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Ronald P. van Rij
Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, P.O. Box 9101, 6500 HB, The Netherlands

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Journal article
Published: 31 July 2021 in Nucleic Acids Research
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In the germline of animals, PIWI interacting (pi)RNAs protect the genome against the detrimental effects of transposon mobilization. In Drosophila, piRNA-mediated cleavage of transposon RNA triggers the production of responder piRNAs via ping-pong amplification. Responder piRNA 3′ end formation by the nuclease Zucchini is coupled to the production of downstream trailer piRNAs, expanding the repertoire of transposon piRNA sequences. In Aedes aegypti mosquitoes, piRNAs are generated from viral RNA, yet, it is unknown how viral piRNA 3′ ends are formed and whether viral RNA cleavage gives rise to trailer piRNA production. Here we report that in Ae. aegypti, virus- and transposon-derived piRNAs have sharp 3′ ends, and are biased for downstream uridine residues, features reminiscent of Zucchini cleavage of precursor piRNAs in Drosophila. We designed a reporter system to study viral piRNA 3′ end formation and found that targeting viral RNA by abundant endogenous piRNAs triggers the production of responder and trailer piRNAs. Using this reporter, we identified the Ae. aegypti orthologs of Zucchini and Nibbler, two nucleases involved in piRNA 3′ end formation. Our results furthermore suggest that autonomous piRNA production from viral RNA can be triggered and expanded by an initial cleavage event guided by genome-encoded piRNAs.

ACS Style

Joep Joosten; Gijs J Overheul; Ronald P Van Rij; Pascal Miesen. Endogenous piRNA-guided slicing triggers responder and trailer piRNA production from viral RNA in Aedes aegypti mosquitoes. Nucleic Acids Research 2021, 1 .

AMA Style

Joep Joosten, Gijs J Overheul, Ronald P Van Rij, Pascal Miesen. Endogenous piRNA-guided slicing triggers responder and trailer piRNA production from viral RNA in Aedes aegypti mosquitoes. Nucleic Acids Research. 2021; ():1.

Chicago/Turabian Style

Joep Joosten; Gijs J Overheul; Ronald P Van Rij; Pascal Miesen. 2021. "Endogenous piRNA-guided slicing triggers responder and trailer piRNA production from viral RNA in Aedes aegypti mosquitoes." Nucleic Acids Research , no. : 1.

Journal article
Published: 01 July 2021 in RNA
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PIWI-interacting (pi)RNAs are small silencing RNAs that are crucial for the defense against transposable elements in germline tissues of animals. In Aedes aegypti mosquitoes, the piRNA pathway also contributes to gene regulation in somatic tissues, illustrating additional roles for piRNAs and PIWI proteins besides transposon repression. Here, we identify a highly abundant endogenous piRNA (propiR1) that associates with both Piwi4 and Piwi5. PropiR1-mediated target silencing requires base pairing in the seed region with supplemental base pairing at the piRNA 3’ end. Yet, propiR1 represses a limited set of targets, among which the lncRNA AAEL027353 (lnc027353). Slicing of lnc027353 initiates production of responder and trailer piRNAs from the cleavage fragment. Expression of propiR1 commences early during embryonic development and mediates degradation of maternally provided lnc027353. Both propiR1 and its lncRNA target are conserved in the closely related Aedes albopictus mosquito, underscoring the importance of this regulatory network for mosquito development.

ACS Style

Valerie Betting; Joep Joosten; Rebecca Halbach; Melissa Thaler; Pascal Miesen; Ronald P Van Rij. A piRNA-lncRNA regulatory network initiates responder and trailer piRNA formation during mosquito embryonic development. RNA 2021, 1 .

AMA Style

Valerie Betting, Joep Joosten, Rebecca Halbach, Melissa Thaler, Pascal Miesen, Ronald P Van Rij. A piRNA-lncRNA regulatory network initiates responder and trailer piRNA formation during mosquito embryonic development. RNA. 2021; ():1.

Chicago/Turabian Style

Valerie Betting; Joep Joosten; Rebecca Halbach; Melissa Thaler; Pascal Miesen; Ronald P Van Rij. 2021. "A piRNA-lncRNA regulatory network initiates responder and trailer piRNA formation during mosquito embryonic development." RNA , no. : 1.

Spotlight
Published: 16 June 2021 in Trends in Parasitology
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Small RNAs are crucial for the regulation of basic cellular processes and protection against viruses and transposons in mosquitoes. Rozen-Gagnon et al. established CLIP (cross-linking and immunoprecipitation) for Argonaute proteins in Aedes aegypti. Their study sheds light on small RNA–target interactions in mosquitoes and provides an important resource for further study.

ACS Style

Rebecca Halbach; Pascal Miesen; Ronald P. van Rij. Zooming in on targets of mosquito small RNAs. Trends in Parasitology 2021, 1 .

AMA Style

Rebecca Halbach, Pascal Miesen, Ronald P. van Rij. Zooming in on targets of mosquito small RNAs. Trends in Parasitology. 2021; ():1.

Chicago/Turabian Style

Rebecca Halbach; Pascal Miesen; Ronald P. van Rij. 2021. "Zooming in on targets of mosquito small RNAs." Trends in Parasitology , no. : 1.

Preprint content
Published: 06 May 2021
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Summary The mRNA-based BNT162b2 vaccine from Pfizer/BioNTech was the first registered COVID-19 vaccine and has been shown to be up to 95% effective in preventing SARS-CoV-2 infections. Little is known about the broad effects of the new class of mRNA vaccines, especially whether they have combined effects on innate and adaptive immune responses. Here we confirmed that BNT162b2 vaccination of healthy individuals induced effective humoral and cellular immunity against several SARS-CoV-2 variants. Interestingly, however, the BNT162b2 vaccine also modulated the production of inflammatory cytokines by innate immune cells upon stimulation with both specific (SARS-CoV-2) and non-specific (viral, fungal and bacterial) stimuli. The response of innate immune cells to TLR4 and TLR7/8 ligands was lower after BNT162b2 vaccination, while fungi-induced cytokine responses were stronger. In conclusion, the mRNA BNT162b2 vaccine induces complex functional reprogramming of innate immune responses, which should be considered in the development and use of this new class of vaccines.

ACS Style

F. Konstantin Föhse; Büsranur Geckin; Gijs J. Overheul; Josephine van de Maat; Gizem Kilic; Ozlem Bulut; Helga Dijkstra; Heidi Lemmers; S. Andrei Sarlea; Maartje Reijnders; Jacobien Hoogerwerf; Jaap Ten Oever; Elles Simonetti; Frank L. van de Veerdonk; Leo A.B. Joosten; Bart L. Haagmans; Reinout van Crevel; Yang Li; Ronald P. van Rij; Corine GeurtsvanKessel; Marien I. de Jonge; Jorge Domínguez-Andrés; Mihai G. Netea. The BNT162b2 mRNA vaccine against SARS-CoV-2 reprograms both adaptive and innate immune responses. 2021, 1 .

AMA Style

F. Konstantin Föhse, Büsranur Geckin, Gijs J. Overheul, Josephine van de Maat, Gizem Kilic, Ozlem Bulut, Helga Dijkstra, Heidi Lemmers, S. Andrei Sarlea, Maartje Reijnders, Jacobien Hoogerwerf, Jaap Ten Oever, Elles Simonetti, Frank L. van de Veerdonk, Leo A.B. Joosten, Bart L. Haagmans, Reinout van Crevel, Yang Li, Ronald P. van Rij, Corine GeurtsvanKessel, Marien I. de Jonge, Jorge Domínguez-Andrés, Mihai G. Netea. The BNT162b2 mRNA vaccine against SARS-CoV-2 reprograms both adaptive and innate immune responses. . 2021; ():1.

Chicago/Turabian Style

F. Konstantin Föhse; Büsranur Geckin; Gijs J. Overheul; Josephine van de Maat; Gizem Kilic; Ozlem Bulut; Helga Dijkstra; Heidi Lemmers; S. Andrei Sarlea; Maartje Reijnders; Jacobien Hoogerwerf; Jaap Ten Oever; Elles Simonetti; Frank L. van de Veerdonk; Leo A.B. Joosten; Bart L. Haagmans; Reinout van Crevel; Yang Li; Ronald P. van Rij; Corine GeurtsvanKessel; Marien I. de Jonge; Jorge Domínguez-Andrés; Mihai G. Netea. 2021. "The BNT162b2 mRNA vaccine against SARS-CoV-2 reprograms both adaptive and innate immune responses." , no. : 1.

Resource
Published: 01 May 2021 in Cell Reports
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Summary As in most arthropods, the PIWI-interacting RNA (piRNA) pathway in the vector mosquito Aedes aegypti is active in diverse biological processes in both soma and germline. To gain insights into piRNA biogenesis and effector complexes, we mapped the interactomes of the somatic PIWI proteins Ago3, Piwi4, Piwi5, and Piwi6 and identify numerous specific interactors as well as cofactors associated with multiple PIWI proteins. We describe the Piwi5 interactor AAEL014965, the direct ortholog of the Drosophila splicing factor pasilla. We find that Ae. aegypti Pasilla encodes a nuclear isoform and a cytoplasmic isoform, the latter of which is required for efficient piRNA production. In addition, we characterize a splice variant of the Tudor protein AAEL008101/Atari that associates with Ago3 and forms a scaffold for PIWI proteins and target RNAs to promote ping-pong amplification of piRNAs. Our study provides a useful resource for follow-up studies of somatic piRNA biogenesis, mechanism, and function in Aedes mosquitoes.

ACS Style

Joep Joosten; Ezgi Taşköprü; Pascal W.T.C. Jansen; Bas Pennings; Michiel Vermeulen; Ronald P. Van Rij. PIWI proteomics identifies Atari and Pasilla as piRNA biogenesis factors in Aedes mosquitoes. Cell Reports 2021, 35, 109073 .

AMA Style

Joep Joosten, Ezgi Taşköprü, Pascal W.T.C. Jansen, Bas Pennings, Michiel Vermeulen, Ronald P. Van Rij. PIWI proteomics identifies Atari and Pasilla as piRNA biogenesis factors in Aedes mosquitoes. Cell Reports. 2021; 35 (5):109073.

Chicago/Turabian Style

Joep Joosten; Ezgi Taşköprü; Pascal W.T.C. Jansen; Bas Pennings; Michiel Vermeulen; Ronald P. Van Rij. 2021. "PIWI proteomics identifies Atari and Pasilla as piRNA biogenesis factors in Aedes mosquitoes." Cell Reports 35, no. 5: 109073.

Commentary
Published: 27 April 2021 in Viruses
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Many recent studies highlight the fundamental importance of viruses. Besides their important role as human and animal pathogens, their beneficial, commensal or harmful functions are poorly understood. By developing and applying tailored bioinformatical tools in important virological models, the Marie Skłodowska-Curie Initiative International Training Network VIROINF will provide a better understanding of viruses and the interaction with their hosts. This will open the door to validate methods of improving viral growth, morphogenesis and development, as well as to control strategies against unwanted microorganisms. The key feature of VIROINF is its interdisciplinary nature, which brings together virologists and bioinformaticians to achieve common goals.

ACS Style

Winfried Goettsch; Niko Beerenwinkel; Li Deng; Lars Dölken; Bas Dutilh; Florian Erhard; Lars Kaderali; Max von Kleist; Roland Marquet; Jelle Matthijnssens; Shawna McCallin; Dino McMahon; Thomas Rattei; Ronald Van Rij; David Robertson; Martin Schwemmle; Noam Stern-Ginossar; Manja Marz. ITN—VIROINF: Understanding (Harmful) Virus-Host Interactions by Linking Virology and Bioinformatics. Viruses 2021, 13, 766 .

AMA Style

Winfried Goettsch, Niko Beerenwinkel, Li Deng, Lars Dölken, Bas Dutilh, Florian Erhard, Lars Kaderali, Max von Kleist, Roland Marquet, Jelle Matthijnssens, Shawna McCallin, Dino McMahon, Thomas Rattei, Ronald Van Rij, David Robertson, Martin Schwemmle, Noam Stern-Ginossar, Manja Marz. ITN—VIROINF: Understanding (Harmful) Virus-Host Interactions by Linking Virology and Bioinformatics. Viruses. 2021; 13 (5):766.

Chicago/Turabian Style

Winfried Goettsch; Niko Beerenwinkel; Li Deng; Lars Dölken; Bas Dutilh; Florian Erhard; Lars Kaderali; Max von Kleist; Roland Marquet; Jelle Matthijnssens; Shawna McCallin; Dino McMahon; Thomas Rattei; Ronald Van Rij; David Robertson; Martin Schwemmle; Noam Stern-Ginossar; Manja Marz. 2021. "ITN—VIROINF: Understanding (Harmful) Virus-Host Interactions by Linking Virology and Bioinformatics." Viruses 13, no. 5: 766.

Journal article
Published: 11 February 2021 in Viruses
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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.

ACS Style

Finny Varghese; Esther van Woudenbergh; Gijs Overheul; Marc Eleveld; Lisa Kurver; Niels van Heerbeek; Arjan van Laarhoven; Pascal Miesen; Gerco Den Hartog; Marien de Jonge; Ronald van Rij. Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro. Viruses 2021, 13, 282 .

AMA Style

Finny Varghese, Esther van Woudenbergh, Gijs Overheul, Marc Eleveld, Lisa Kurver, Niels van Heerbeek, Arjan van Laarhoven, Pascal Miesen, Gerco Den Hartog, Marien de Jonge, Ronald van Rij. Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro. Viruses. 2021; 13 (2):282.

Chicago/Turabian Style

Finny Varghese; Esther van Woudenbergh; Gijs Overheul; Marc Eleveld; Lisa Kurver; Niels van Heerbeek; Arjan van Laarhoven; Pascal Miesen; Gerco Den Hartog; Marien de Jonge; Ronald van Rij. 2021. "Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro." Viruses 13, no. 2: 282.

Preprint content
Published: 24 December 2020
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a new human pathogen in late 2019 and has infected an estimated 10% of the global population 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, 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 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, in line with its activity to neutralize the acidic environment in endosomes. We assessed infection of primary human nasal epithelial cells cultured on an air-liquid interface and found that SARS-CoV-2 infection induced and repressed expression of a specific set 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.

ACS Style

Finny S. Varghese; Esther van Woudenbergh; Gijs J. Overheul; Marc J. Eleveld; Lisa Kurver; Niels van Heerbeek; Arjan van Laarhoven; Pascal Miesen; Gerco Den Hartog; Marien I. de Jonge; Ronald P. van Rij. Berberine and obatoclax inhibit SARS-CoV-2 replication in primary human nasal epithelial cells in vitro. 2020, 1 .

AMA Style

Finny S. Varghese, Esther van Woudenbergh, Gijs J. Overheul, Marc J. Eleveld, Lisa Kurver, Niels van Heerbeek, Arjan van Laarhoven, Pascal Miesen, Gerco Den Hartog, Marien I. de Jonge, Ronald P. van Rij. Berberine and obatoclax inhibit SARS-CoV-2 replication in primary human nasal epithelial cells in vitro. . 2020; ():1.

Chicago/Turabian Style

Finny S. Varghese; Esther van Woudenbergh; Gijs J. Overheul; Marc J. Eleveld; Lisa Kurver; Niels van Heerbeek; Arjan van Laarhoven; Pascal Miesen; Gerco Den Hartog; Marien I. de Jonge; Ronald P. van Rij. 2020. "Berberine and obatoclax inhibit SARS-CoV-2 replication in primary human nasal epithelial cells in vitro." , no. : 1.

Preprint content
Published: 30 October 2020
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Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use.

ACS Style

The COVID Moonshot Consortium; Hagit Achdout; Anthony Aimon; Elad Bar-David; Haim Barr; Amir Ben-Shmuel; James Bennett; Melissa L Bobby; Juliane Brun; Sarma Bvnbs; Mark Calmiano; Anna Carbery; Emma Cattermole; John D. Chodera; Austin Clyde; Joseph E. Coffland; Galit Cohen; Jason Cole; Alessandro Contini; Lisa Cox; Milan Cvitkovic; Alex Dias; Alice Douangamath; Shirly Duberstein; Tim Dudgeon; Louise Dunnett; Peter K. Eastman; Noam Erez; Michael Fairhead; Daren Fearon; Oleg Fedorov; Matteo Ferla; Holly Foster; Richard Foster; Ronen Gabizon; Paul Gehrtz; Carina Gileadi; Charline Giroud; William G. Glass; Robert Glen; Itai Glinert; Marian Gorichko; Tyler Gorrie-Stone; Edward J Griffen; Jag Heer; Michelle Hill; Sam Horrell; Matthew F.D. Hurley; Tomer Israely; Andrew Jajack; Eric Jnoff; Tobias John; Anastassia L. Kantsadi; Peter W. Kenny; John L. Kiappes; Lizbe Koekemoer; Boris Kovar; Tobias Krojer; Alpha Albert Lee; Bruce A. Lefker; Haim Levy; Nir London; Petra Lukacik; Hannah Bruce Macdonald; Beth MacLean; Tika R. Malla; Tatiana Matviiuk; Willam McCorkindale; Sharon Melamed; Oleg Michurin; Halina Mikolajek; Aaron Morris; Garrett M. Morris; Melody Jane Morwitzer; Demetri Moustakas; Jose Brandao Neto; Vladas Oleinikovas; Gijs J. Overheul; David Owen; Ruby Pai; Jin Pan; Nir Paran; Benjamin Perry; Maneesh Pingle; Jakir Pinjari; Boaz Politi; Ailsa Powell; Vladimir Psenak; Reut Puni; Victor L. Rangel; Rambabu N. Reddi; St Patrick Reid; Efrat Resnick; Matthew C. Robinson; Ralph P. Robinson; Dominic Rufa; Christopher Schofield; Aarif Shaikh; Jiye Shi; Khriesto Shurrush; Assa Sittner; Rachael Skyner; Adam Smalley; Mihaela D. Smilova; John Spencer; Claire Strain-Damerell; Vishwanath Swamy; Hadas Tamir; Rachael Tennant; Andrew Thompson; Warren Thompson; Susana Tomasio; Anthony Tumber; Ioannis Vakonakis; Ronald P. Van Rij; Finny S. Varghese; Mariana Vaschetto; Einat B. Vitner; Vincent Voelz; Annette Von Delft; Frank Von Delft; Martin Walsh; Walter Ward; Charlie Weatherall; Shay Weiss; Conor Francis Wild; Matthew Wittmann; Nathan Wright; Yfat Yahalom-Ronen; Daniel Zaidmann; Hadeer Zidane; Nicole Zitzmann. COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning. 2020, 1 .

AMA Style

The COVID Moonshot Consortium, Hagit Achdout, Anthony Aimon, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, Melissa L Bobby, Juliane Brun, Sarma Bvnbs, Mark Calmiano, Anna Carbery, Emma Cattermole, John D. Chodera, Austin Clyde, Joseph E. Coffland, Galit Cohen, Jason Cole, Alessandro Contini, Lisa Cox, Milan Cvitkovic, Alex Dias, Alice Douangamath, Shirly Duberstein, Tim Dudgeon, Louise Dunnett, Peter K. Eastman, Noam Erez, Michael Fairhead, Daren Fearon, Oleg Fedorov, Matteo Ferla, Holly Foster, Richard Foster, Ronen Gabizon, Paul Gehrtz, Carina Gileadi, Charline Giroud, William G. Glass, Robert Glen, Itai Glinert, Marian Gorichko, Tyler Gorrie-Stone, Edward J Griffen, Jag Heer, Michelle Hill, Sam Horrell, Matthew F.D. Hurley, Tomer Israely, Andrew Jajack, Eric Jnoff, Tobias John, Anastassia L. Kantsadi, Peter W. Kenny, John L. Kiappes, Lizbe Koekemoer, Boris Kovar, Tobias Krojer, Alpha Albert Lee, Bruce A. Lefker, Haim Levy, Nir London, Petra Lukacik, Hannah Bruce Macdonald, Beth MacLean, Tika R. Malla, Tatiana Matviiuk, Willam McCorkindale, Sharon Melamed, Oleg Michurin, Halina Mikolajek, Aaron Morris, Garrett M. Morris, Melody Jane Morwitzer, Demetri Moustakas, Jose Brandao Neto, Vladas Oleinikovas, Gijs J. Overheul, David Owen, Ruby Pai, Jin Pan, Nir Paran, Benjamin Perry, Maneesh Pingle, Jakir Pinjari, Boaz Politi, Ailsa Powell, Vladimir Psenak, Reut Puni, Victor L. Rangel, Rambabu N. Reddi, St Patrick Reid, Efrat Resnick, Matthew C. Robinson, Ralph P. Robinson, Dominic Rufa, Christopher Schofield, Aarif Shaikh, Jiye Shi, Khriesto Shurrush, Assa Sittner, Rachael Skyner, Adam Smalley, Mihaela D. Smilova, John Spencer, Claire Strain-Damerell, Vishwanath Swamy, Hadas Tamir, Rachael Tennant, Andrew Thompson, Warren Thompson, Susana Tomasio, Anthony Tumber, Ioannis Vakonakis, Ronald P. Van Rij, Finny S. Varghese, Mariana Vaschetto, Einat B. Vitner, Vincent Voelz, Annette Von Delft, Frank Von Delft, Martin Walsh, Walter Ward, Charlie Weatherall, Shay Weiss, Conor Francis Wild, Matthew Wittmann, Nathan Wright, Yfat Yahalom-Ronen, Daniel Zaidmann, Hadeer Zidane, Nicole Zitzmann. COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning. . 2020; ():1.

Chicago/Turabian Style

The COVID Moonshot Consortium; Hagit Achdout; Anthony Aimon; Elad Bar-David; Haim Barr; Amir Ben-Shmuel; James Bennett; Melissa L Bobby; Juliane Brun; Sarma Bvnbs; Mark Calmiano; Anna Carbery; Emma Cattermole; John D. Chodera; Austin Clyde; Joseph E. Coffland; Galit Cohen; Jason Cole; Alessandro Contini; Lisa Cox; Milan Cvitkovic; Alex Dias; Alice Douangamath; Shirly Duberstein; Tim Dudgeon; Louise Dunnett; Peter K. Eastman; Noam Erez; Michael Fairhead; Daren Fearon; Oleg Fedorov; Matteo Ferla; Holly Foster; Richard Foster; Ronen Gabizon; Paul Gehrtz; Carina Gileadi; Charline Giroud; William G. Glass; Robert Glen; Itai Glinert; Marian Gorichko; Tyler Gorrie-Stone; Edward J Griffen; Jag Heer; Michelle Hill; Sam Horrell; Matthew F.D. Hurley; Tomer Israely; Andrew Jajack; Eric Jnoff; Tobias John; Anastassia L. Kantsadi; Peter W. Kenny; John L. Kiappes; Lizbe Koekemoer; Boris Kovar; Tobias Krojer; Alpha Albert Lee; Bruce A. Lefker; Haim Levy; Nir London; Petra Lukacik; Hannah Bruce Macdonald; Beth MacLean; Tika R. Malla; Tatiana Matviiuk; Willam McCorkindale; Sharon Melamed; Oleg Michurin; Halina Mikolajek; Aaron Morris; Garrett M. Morris; Melody Jane Morwitzer; Demetri Moustakas; Jose Brandao Neto; Vladas Oleinikovas; Gijs J. Overheul; David Owen; Ruby Pai; Jin Pan; Nir Paran; Benjamin Perry; Maneesh Pingle; Jakir Pinjari; Boaz Politi; Ailsa Powell; Vladimir Psenak; Reut Puni; Victor L. Rangel; Rambabu N. Reddi; St Patrick Reid; Efrat Resnick; Matthew C. Robinson; Ralph P. Robinson; Dominic Rufa; Christopher Schofield; Aarif Shaikh; Jiye Shi; Khriesto Shurrush; Assa Sittner; Rachael Skyner; Adam Smalley; Mihaela D. Smilova; John Spencer; Claire Strain-Damerell; Vishwanath Swamy; Hadas Tamir; Rachael Tennant; Andrew Thompson; Warren Thompson; Susana Tomasio; Anthony Tumber; Ioannis Vakonakis; Ronald P. Van Rij; Finny S. Varghese; Mariana Vaschetto; Einat B. Vitner; Vincent Voelz; Annette Von Delft; Frank Von Delft; Martin Walsh; Walter Ward; Charlie Weatherall; Shay Weiss; Conor Francis Wild; Matthew Wittmann; Nathan Wright; Yfat Yahalom-Ronen; Daniel Zaidmann; Hadeer Zidane; Nicole Zitzmann. 2020. "COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning." , no. : 1.

Preprint content
Published: 08 July 2020
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In the germline of animals, PIWI interacting (pi)RNAs protect the genome against the detrimental effects of transposon mobilization. In Drosophila, piRNA-mediated cleavage of transposon RNA triggers the production of responder piRNAs via ping-pong amplification. Responder piRNA 3’ end formation is coupled to the production of downstream trailer piRNAs mediated by the nuclease Zucchini, expanding the repertoire of transposon piRNA sequences. In Aedes aegypti mosquitoes, piRNAs are generated from viral RNA, yet, it is unknown how viral piRNA 3’ ends are formed and whether viral RNA cleavage gives rise to trailer piRNA production. Here we report that in Ae. aegypti, virus- and transposon-derived piRNAs have sharp 3’ ends, and are biased for downstream uridine residues, features reminiscent of Zucchini cleavage of precursor piRNAs in Drosophila. We designed a reporter system to study viral piRNA 3’ end formation and found that targeting viral RNA by abundant endogenous piRNAs triggers the production of responder and trailer piRNAs. Using this reporter, we identified the Ae. aegypti orthologs of Zucchini and Nibbler, two nucleases involved in piRNA 3’ end formation. Our results furthermore suggest that autonomous piRNA production from viral RNA can be triggered and expanded by an initial cleavage event guided by genome-encoded piRNAs.

ACS Style

Joep Joosten; Gijs J. Overheul; Ronald P. Van Rij; Pascal Miesen. Endogenous piRNA-guided slicing triggers responder and trailer piRNA production from viral RNA in Aedes aegypti mosquitoes. 2020, 1 .

AMA Style

Joep Joosten, Gijs J. Overheul, Ronald P. Van Rij, Pascal Miesen. Endogenous piRNA-guided slicing triggers responder and trailer piRNA production from viral RNA in Aedes aegypti mosquitoes. . 2020; ():1.

Chicago/Turabian Style

Joep Joosten; Gijs J. Overheul; Ronald P. Van Rij; Pascal Miesen. 2020. "Endogenous piRNA-guided slicing triggers responder and trailer piRNA production from viral RNA in Aedes aegypti mosquitoes." , no. : 1.

Journal article
Published: 10 June 2020 in Trends in Microbiology
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RNA interference (RNAi) is a powerful host defense mechanism against viruses. As a counter-defense, many viruses encode suppressors of RNAi, which – in plants – has provoked counter-counter-defense strategies. Recently, a mechanism was proposed in Drosophila (Zhang et al.) wherein a long noncoding RNA senses a virus-encoded RNAi suppressor to activate an innate immune response.

ACS Style

Valerie Betting; Ronald P. Van Rij. Countering Counter-Defense to Antiviral RNAi. Trends in Microbiology 2020, 28, 600 -602.

AMA Style

Valerie Betting, Ronald P. Van Rij. Countering Counter-Defense to Antiviral RNAi. Trends in Microbiology. 2020; 28 (8):600-602.

Chicago/Turabian Style

Valerie Betting; Ronald P. Van Rij. 2020. "Countering Counter-Defense to Antiviral RNAi." Trends in Microbiology 28, no. 8: 600-602.

Book chapter
Published: 27 May 2020 in International Review of Cytology
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The phenotypic manifestations of disease induced by viruses and subviral infectious entities are the result of complex molecular interactions between host and viral factors. The viral determinants of the diseased phenotype have traditionally been sought at the level of structural or non-structural proteins. However, the discovery of RNA silencing mechanisms has led to speculations that determinants of the diseased phenotype are caused by viral nucleic acid sequences in addition to proteins. RNA silencing is a gene regulation mechanism conserved within eukaryotic kingdoms (with the exception of some yeast species), and in plants and insects it also functions as an antiviral mechanism. Non-coding RNAs of viral origin, ranging in size from 21 to 24 nucleotides (viral small interfering RNAs, vsiRNAs) accumulate in virus-infected tissues and organs, in some cases to comparable levels as the entire complement of host-encoded small interfering RNAs. Upon incorporation into RNA-induced silencing complexes, vsiRNAs can mediate cleavage or induce translational inhibition of nucleic acid targets in a sequence-specific manner. This review focuses on recent findings that suggest an increased complexity of small RNA-based interactions between virus and host. We mainly address plant viruses, but where applicable discuss insect viruses as well. Prominence is given to studies that have indisputably demonstrated that vsiRNAs determine diseased phenotype by either carrying sequence determinants or, indirectly, by altering host-gene regulatory pathways. Results from these studies suggest biotechnological applications, which are also discussed.

ACS Style

Paola Leonetti; Pascal Miesen; Ronald P. van Rij; Vitantonio Pantaleo. Viral and subviral derived small RNAs as pathogenic determinants in plants and insects. International Review of Cytology 2020, 1 -36.

AMA Style

Paola Leonetti, Pascal Miesen, Ronald P. van Rij, Vitantonio Pantaleo. Viral and subviral derived small RNAs as pathogenic determinants in plants and insects. International Review of Cytology. 2020; ():1-36.

Chicago/Turabian Style

Paola Leonetti; Pascal Miesen; Ronald P. van Rij; Vitantonio Pantaleo. 2020. "Viral and subviral derived small RNAs as pathogenic determinants in plants and insects." International Review of Cytology , no. : 1-36.

Preprint content
Published: 30 March 2020
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SummaryEndogenous viral elements (EVEs) are viral sequences integrated in host genomes. A large number of non-retroviral EVEs was recently detected in Aedes mosquito genomes, leading to the hypothesis that mosquito EVEs may control exogenous infections by closely related viruses. Here, we experimentally investigated the role of an EVE naturally found in Aedes aegypti populations and derived from the widespread insect-specific virus, cell-fusing agent virus (CFAV). Using CRISPR/Cas9 genome editing, we created an Ae. aegypti line lacking the CFAV EVE. Absence of the EVE resulted in increased CFAV replication in ovaries, possibly modulating vertical transmission of the virus. Viral replication was controlled by targeting of viral RNA by EVE-derived piRNAs. Our results provide evidence that antiviral piRNAs are produced in the presence of a naturally occurring EVE and its cognate virus, demonstrating a functional link between non-retroviral EVEs and antiviral immunity in a natural insect-virus interaction.

ACS Style

Yasutsugu Suzuki; Artem Baidaliuk; Pascal Miesen; Lionel Frangeul; Anna B. Crist; Sarah H. Merkling; Albin Fontaine; Sebastian Lequime; Isabelle Moltini-Conclois; Hervé Blanc; Ronald P. Van Rij; Louis Lambrechts; Maria-Carla Saleh. Non-retroviral endogenous viral element limits cognate virus replication in Aedes aegypti ovaries. 2020, 1 .

AMA Style

Yasutsugu Suzuki, Artem Baidaliuk, Pascal Miesen, Lionel Frangeul, Anna B. Crist, Sarah H. Merkling, Albin Fontaine, Sebastian Lequime, Isabelle Moltini-Conclois, Hervé Blanc, Ronald P. Van Rij, Louis Lambrechts, Maria-Carla Saleh. Non-retroviral endogenous viral element limits cognate virus replication in Aedes aegypti ovaries. . 2020; ():1.

Chicago/Turabian Style

Yasutsugu Suzuki; Artem Baidaliuk; Pascal Miesen; Lionel Frangeul; Anna B. Crist; Sarah H. Merkling; Albin Fontaine; Sebastian Lequime; Isabelle Moltini-Conclois; Hervé Blanc; Ronald P. Van Rij; Louis Lambrechts; Maria-Carla Saleh. 2020. "Non-retroviral endogenous viral element limits cognate virus replication in Aedes aegypti ovaries." , no. : 1.

Preprint content
Published: 24 March 2020
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PIWI-interacting (pi)RNAs are small silencing RNAs that are crucial for the defense against transposable elements in germline tissues of animals. In Aedes aegypti mosquitoes, the piRNA pathway also contributes to gene regulation in somatic tissues, illustrating additional roles for piRNAs and PIWI proteins besides transposon repression. Here, we identify a highly abundant endogenous piRNA (propiR1) that associates with both Piwi4 and Piwi5. PropiR1-mediated target silencing requires base pairing in the seed region with supplemental base pairing at the piRNA 3’ end. Yet, propiR1 represses a limited set of targets, among which the lncRNA AAEL027353 (lnc027353). Slicing of lnc027353 initiates production of responder and trailer piRNAs from the cleavage fragment. Expression of propiR1 commences early during embryonic development and mediates degradation of maternally provided lnc027353. Both propiR1 and its lncRNA target are conserved in the closely related Aedes albopictus mosquito, underscoring the importance of this regulatory network for mosquito development.

ACS Style

Valerie Betting; Joep Joosten; Rebecca Halbach; Melissa Thaler; Pascal Miesen; Ronald P. Van Rij. A piRNA-lncRNA regulatory network initiates responder and trailer piRNA formation during mosquito embryonic development. 2020, 1 .

AMA Style

Valerie Betting, Joep Joosten, Rebecca Halbach, Melissa Thaler, Pascal Miesen, Ronald P. Van Rij. A piRNA-lncRNA regulatory network initiates responder and trailer piRNA formation during mosquito embryonic development. . 2020; ():1.

Chicago/Turabian Style

Valerie Betting; Joep Joosten; Rebecca Halbach; Melissa Thaler; Pascal Miesen; Ronald P. Van Rij. 2020. "A piRNA-lncRNA regulatory network initiates responder and trailer piRNA formation during mosquito embryonic development." , no. : 1.

Preprint content
Published: 28 February 2020
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The Asian tiger mosquito Aedes albopictus is globally expanding and has become the main vector for human arboviruses in Europe. Here we present AalbF2, a dramatically improved assembly of the Ae. albopictus genome that has revealed widespread viral insertions, novel microRNAs and piRNA clusters, the sex determining locus, new immunity genes, and has enabled genome-wide studies of geographically diverse Ae. albopictus populations and analyses of the developmental and stage-dependent network of expression data. Additionally, we built the first physical map for this species with 75% of the assembled genome anchored to the chromosomes. These up-to-date resources of the genome provide a foundation to improve understanding of the adaptation potential and the epidemiological relevance of this species and foster the development of innovative control measures.One Sentence SummaryLong-read and Hi-C-based de novo assembly of the arboviral vector Aedes albopictus genome fosters deeper understanding of its biological features.

ACS Style

Umberto Palatini; R.A. Masri; Luciano V Cosme; Sergey Koren; Francoise Thibaud-Nissen; James K Biedler; Flavia Krsticevic; Spencer Johnston; Rebecca Halbach; Jacob E Crawford; Igor Antoshechkin; Anna-Bella Failloux; Elisa Pischedda; Michele Marconcini; Jay Ghurye; Arang Rhie; Atashi Sharma; Dmitrii A Karagodin; J. Jenrette; Stephanie Gamez; Pascal Miesen; Adalgisa Caccone; Maria V Sharakhova; Zhijian Tu; Philippos Aris Papathanos; Ronald P. Van Rij; Omar S Akbari; Jeffrey Powell; Adam M. Phillippy; Bonizzoni M.. Improved reference genome of the arboviral vector Aedes albopictus. 2020, 1 .

AMA Style

Umberto Palatini, R.A. Masri, Luciano V Cosme, Sergey Koren, Francoise Thibaud-Nissen, James K Biedler, Flavia Krsticevic, Spencer Johnston, Rebecca Halbach, Jacob E Crawford, Igor Antoshechkin, Anna-Bella Failloux, Elisa Pischedda, Michele Marconcini, Jay Ghurye, Arang Rhie, Atashi Sharma, Dmitrii A Karagodin, J. Jenrette, Stephanie Gamez, Pascal Miesen, Adalgisa Caccone, Maria V Sharakhova, Zhijian Tu, Philippos Aris Papathanos, Ronald P. Van Rij, Omar S Akbari, Jeffrey Powell, Adam M. Phillippy, Bonizzoni M.. Improved reference genome of the arboviral vector Aedes albopictus. . 2020; ():1.

Chicago/Turabian Style

Umberto Palatini; R.A. Masri; Luciano V Cosme; Sergey Koren; Francoise Thibaud-Nissen; James K Biedler; Flavia Krsticevic; Spencer Johnston; Rebecca Halbach; Jacob E Crawford; Igor Antoshechkin; Anna-Bella Failloux; Elisa Pischedda; Michele Marconcini; Jay Ghurye; Arang Rhie; Atashi Sharma; Dmitrii A Karagodin; J. Jenrette; Stephanie Gamez; Pascal Miesen; Adalgisa Caccone; Maria V Sharakhova; Zhijian Tu; Philippos Aris Papathanos; Ronald P. Van Rij; Omar S Akbari; Jeffrey Powell; Adam M. Phillippy; Bonizzoni M.. 2020. "Improved reference genome of the arboviral vector Aedes albopictus." , no. : 1.

Preprint content
Published: 15 January 2020
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Tandem repeat elements such as the highly diverse class of satellite repeats occupy large parts of eukaryotic chromosomes. Most occur at (peri)centromeric and (sub)telomeric regions and have been implicated in chromosome organization, stabilization, and segregation1. Others are located more dispersed throughout the genome, but their functions remained largely enigmatic. Satellite repeats in euchromatic regions were hypothesized to regulate gene expression in cis by modulation of the local heterochromatin, or in trans via repeat-derived transcripts2,3. Yet, due to a lack of experimental models, gene regulatory potential of satellite repeats remains largely unexplored. Here we show that, in the vector mosquito Aedes aegypti, a satellite repeat promotes sequence-specific gene silencing via the expression of two abundant PIWI-interacting RNAs (piRNAs). Strikingly, whereas satellite repeats and piRNA sequences generally evolve extremely fast4-6, this locus was conserved for approximately 200 million years, suggesting a central function in mosquito biology. Tandem repeat-derived piRNA production commenced shortly after egg-laying and inactivation of the most abundant of the two piRNAs in early embryos resulted in an arrest of embryonic development. Transcriptional profiling in these embryos revealed the failure to degrade maternally provided transcripts that are normally cleared during maternal-to-zygotic transition. Our results reveal a novel mechanism in which satellite repeats regulate global gene expression in trans via piRNA-mediated gene silencing, which is fundamental to embryonic development. These findings highlight the regulatory potential of this enigmatic class of repeats.

ACS Style

Rebecca Halbach; Pascal Miesen; Joep Joosten; Ezgi Taşköprü; Bas Pennings; Chantal B.F. Vogels; Sarah H. Merkling; Constantianus J. Koenraadt; Louis Lambrechts; Ronald P. Van Rij. An ancient satellite repeat controls gene expression and embryonic development in Aedes aegypti through a highly conserved piRNA. 2020, 1 .

AMA Style

Rebecca Halbach, Pascal Miesen, Joep Joosten, Ezgi Taşköprü, Bas Pennings, Chantal B.F. Vogels, Sarah H. Merkling, Constantianus J. Koenraadt, Louis Lambrechts, Ronald P. Van Rij. An ancient satellite repeat controls gene expression and embryonic development in Aedes aegypti through a highly conserved piRNA. . 2020; ():1.

Chicago/Turabian Style

Rebecca Halbach; Pascal Miesen; Joep Joosten; Ezgi Taşköprü; Bas Pennings; Chantal B.F. Vogels; Sarah H. Merkling; Constantianus J. Koenraadt; Louis Lambrechts; Ronald P. Van Rij. 2020. "An ancient satellite repeat controls gene expression and embryonic development in Aedes aegypti through a highly conserved piRNA." , no. : 1.

Journal article
Published: 01 January 2020 in Journal of General Virology
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The genus Alphavirus harbours mostly insect-transmitted viruses that cause severe disease in humans, livestock and wildlife. Thus far, only three alphaviruses with a host range restricted to insects have been found in mosquitoes from the Old World, namely Eilat virus (EILV), Taï Forest alphavirus (TALV) and Mwinilunga alphavirus (MWAV). In this study, we found a novel alphavirus in one Culex declarator mosquito sampled in Panama. The virus was isolated in C6/36 mosquito cells, and full genome sequencing revealed an 11 468 nt long genome with maximum pairwise nucleotide identity of 62.7% to Sindbis virus. Phylogenetic analyses placed the virus as a solitary deep rooting lineage in a basal relationship to the Western equine encephalitis antigenic complex and to the clade comprising EILV, TALV and MWAV, indicating the detection of a novel alphavirus, tentatively named Agua Salud alphavirus (ASALV). No growth of ASALV was detected in vertebrate cell lines, including cell lines derived from ectothermic animals, and replication of ASALV was strongly impaired above 31 °C, suggesting that ASALV represents the first insect-restricted alphavirus of the New World.

ACS Style

Kyra Hermanns; Marco Marklewitz; Florian Zirkel; Gijs J. Overheul; Rachel A. Page; Jose R. Loaiza; Christian Drosten; Ronald P. Van Rij; Sandra Junglen. Agua Salud alphavirus defines a novel lineage of insect-specific alphaviruses discovered in the New World. Journal of General Virology 2020, 101, 96 -104.

AMA Style

Kyra Hermanns, Marco Marklewitz, Florian Zirkel, Gijs J. Overheul, Rachel A. Page, Jose R. Loaiza, Christian Drosten, Ronald P. Van Rij, Sandra Junglen. Agua Salud alphavirus defines a novel lineage of insect-specific alphaviruses discovered in the New World. Journal of General Virology. 2020; 101 (1):96-104.

Chicago/Turabian Style

Kyra Hermanns; Marco Marklewitz; Florian Zirkel; Gijs J. Overheul; Rachel A. Page; Jose R. Loaiza; Christian Drosten; Ronald P. Van Rij; Sandra Junglen. 2020. "Agua Salud alphavirus defines a novel lineage of insect-specific alphaviruses discovered in the New World." Journal of General Virology 101, no. 1: 96-104.

Journal article
Published: 11 November 2019 in Proceedings of the National Academy of Sciences
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Coevolution of viruses and their hosts may lead to viral strategies to avoid, evade, or suppress antiviral immunity. An example is antiviral RNA interference (RNAi) in insects: the host RNAi machinery processes viral double-stranded RNA into small interfering RNAs (siRNAs) to suppress viral replication, whereas insect viruses encode suppressors of RNAi, many of which inhibit viral small interfering RNA (vsiRNA) production. Yet, many studies have analyzed viral RNAi suppressors in heterologous systems, due to the lack of experimental systems to manipulate the viral genome of interest, raising questions about in vivo functions of RNAi suppressors. To address this caveat, we generated an RNAi suppressor-defective mutant of invertebrate iridescent virus 6 (IIV6), a large DNA virus in which we previously identified the 340R protein as a suppressor of RNAi. Loss of 340R did not affect vsiRNA production, indicating that 340R binds siRNA duplexes to prevent RNA-induced silencing complex assembly. Indeed, vsiRNAs were not efficiently loaded into Argonaute 2 during wild-type IIV6 infection. Moreover, IIV6 induced a limited set of mature microRNAs in a 340R-dependent manner, most notably miR-305–3p, which we attribute to stabilization of the miR-305–5p:3p duplex by 340R. The IIV6 340R deletion mutant did not have a replication defect in cells, but was strongly attenuated in adult Drosophila. This in vivo replication defect was completely rescued in RNAi mutant flies, indicating that 340R is a bona fide RNAi suppressor, the absence of which uncovers a potent antiviral immune response that suppresses virus accumulation ∼100-fold. Together, our work indicates that viral RNAi suppressors may completely mask antiviral immunity.

ACS Style

Alfred W. Bronkhorst; Rob Vogels; Gijs J. Overheul; Bas Pennings; Valérie Gausson-Dorey; Pascal Miesen; Ronald P. van Rij. A DNA virus-encoded immune antagonist fully masks the potent antiviral activity of RNAi in Drosophila. Proceedings of the National Academy of Sciences 2019, 116, 24296 -24302.

AMA Style

Alfred W. Bronkhorst, Rob Vogels, Gijs J. Overheul, Bas Pennings, Valérie Gausson-Dorey, Pascal Miesen, Ronald P. van Rij. A DNA virus-encoded immune antagonist fully masks the potent antiviral activity of RNAi in Drosophila. Proceedings of the National Academy of Sciences. 2019; 116 (48):24296-24302.

Chicago/Turabian Style

Alfred W. Bronkhorst; Rob Vogels; Gijs J. Overheul; Bas Pennings; Valérie Gausson-Dorey; Pascal Miesen; Ronald P. van Rij. 2019. "A DNA virus-encoded immune antagonist fully masks the potent antiviral activity of RNAi in Drosophila." Proceedings of the National Academy of Sciences 116, no. 48: 24296-24302.

Journal article
Published: 24 September 2019 in Scientific Reports
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RNA interference (RNAi) has strong antiviral activity in a range of animal phyla, but the extent to which RNAi controls virus infection in chordates, and specifically mammals remains incompletely understood. Here we analyze the antiviral activity of RNAi against a number of positive-sense RNA viruses using Argonaute-2 deficient human cells. In line with absence of virus-derived siRNAs, Sindbis virus, yellow fever virus, and encephalomyocarditis virus replicated with similar kinetics in wildtype cells and Argonaute-2 deficient cells. Coxsackievirus B3 (CVB3) carrying mutations in the viral 3A protein, previously proposed to be a virus-encoded suppressor of RNAi in another picornavirus, human enterovirus 71, had a strong replication defect in wildtype cells. However, this defect was not rescued in Argonaute-2 deficient cells, arguing against a role of CVB3 3A as an RNAi suppressor. In agreement, neither infection with wildtype nor 3A mutant CVB3 resulted in small RNA production with the hallmarks of canonical vsiRNAs. Together, our results argue against strong antiviral activity of RNAi under these experimental conditions, but do not exclude that antiviral RNAi may be functional under other cellular, experimental, or physiological conditions in mammals.

ACS Style

Susan Schuster; Gijs Overheul; Lisa Bauer; Frank J. M. Van Kuppeveld; Ronald P. Van Rij. No evidence for viral small RNA production and antiviral function of Argonaute 2 in human cells. Scientific Reports 2019, 9, 1 -11.

AMA Style

Susan Schuster, Gijs Overheul, Lisa Bauer, Frank J. M. Van Kuppeveld, Ronald P. Van Rij. No evidence for viral small RNA production and antiviral function of Argonaute 2 in human cells. Scientific Reports. 2019; 9 (1):1-11.

Chicago/Turabian Style

Susan Schuster; Gijs Overheul; Lisa Bauer; Frank J. M. Van Kuppeveld; Ronald P. Van Rij. 2019. "No evidence for viral small RNA production and antiviral function of Argonaute 2 in human cells." Scientific Reports 9, no. 1: 1-11.

Review
Published: 16 May 2019 in Viruses
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The RNA interference (RNAi) pathway is a potent antiviral defense mechanism in plants and invertebrates, in response to which viruses evolved suppressors of RNAi. In mammals, the first line of defense is mediated by the type I interferon system (IFN); however, the degree to which RNAi contributes to antiviral defense is still not completely understood. Recent work suggests that antiviral RNAi is active in undifferentiated stem cells and that antiviral RNAi can be uncovered in differentiated cells in which the IFN system is inactive or in infections with viruses lacking putative viral suppressors of RNAi. In this review, we describe the mechanism of RNAi and its antiviral functions in insects and mammals. We draw parallels and highlight differences between (antiviral) RNAi in these classes of animals and discuss open questions for future research.

ACS Style

Susan Schuster; Pascal Miesen; Ronald P. Van Rij. Antiviral RNAi in Insects and Mammals: Parallels and Differences. Viruses 2019, 11, 448 .

AMA Style

Susan Schuster, Pascal Miesen, Ronald P. Van Rij. Antiviral RNAi in Insects and Mammals: Parallels and Differences. Viruses. 2019; 11 (5):448.

Chicago/Turabian Style

Susan Schuster; Pascal Miesen; Ronald P. Van Rij. 2019. "Antiviral RNAi in Insects and Mammals: Parallels and Differences." Viruses 11, no. 5: 448.