microenvironmental cell types were estimated with the MCP-counter package. Results We identified 491 differentially expressed circRNAs (DECs) and 212 differentially expressed genes (DEGs), and 6 DECs were further confirmed by q-PCR. A ceRNA regulatory network which included 6 DECs, 5 miRNAs, and 63 mRNAs was established. Lipid biosynthetic process was significantly up-regulated in TSC-RAML, and the humoral immune response and the leukocyte chemotaxis pathway were found to be down-regulated. Fibroblasts are enriched in TSC-RAML, and the up-regulation of circRNA_000799 and circRNA_025332 may be significantly correlated to the infiltration of the fibroblasts. Conclusion circRNAs may regulate the lipid metabolism of TSC-RAML by regulation of the miRNAs. Fibroblasts are enriched in TSC-RAMLs, and the population of fibroblast may be related to the alteration of circRNAs of TSC-RAML. Lipid metabolism in fibroblasts is a potential treatment target for TSC-RAML.

scholarly journals Targeting Viral Surface Proteins through Structure-Based Design

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1320
Author(s):  
Yogesh B Narkhede ◽  
Karen J Gonzalez ◽  
Eva-Maria Strauch
Keyword(s):  
Public Health ◽  
Viral Infections ◽  
Respiratory Viruses ◽  
Surface Proteins ◽  
Host Cells ◽  
Viral Fusion ◽  
Health It ◽  
Viral Particles ◽  
Pathogenic Viruses ◽  
Viral Surface

The emergence of novel viral infections of zoonotic origin and mutations of existing human pathogenic viruses represent a serious concern for public health. It warrants the establishment of better interventions and protective therapies to combat the virus and prevent its spread. Surface glycoproteins catalyzing the fusion of viral particles and host cells have proven to be an excellent target for antivirals as well as vaccines. This review focuses on recent advances for computational structure-based design of antivirals and vaccines targeting viral fusion machinery to control seasonal and emerging respiratory viruses.

scholarly journals Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 282
Author(s):  
Finny S. Varghese ◽  
Esther van Woudenbergh ◽  
Gijs J. Overheul ◽  
Marc J. Eleveld ◽  
Lisa Kurver ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Early Stage ◽  
Antiviral Drugs ◽  
Target Cells ◽  
Nasal Epithelial Cells ◽  
Cytokines And Chemokines ◽  
Human Nasal Epithelial Cells ◽  
Apoptotic Protein ◽  
Air Liquid Interface

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a new human pathogen in late 2019 and it has infected over 100 million people in less than a year. There is a clear need for effective antiviral drugs to complement current preventive measures, including vaccines. In this study, we demonstrate that berberine and obatoclax, two broad-spectrum antiviral compounds, are effective against multiple isolates of SARS-CoV-2. Berberine, a plant-derived alkaloid, inhibited SARS-CoV-2 at low micromolar concentrations and obatoclax, which was originally developed as an anti-apoptotic protein antagonist, was effective at sub-micromolar concentrations. Time-of-addition studies indicated that berberine acts on the late stage of the viral life cycle. In agreement, berberine mildly affected viral RNA synthesis, but it strongly reduced infectious viral titers, leading to an increase in the particle-to-pfu ratio. In contrast, obatoclax acted at the early stage of the infection, which is in line with its activity to neutralize the acidic environment in endosomes. We assessed infection of primary human nasal epithelial cells that were cultured on an air-liquid interface and found that SARS-CoV-2 infection induced and repressed expression of specific sets of cytokines and chemokines. Moreover, both obatoclax and berberine inhibited SARS-CoV-2 replication in these primary target cells. We propose berberine and obatoclax as potential antiviral drugs against SARS-CoV-2 that could be considered for further efficacy testing.

scholarly journals Intercellular Transmission of Naked Viruses through Extracellular Vesicles: Focus on Polyomaviruses

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1086
Author(s):  
Francois Helle ◽  
Lynda Handala ◽  
Marine Bentz ◽  
Gilles Duverlie ◽  
Etienne Brochot
Keyword(s):  
Immune System ◽  
Extracellular Vesicles ◽  
Rna Viruses ◽  
Viral Transmission ◽  
Viral Fitness ◽  
Host Cells ◽  
Dna Viruses ◽  
Recent Advances ◽  
Viral Particles ◽  
Similar Strategy

Extracellular vesicles have recently emerged as a novel mode of viral transmission exploited by naked viruses to exit host cells through a nonlytic pathway. Extracellular vesicles can allow multiple viral particles to collectively traffic in and out of cells, thus enhancing the viral fitness and diversifying the transmission routes while evading the immune system. This has been shown for several RNA viruses that belong to the Picornaviridae, Hepeviridae, Reoviridae, and Caliciviridae families; however, recent studies also demonstrated that the BK and JC viruses, two DNA viruses that belong to the Polyomaviridae family, use a similar strategy. In this review, we provide an update on recent advances in understanding the mechanisms used by naked viruses to hijack extracellular vesicles, and we discuss the implications for the biology of polyomaviruses.

Angiotensin Converting Enzyme 2 (ACE2) Expression in the Visual System

2021 ◽  
Author(s):  
James M. Hill ◽  
Christian Clement ◽  
L. Arceneaux ◽  
Walter Lukiw
Keyword(s):  
Signal Processing ◽  
Angiotensin Converting Enzyme ◽  
Occipital Lobe ◽  
Cell Types ◽  
Receptor Expression ◽  
Host Cells ◽  
Visual Signal ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
The Brain

Abstract Background: Multiple lines of evidence currently indicate that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)gains entry into human host cells via a high-affinity interaction with the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor. Research has further shown the widespread expression of the ACE2 receptor on the surface of many different immune, non-immune and neural host cell types, and that SARS-CoV-2 has there markable capability to attack many different types of human-host cells simultaneously. One principal neuroanatomical region for highACE2 expression patterns occurs in the brainstem, an area of the brain containing regulatory centers for respiration, and this may in part explain the predisposition of many COVID-19 patients to respiratory distress. Early studies also indicated extensive ACE2 expression in the whole eye and the brain’s visual circuitry. In this study we analyzed ACE2 receptor expression at the mRNA and protein level in multiple cell types involved in human vision, including cell types of the external eye and several deep brain regions known to be involved in the processing of visual signals.Methods: ACE2 mRNA and protein analysis; multiple eye and brain cells and tissues; gamma32P-adenosine tri-phosphate ([γ-32P]dATP) radiolabeled probes; Northern analysis; ELISA.Results: The four main findings were: (i)that many different optical and neural cell types of the human visual system provide receptors essential for SARS-CoV-2 invasion; (ii)the remarkable ubiquity of ACE2 presence in cells of the eye and anatomical regions of the brain involved in visual signal processing; (iii)that ACE2 receptor expression in different ocular cell types and visual processing centers of the brain provide multiple compartments for SARS-CoV-2 infiltration; and (iv)a gradient of increasing ACE2 expression from the anterior surface of the eye to the visual signal processing areas of the occipital lobe and the primary visual neocortex.Conclusion: A gradient of ACE2 expression from the eye surface to the occipital lobe provide the SARS-CoV-2 virus a novel pathway from the outer eye into deeper anatomical regions of the brain involved in vision. These findings may explain, in part, the many recently reported neuro-ophthalmic manifestations of SARS-CoV-2infection in COVID-19 affected patients.

scholarly journals New Isolates of Pandoraviruses: Contribution to the Study of Replication Cycle Steps

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Ana Cláudia dos Santos Pereira Andrade ◽  
Paulo Victor de Miranda Boratto ◽  
Rodrigo Araújo Lima Rodrigues ◽  
Talita Machado Bastos ◽  
Bruna Luiza Azevedo ◽  
...  
Keyword(s):  
Time Course ◽  
Replication Cycle ◽  
Host Cells ◽  
Comprehensive Description ◽  
Genomic Features ◽  
New Information ◽  
Viral Particles ◽  
Infected Cells ◽  
Giant Viruses ◽  
Electron Lucent

ABSTRACT Giant viruses are complex members of the virosphere, exhibiting outstanding structural and genomic features. Among these viruses, the pandoraviruses are some of the most intriguing members, exhibiting giant particles and genomes presenting at up to 2.5 Mb, with many genes having no known function. In this work, we analyzed, by virological and microscopic methods, the replication cycle steps of three new pandoravirus isolates from samples collected in different regions of Brazil. Our data indicate that all analyzed pandoravirus isolates can deeply modify the Acanthamoeba cytoplasmic environment, recruiting mitochondria and membranes into and around the electron-lucent viral factories. We also observed that the viral factories start forming before the complete degradation of the cellular nucleus. Various patterns of pandoravirus particle morphogenesis were observed, and the assembly of the particles seemed to be started either by the apex or by the opposite side. On the basis of the counting of viral particles during the infection time course, we observed that pandoravirus particles could undergo exocytosis after their morphogenesis in a process that involved intense recruitment of membranes that wrapped the just-formed particles. The treatment of infected cells with brefeldin affected particle exocytosis in two of the three analyzed strains, indicating biological variability among isolates. Despite such particle exocytosis, the lysis of host cells also contributed to viral release. This work reinforces knowledge of and reveals important steps in the replication cycle of pandoraviruses. IMPORTANCE The emerging Pandoraviridae family is composed of some of the most complex viruses known to date. Only a few pandoravirus isolates have been described until now, and many aspects of their life cycle remain to be elucidated. A comprehensive description of the replication cycle is pivotal to a better understanding of the biology of the virus. For this report, we describe new pandoraviruses and used different methods to better characterize the steps of the replication cycle of this new group of viruses. Our results provide new information about the diversity and biology of these giant viruses.

scholarly journals Molecular biology of baculovirus and its use in biological control in Brazil

1999 ◽  
Vol 34 (10) ◽  
pp. 1733-1761 ◽  
Author(s):  
Maria Elita Batista de Castro ◽  
Marlinda Lobo de Souza ◽  
William Sihler ◽  
Júlio Carlyle Macedo Rodrigues ◽  
Bergmann Morais Ribeiro
Keyword(s):  
Molecular Biology ◽  
Recombinant Dna ◽  
Host Cells ◽  
Virus Propagation ◽  
Viral Particles ◽  
Occlusion Bodies ◽  
Budded Virus ◽  
Recombinant Dna Techniques ◽  
High Level ◽  
Eukaryotic Organisms

Baculoviruses are insect viruses found mainly in Lepidoptera. The family Baculoviridae is taxonomically divided in two genera, Nucleopolyhedrovirus and Granulovirus, which differ by occlusion body morphology. NPVs (Nucleopolyhedroviruses) have polyhedrical inclusion bodies (PIBs) containing multiple viral particles, while GVs (Granuloviruses) appear to be generally single particles occluded in oval shaped occlusion bodies. During the life cycle, two different viral progenies are produced: BV (Budded Virus) and PDV (Polyhedra Derived Virus), which are essential for the infectious process and virus propagation in host cells. Baculoviruses are being used for pest control and they are especially safe due to their specificity and invertebrate-restricted host range. Baculoviruses have been used as vectors for high level protein expression ofheterologous genes from prokaryotic and eukaryotic organisms. Also, recombinant DNA techniques have allowed the production of genetically modified viral insecticides. This study is a review on the taxonomy, structure, replication and molecular biology of baculoviruses, as well as their use as bioinsecticides in Brazil.

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