Olga Dolnik

Philipps University of Marburg

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Stephan Becker

Philipps University of Marburg

Viktor E. Volchkov

École Normale Supérieure de Lyon

John M. Dye

United States Army Medical Research Institute of Infectious Diseases

Netesov Sv

Novosibirsk State University

Elke Mühlberger

Boston University

Alexander Bukreyev

The University of Texas Medical Branch at Galveston

Jonathan S. Towner

Centers for Disease Control and Prevention

Janusz T. Pawęska

University of Pretoria

Jens H. Kuhn

National Institutes of Health

Sophie J. Smither

Defence Science and Technology Laboratory

Cooperative Institutions

National Institutes of Health

Philipps University of Marburg

German Center for Infection Research

National Institute of Allergy and Infectious Diseases

Centers for Disease Control and Prevention

Institute of Virology of the Slovak Academy of Sciences

United States Army Medical Research Institute of Infectious Diseases

The University of Texas Medical Branch at Galveston

Centre National de la Recherche Scientifique

Harvard University

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Inclusion Bodies Are a Site of Ebolavirus Replication

Journal of Virology (2012)

Thomas Hoenen Reed S. Shabman Allison Groseth Astrid Herwig Michaela Weber

Inclusion bodies are a characteristic feature of ebolavirus infections in cells. They contain large numbers of preformed nucleocapsids, but their biological significance has been debated, and they have been suggested to be aggregates of viral proteins without any further biological function. However, recent data for other viruses that produce similar structures have suggested that inclusion bodies might be involved in genome replication and transcription. In order to study filovirus inclusion bodies, we fused mCherry to the ebolavirus polymerase L, which is found in inclusion bodies. The resulting L-mCherry fusion protein was functional in minigenome assays and incorporated into virus-like particles. Importantly, L-mCherry fluorescence in transfected cells was readily detectable and distributed in a punctate pattern characteristic for inclusion bodies. A recombinant ebolavirus encoding L-mCherry instead of L was rescued and showed virtually identical growth kinetics and endpoint titers to those for wild-type virus. Using this virus, we showed that the onset of inclusion body formation corresponds to the onset of viral genome replication, but that viral transcription occurs prior to inclusion body formation. Live-cell imaging further showed that inclusion bodies are highly dynamic structures and that they can undergo dramatic reorganization during cell division. Finally, by labeling nascent RNAs using click technology we showed that inclusion bodies are indeed the site of viral RNA synthesis. Based on these data we conclude that, rather than being inert aggregates of nucleocapsids, ebolavirus inclusion bodies are in fact complex and dynamic structures and an important site at which viral RNA replication takes place.

Ebolavirus

Inclusion bodies

mCherry

10.1128/jvi.01525-12

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Citations (210)

Taxonomy of the order Mononegavirales: update 2018

Archives of Virology (2018)

Gaya K. Amarasinghe Nidia Aréchiga-Ceballos Ashley C. Banyard Christopher F. Basler Sina Bavari

Mononegavirales

Virus classification

10.1007/s00705-018-3814-x

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Citations (189)

Shedding of Ebola Virus Surface Glycoprotein Is a Mechanism of Self-regulation of Cellular Cytotoxicity and Has a Direct Effect on Virus Infectivity

The Journal of Infectious Diseases (2015)

Olga Dolnik Valentina A. Volchkova Beatriz Escudero-Pérez Philip Lawrence Hans‐Dieter Klenk

The surface glycoprotein (GP) is responsible for Ebola virus (EBOV) attachment and membrane fusion during virus entry. Surface expression of highly glycosylated GP causes marked cytotoxicity via masking of a wide range of cellular surface molecules, including integrins. Considerable amounts of surface GP are shed from virus-infected cells in a soluble truncated form by tumor necrosis factor α–converting enzyme. In this study, the role of GP shedding was investigated using a reverse genetics approach by comparing recombinant viruses possessing amino acid substitutions at the GP shedding site. Virus with an L635V substitution showed a substantial decrease in shedding, whereas a D637V substitution resulted in a striking increase in the release of shed GP. Variations in shedding efficacy correlated with observed differences in the amounts of shed GP in the medium, GP present in virus-infected cells, and GP present on virions. An increase in shedding appeared to be associated with a reduction in viral cytotoxicity, and, vice versa, the virus that shed less was more cytotoxic. An increase in shedding also resulted in a reduction in viral infectivity, whereas a decrease in shedding efficacy enhanced viral growth characteristics in vitro. Differences in shedding efficacy and, as a result, differences in the amount of mature GP available for incorporation into budding virions did not equate to differences in overall release of viral particles. Likewise, data suggest that the resulting differences in the amount of mature GP on the cell surface led to variations in the GP content of released particles and, as a consequence, in infectivity. In conclusion, fine-tuning of the levels of EBOV GP expressed at the surface of virus-infected cells via GP shedding plays an important role in EBOV replication by orchestrating the balance between optimal virion GP content and cytotoxicity caused by GP.

Infectivity

Viral Shedding

10.1093/infdis/jiv268

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Citations (19)

Structural characterization and membrane binding properties of the matrix protein VP40 of ebola virus

Journal of Molecular Biology (2000)

Rob W.H. Ruigrok Guy Schoehn Andréa Dessen Éric Forest Viktor E. Volchkov

VP40

Proteolysis

Ebolavirus

Marburg virus

10.1006/jmbi.2000.3822

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Citations (159)

Correction to: 2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales

Archives of Virology (2021)

Jens H. Kuhn Scott Adkins Bernard Agwanda Rim Al Kubrusli Sergey V. Alkhovsky

10.1007/s00705-021-05266-w

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TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

Life Science Alliance (2020)

Dorothea Bestle Miriam Ruth Heindl Hannah Limburg Thuy Van Lam van Oliver Pilgram

The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study, we show that S can be cleaved by the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2′ site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 human airway epithelial cells through antisense-mediated knockdown of TMPRSS2 expression. Furthermore, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851 in human airway cells. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Combining various TMPRSS2 inhibitors with furin inhibitor MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. Therefore, this approach has considerable therapeutic potential for treatment of COVID-19.

Furin

TMPRSS2

Proprotein Convertases

SLPI

Protease inhibitor (pharmacology)

10.26508/lsa.202000786

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Citations (764)

Recovery of Infectious Ebola Virus from Complementary DNA: RNA Editing of the GP Gene and Viral Cytotoxicity

Science (2001)

Viktor E. Volchkov Valentina A. Volchkova Elke Mühlberger Larissa Kolesnikova Michael Weik

To study the mechanisms underlying the high pathogenicity of Ebola virus, we have established a system that allows the recovery of infectious virus from cloned cDNA and thus permits genetic manipulation. We created a mutant in which the editing site of the gene encoding envelope glycoprotein (GP) was eliminated. This mutant no longer expressed the nonstructural glycoprotein sGP. Synthesis of GP increased, but most of it accumulated in the endoplasmic reticulum as immature precursor. The mutant was significantly more cytotoxic than wild-type virus, indicating that cytotoxicity caused by GP is down-regulated by the virus through transcriptional RNA editing and expression of sGP.

10.1126/science.1057269

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Citations (294)

Parasites and pathogenes in population of Chaffinch Fringilla coelebs from Masurian Lakeland, NE Poland

Acta Ornithologica (2000)

Alicja Gryczyńska Olga Dolnik Agnieszka Pawełczyk Tomasz D. Mazgajski M. Siemiatkowski

The aim of the study was to contribute the knowledge about the coincidence and species selectivity of bird parasites. The subject of our study were Chaffinches captured in Masurian Lake region (NE Poland) from 1996 to 1998. Each bird caught was visually examined for the presence of ticks. Birds' droppings and small volumes of birds' blood were collected in order to ascertain the presence of coccidia and blood parasites. Additionally the presence of bacteria Borrelia burgdorferi - the causative agent of Lyme borreliosis in birds' blood was measured with the nested-polymerase chain reaction method. In total amount of 225 Chaffinches were captured. 44% of them were infested by ticks belonging to Ixodes ricinus species (larvae and nymphs) only. Coccidia from genus Isospora were found in 80% (n = 35) of birds. Protozoans from genus Haemoproteus were ascertained in 53% (n = 59) of Chaffinches and bacteria B. burgdorferi was found in 12.7% (n = 166) of the birds. Three groups of parasites (I. ricinus, Isospora sp., Haemoproteus sp.) were found together in 26% (n = 38) of Chaffinches whereas only 5% of the birds had no parasite infection.

Coccidia

Isospora

Haemoproteus

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Citations (2)

MP256EBOLA GLYCOPROTEINS AND ACUTE KIDNEY INJURY

Nephrology Dialysis Transplantation (2017)

Benjamin Koch Olga Dolnik Stefan Büttner Stephan Becker Helmut Geiger

10.1093/ndt/gfx166.mp256

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Citations (1)