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Host innate immune responses to viral RNA

English title Host innate immune responses to viral RNA
Applicant Thiel Volker
Number 173085
Funding scheme Project funding (Div. I-III)
Research institution Institut für Virologie und Immunologie Depart. Infektionskrankheiten und Pathologie Universität Bern
Institution of higher education Other Research Institutes - FINST
Main discipline Molecular Biology
Start/End 01.09.2017 - 31.08.2021
Approved amount 1'008'000.00
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All Disciplines (4)

Discipline
Molecular Biology
Cellular Biology, Cytology
Immunology, Immunopathology
Biochemistry

Keywords (9)

viral RNA synthesis; innate immunity; type I interferon; RNA decay; reverse genetics; viral RNA sensing; RNA virus; Coronavirus; virus replication complex

Lay Summary (German)

Lead
Coronaviren sind RNA Viren die schon sehr lange bekannt dafür sind in Nutz- und Haustieren zu schwere Erkrankungen zu führen. Im Menschen konnte man erst durch das Auftreten von zoologischen Viren, z.B. dem SARS-Coroanvirus und dem MERS-Coronavirus, schwere Erkrankungen beobachten. Eine wichtige Voraussetzung zur Etablierung einer robusten Virusvermehrung bei Coronaviren ist deren Eigenschaft frühen antivitalen Wirtsantworten zu entkommen.
Lay summary

Wir gehen davon aus, dass Coronaviren Mechanismen entwickelt haben die den Ort der Genom-Vermehrung, den sogenannten Replikationskomplex, schützen. Dieser Komplex befindet sich an zellulären Membranen in Zytoplasma von infizierten Zellen. In unserem Projekt wollen wir wichtige Virus-Wirt-Interaktionen identifizieren die direkt am Replikationskomplex stattfinden. Wir sind dabei besonders daran interessiert Wirts-Proteine zu finden die entweder von Coronaviren zur Genom-Vermehrung benutzt werden, oder die die coronavirale Genom-Vermehrung hemmen können. Wir denken dass ähnliche Mechanismen bei anderen Viren eine Rolle spielen und unsere Ergebnisse über Coronaviren hinaus von Bedeutung sein können. Die Erforschung dieser Mechanismen wird zudem auch die Entwicklung von neuen Strategien zur Bekämpfung von coronaviralen Infektion ermöglichen.

Direct link to Lay Summary Last update: 12.07.2017

Lay Summary (English)

Lead
Coronaviruses (CoVs) are RNA viruses that have long been known to cause severe disease in livestock and companion animals. In humans, severe and fatal respiratory diseases have beenobserved through the emergence of zoonotic CoVs, such as SARS-CoV and MERS-CoV. There’saccumulating evidence that early events during CoV infection are decisive for disease severity and outcome.
Lay summary

We hypothesize that CoVs have evolved mechanisms to protect their site of RNA replication in the host cell cytoplasm. This site is characterized by the coronaviral replicase complex that is associated with cytoplasmic host cell membranes. In this project we aim to identify critical virus-host interactions that take place at, or near, the viral replicase complex. Specifically, we are interested to identify host cell proteins that either promote or inhibit virus replication. We expect that similar virus-host interactions take place during infection with other RNA viruses. Our anticipated results will therefore have impact beyond coronaviruses and will be instructive to develop novel strategies to combat RNA virus infections.

Direct link to Lay Summary Last update: 12.07.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome
Bhatt Pramod R., Scaiola Alain, Loughran Gary, Leibundgut Marc, Kratzel Annika, Meurs Romane, Dreos René, O’Connor Kate M., McMillan Angus, Bode Jeffrey W., Thiel Volker, Gatfield David, Atkins John F., Ban Nenad (2021), Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome, in Science, 372(6548), 1306-1313.
No Evidence for Human Monocyte-Derived Macrophage Infection and Antibody-Mediated Enhancement of SARS-CoV-2 Infection
García-Nicolás Obdulio, V’kovski Philip, Zettl Ferdinand, Zimmer Gert, Thiel Volker, Summerfield Artur (2021), No Evidence for Human Monocyte-Derived Macrophage Infection and Antibody-Mediated Enhancement of SARS-CoV-2 Infection, in Frontiers in Cellular and Infection Microbiology, 11, 1-10.
SARS-CoV-2 spike D614G change enhances replication and transmission
Zhou Bin, Thao Tran Thi Nhu, Hoffmann Donata, Taddeo Adriano, Ebert Nadine, Labroussaa Fabien, Pohlmann Anne, King Jacqueline, Steiner Silvio, Kelly Jenna N., Portmann Jasmine, Halwe Nico Joel, Ulrich Lorenz, Trüeb Bettina Salome, Fan Xiaoyu, Hoffmann Bernd, Wang Li, Thomann Lisa, Lin Xudong, Stalder Hanspeter, Pozzi Berta, de Brot Simone, Jiang Nannan, Cui Dan, et al. (2021), SARS-CoV-2 spike D614G change enhances replication and transmission, in Nature, 592(7852), 122-127.
Coronavirus biology and replication: implications for SARS-CoV-2
V’kovski Philip, Kratzel Annika, Steiner Silvio, Stalder Hanspeter, Thiel Volker (2021), Coronavirus biology and replication: implications for SARS-CoV-2, in Nature Reviews Microbiology, 19(3), 155-170.
Identification of an Antiviral Compound from the Pandemic Response Box that Efficiently Inhibits SARS-CoV-2 Infection In Vitro
Holwerda Melle, V’kovski Philip, Wider Manon, Thiel Volker, Dijkman Ronald (2020), Identification of an Antiviral Compound from the Pandemic Response Box that Efficiently Inhibits SARS-CoV-2 Infection In Vitro, in Microorganisms, 8(12), 1872-1872.
LY6E impairs coronavirus fusion and confers immune control of viral disease
Pfaender Stephanie, Mar Katrina B., Michailidis Eleftherios, Kratzel Annika, Boys Ian N., V’kovski Philip, Fan Wenchun, Kelly Jenna N., Hirt Dagny, Ebert Nadine, Stalder Hanspeter, Kleine-Weber Hannah, Hoffmann Markus, Hoffmann Hans-Heinrich, Saeed Mohsan, Dijkman Ronald, Steinmann Eike, Wight-Carter Mary, McDougal Matthew B., Hanners Natasha W., Pöhlmann Stefan, Gallagher Tom, Todt Daniel, Zimmer Gert, et al. (2020), LY6E impairs coronavirus fusion and confers immune control of viral disease, in Nature Microbiology, 5(11), 1330-1339.
SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation
Schubert Katharina, Karousis Evangelos D., Jomaa Ahmad, Scaiola Alain, Echeverria Blanca, Gurzeler Lukas-Adrian, Leibundgut Marc, Thiel Volker, Mühlemann Oliver, Ban Nenad (2020), SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation, in Nature Structural & Molecular Biology, 27(10), 959-966.
CoronavirusesMethods and Protocols
Thao Tran Thi Nhu, Labroussaa Fabien, Ebert Nadine, Jores Joerg, Thiel Volker (2020), CoronavirusesMethods and Protocols, Springer US, New York, NY.
CoronavirusesMethods and Protocols
V’kovski Philip, Steiner Silvio, Thiel Volker (2020), CoronavirusesMethods and Protocols, Springer US, New York, NY.
Inactivation of Severe Acute Respiratory Syndrome Coronavirus 2 by WHO-Recommended Hand Rub Formulations and Alcohols
Kratzel Annika, Todt Daniel, V’kovski Philip, Steiner Silvio, Gultom Mitra, Thao Tran Thi Nhu, Ebert Nadine, Holwerda Melle, Steinmann Jörg, Niemeyer Daniela, Dijkman Ronald, Kampf Günter, Drosten Christian, Steinmann Eike, Thiel Volker, Pfaender Stephanie (2020), Inactivation of Severe Acute Respiratory Syndrome Coronavirus 2 by WHO-Recommended Hand Rub Formulations and Alcohols, in Emerging Infectious Diseases, 26(7), 1-3.
Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform
Thao Tran Thi Nhu, Labroussaa Fabien, Ebert Nadine, V’kovski Philip, Stalder Hanspeter, Portmann Jasmine, Kelly Jenna, Steiner Silvio, Holwerda Melle, Kratzel Annika, Gultom Mitra, Schmied Kimberly, Laloli Laura, Hüsser Linda, Wider Manon, Pfaender Stephanie, Hirt Dagny, Cippà Valentina, Crespo-Pomar Silvia, Schröder Simon, Muth Doreen, Niemeyer Daniela, Corman Victor, Müller Marcel A., et al. (2020), Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform, in Nature, 1-5.
Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry
Blockus Sebastian, Sake Svenja M., Wetzke Martin, Grethe Christina, Graalmann Theresa, Pils Marina, Le Goffic Ronan, Galloux Marie, Prochnow Hans, Rox Katharina, Hüttel Stephan, Rupcic Zeljka, Wiegmann Bettina, Dijkman Ronald, Rameix-Welti Marie-Anne, Eléouët Jean-François, Duprex W Paul, Thiel Volker, Hansen Gesine, Brönstrup Mark, Haid Sibylle, Pietschmann Thomas (2020), Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry, in Antiviral Research, 177, 104774-104774.
Viral RNA in an m6A disguise
Thiel Volker (2020), Viral RNA in an m6A disguise, in Nature Microbiology, 5(4), 531-532.
Establishment of Primary Transgenic Human Airway Epithelial Cell Cultures to Study Respiratory Virus–Host Interactions
Jonsdottir Hulda R., Marti Sabrina, Geerts Dirk, Rodriguez Regulo, Thiel Volker, Dijkman Ronald (2019), Establishment of Primary Transgenic Human Airway Epithelial Cell Cultures to Study Respiratory Virus–Host Interactions, in Viruses, 11(8), 747-747.
Determination of host proteins composing the microenvironment of coronavirus replicase complexes by proximity-labeling
V'kovski Philip, Gerber Markus, Kelly Jenna, Pfaender Stephanie, Ebert Nadine, Braga Lagache Sophie, Simillion Cedric, Portmann Jasmine, Stalder Hanspeter, Gaschen Véronique, Bruggmann Rémy, Stoffel Michael H, Heller Manfred, Dijkman Ronald, Thiel Volker (2019), Determination of host proteins composing the microenvironment of coronavirus replicase complexes by proximity-labeling, in eLife, 8, 1-30.
The Small-Compound Inhibitor K22 Displays Broad Antiviral Activity against Different Members of the Family Flaviviridae and Offers Potential as a Panviral Inhibitor
García-Nicolás Obdulio, V'kovski Philip, Vielle Nathalie J., Ebert Nadine, Züst Roland, Portmann Jasmine, Stalder Hanspeter, Gaschen Véronique, Vieyres Gabrielle, Stoffel Michael, Schweizer Matthias, Summerfield Artur, Engler Olivier, Pietschmann Thomas, Todt Daniel, Alves Marco P., Thiel Volker, Pfaender Stephanie (2018), The Small-Compound Inhibitor K22 Displays Broad Antiviral Activity against Different Members of the Family Flaviviridae and Offers Potential as a Panviral Inhibitor, in Antimicrobial Agents and Chemotherapy, 62(11), 1-10.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of the Swiss Society for Microbiology 2019 Talk given at a conference 2 oral presentations, 2 poster presentations 03.09.2019 Zuerich, Switzerland Thiel Volker; Kelly Jenna Nicole; V'Kovski Philip; Pfänder Stephanie; Kratzel Annika; Ebert Nadine;
Annual Meeting of the American Society of Virology, ASV 2019 Talk given at a conference Single cell analysis of the human respiratory epithelium during influenza virus infection reveals cell type-specific viral distribution and innate immune responses 21.07.2019 Minneapolis, United States of America Kelly Jenna Nicole; Thiel Volker;
Positive-strand RNA meeting - Keystone meeting Poster 2 Posters 09.06.2019 Killarney, Ireland Pfänder Stephanie; V'Kovski Philip;
European Congress of Virology Talk given at a conference 1 plenary talk, 2 selected oral talks, 6 poster presentations 28.04.2019 Rotterdam, Netherlands Thiel Volker; Kratzel Annika; V'Kovski Philip; Pfänder Stephanie; Ebert Nadine; Kelly Jenna Nicole;
3rd Annual Meeting of the European Bioinformatics Center Talk given at a conference Determination of host proteins composing the microenvironment of coronavirus replicase complexes 28.03.2019 Glasgow, Great Britain and Northern Ireland Thiel Volker;
3rd Annual Meeting of the European Bioinformatics Center Talk given at a conference Single cell resolution of influenza virus infection in its natural target cells 28.03.2019 Glasgow, Great Britain and Northern Ireland Kelly Jenna Nicole; Thiel Volker;
29th Annual Meeting of the Society for Virology Talk given at a conference 1 oral and 2 poster presentations 20.03.2019 Duesseldorf, Germany Pfänder Stephanie; V'Kovski Philip; Thiel Volker; Ebert Nadine; Kratzel Annika; Kelly Jenna Nicole;
RNA viruses at the host interface- novel aspects of viral replication - International Symposium Talk given at a conference Illuminating the coronavirus replicase: a platform for virus-host interactions 19.09.2018 Marburg, Germany Thiel Volker;
Annual Meeting of the Swiss Society for Microbiology 2018 Talk given at a conference Elucidation of the molecular microenvironment of coronavirus replicase complexes reveals close association with host cell translation 28.08.2018 Lausanne, Switzerland Thiel Volker; V'Kovski Philip; Pfänder Stephanie; Kelly Jenna Nicole;
2nd International Symposium on RNA virus persistence: mechanisms and consequences Individual talk Illuminating the coronavirus replicase: a platform for virus-host interactions 23.08.2018 Freiburg, Germany Thiel Volker;
Annual Meeting of the American Society of Virology, ASV 2018 Talk given at a conference Elucidation of the molecular microenvironment of coronavirus replicase complexes reveals close association with host cell translation 15.07.2018 College Park, Maryland, United States of America V'Kovski Philip; Thiel Volker; Kelly Jenna Nicole;
Institutional Seminar, Institute of Virology, Lubbock, Germany Individual talk Illuminating coronavirus replication: from RNA synthesis to pathogenensis 03.07.2018 Luebeck, Germany Thiel Volker;
Institutional Seminar, Paul-Ehrlich Institute (PEI), Langen, D Individual talk Illuminating coronavirus replication: from RNA synthesis to pathogenensis 26.04.2018 Langen, Germany Thiel Volker;
28th Annual Meeting of the Society for Virology Individual talk 1 oral presentation, 2 poster presentations 14.03.2018 Wuerzburg, Germany V'Kovski Philip; Pfänder Stephanie; Thiel Volker; Ebert Nadine;
65th Annual Meeting of the Japanese Society for Virology Talk given at a conference Plenary lecture 24.10.2017 Osaka, Japan Thiel Volker;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television various reports SRF Rhaeto-Romanic Switzerland German-speaking Switzerland Italian-speaking Switzerland Western Switzerland 2020

Associated projects

Number Title Start Funding scheme
149784 Host innate immune responses to viral RNA 01.04.2014 Project funding (Div. I-III)
160780 Viral Plasticity Underlying Tropism And Pathogenesis/ Innate Immune Evasion Of Emerging Viruses 01.11.2015 Sinergia
201278 The coronavirus replicase complex: structure-function relationship and virus-host interaction 01.09.2021 Project funding (Div. I-III)
196387 A multidisciplinary approach to identify vulnerabilities of SARS-CoV-2 for vaccine development 01.06.2020 Special Call on Coronaviruses
201278 The coronavirus replicase complex: structure-function relationship and virus-host interaction 01.09.2021 Project funding (Div. I-III)
198473 Recoding the SARS-CoV-2 genome - A multidisciplinary approach to generate live-attenuated coronavirus vaccines 01.11.2020 NRP 78 Covid-19
149784 Host innate immune responses to viral RNA 01.04.2014 Project funding (Div. I-III)
165076 Zoonotic transmission of coronaviruses 01.03.2016 Project funding (Div. I-III)

Abstract

"Host innate immune responses to viral RNA"Background: Coronaviruses (CoVs) are RNA viruses that have long been known to cause severe disease in livestock and companion animals. In humans, severe and fatal respiratory diseases have been observed through the emergence of zoonotic CoVs, such as SARS-CoV and MERS-CoV. CoVs are well known to efficiently evade early innate immune responses and enzymatic functions within - and virus-host interactions at - the CoV replication/transcription complex (RTC) are key to efficiently evade early innate immune responses. Working hypothesis and aims: We hypothesize that induction of early innate immune responses to CoV heavily rely on the ability of host cell innate immune sensors to access and recognize viral RNA and that CoVs have evolved efficacious mechanisms to prevent early detection of viral RNA. We further hypothesize that these early virus-host interactions predominantly take place at the CoV RTC. In order to mechanistically understand these innate immune evasion strategies, we will “illuminate” the cellular environment of the CoV RTC to identify host cell factors that are required for CoV replication, and host cell factors that are targeting the CoV RTC to restrict CoV replication. The reverse genetic systems for the mouse hepatitis virus (MHV) and human coronavirus 229E (HCoV-229E) and well characterized recombinant mutant viruses will be used in combination with murine and human models of infection to dissect key steps and key molecules involved in early innate immune responses on the molecular level. We will furthermore employ state-of-the-art technologies involving biotin ligase-mediated proximity labeling and proteomics, CRISPR/Cas9-based functional screens, and transcriptomics in combination with ribosomal profiling to obtain a detailed mechanistic view on (i) key interactions involved in early innate immune responses, (ii) the kinetics of these interactions and (iii) the kinetics of the global host cell response under well-defined conditions. These studies will provide spatial and temporal view of basic principles of viral RNA recognition and antiviral innate immune mechanisms in different primary cell types following virus infection. Expected significance: Our proposed studies will reveal basic principles of viral RNA sensing and antiviral innate immune effector mechanisms that are highly relevant also beyond CoV infections. We expect to identify key molecules, mechanisms and pathways that promote or restrict viral replication at the site of viral RNA synthesis. This information will further our understanding on fundamental aspects of viral RNA synthesis and innate immune responses to RNA virus infection, and will facilitate the development of novel strategies to interfere with viral RNA replication during the early phase of infections.
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