Project

Back to overview

Viral Plasticity Underlying Tropism And Pathogenesis/ Innate Immune Evasion Of Emerging Viruses

English title Viral Plasticity Underlying Tropism And Pathogenesis/ Innate Immune Evasion Of Emerging Viruses
Applicant Thiel Volker
Number 160780
Funding scheme Sinergia
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 01.11.2015 - 31.10.2019
Approved amount 1'846'550.00
Show all

All Disciplines (5)

Discipline
Molecular Biology
Cellular Biology, Cytology
Biochemistry
Immunology, Immunopathology
Genetics

Keywords (10)

type I interferon; Coronavirus; adaptation; quasispecies; viral plasticity; Flavivirus; innate immunity; RNA virus; Arenavirus; zoonosis

Lay Summary (German)

Lead
Plastizität von Viren: Einfluss auf Tropismus, Pathogenität und angeborene Immunität
Lay summary

In den letzten Jahren haben wir mehrere neuartige Viren beobachtet die aus einen Reservoir in Tieren auf den Menschen übergesprungen sind. Diese zoologischen Viren verursachten häufig schwere, nicht-behandelbare, und of auch tödliche Krankheiten im Menschen. Darunter befinden sich Flavi-, Corona-, und Arenaviren, die als RNA Viren für eine hohe Mutationsrate und demzufolge eine hohe Diversität bekannt sind. Tatsächlich entsteht bei jeder Infektion ein Schwarm von Viren der eine Vielzahl von genetischen Varianten enthält und der als "Quasispezies" bezeichnet wird. Die virale Quasispezies ermöglicht eine rasche Anpassung an veränderte Lebensbedingungen und ermöglicht Viren neue Gewebe und Wirte zu infizieren, und der angeborenen Immunantwort des Wirtes zu entkommen.

In diesem Projekt werden wir mithilfe von "next-generation" Sequenziertechniken eine real-time Aufnahme der Quasispezies-Dynamik erstellen und die Bedeutung der Quasispezies im Kontext von zoologischen Infektionen und Interaktionen mit der angeborenen Immunität untersuchen. Unsere Studien beinhalten pathogene Coronaviren (Thiel), neurotrope Flaviviren (Leib, Gäumann) und hämorrhagische Arenaviren (Kunz). Durch die Verwendung von natürlichen Zielzellen, die wesentliche Eigenschaften der entsprechenden Gewebe in vivo haben, versuchen wir die temporale Dynamik von genetischen Veränderungen innerhalb der viralen Quasispezies als Funktion von Virus-Wirt Interaktionen und Adaptation an eine veränderte Umgebung darzustellen.

 

Direct link to Lay Summary Last update: 18.09.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Comparison of the Innate Immune Responses to Pathogenic and Nonpathogenic Clade B New World Arenaviruses
Moreno Hector, Möller Rebecca, Fedeli Chiara, Gerold Gisa, Kunz Stefan (2019), Comparison of the Innate Immune Responses to Pathogenic and Nonpathogenic Clade B New World Arenaviruses, in Journal of Virology, 93(19), 1-19.
Limited Correlation of Shotgun Metagenomics Following Host Depletion and Routine Diagnostics for Viruses and Bacteria in Low Concentrated Surrogate and Clinical Samples
Oechslin Corinne P., Lenz Nicole, Liechti Nicole, Ryter Sarah, Agyeman Philipp, Bruggmann Rémy, Leib Stephen L., Beuret Christian M. (2018), Limited Correlation of Shotgun Metagenomics Following Host Depletion and Routine Diagnostics for Viruses and Bacteria in Low Concentrated Surrogate and Clinical Samples, in Frontiers in Cellular and Infection Microbiology, 8, 375.
Evaluation of antivirals against tick-borne encephalitis virus in organotypic brain slices of rat cerebellum
Lenz Nicole, Engler Olivier, Grandgirard Denis, Leib Stephen L., Ackermann-Gäumann Rahel (2018), Evaluation of antivirals against tick-borne encephalitis virus in organotypic brain slices of rat cerebellum, in PLOS ONE, 13(10), e0205294-e0205294.
Synthetic viruses—Anything new?
Thiel Volker (2018), Synthetic viruses—Anything new?, in PLOS Pathogens, 14(10), e1007019-e1007019.
Virologists—Heroes need weapons
Hufsky Franziska, Ibrahim Bashar, Beer Martin, Deng Li, Mercier Philippe Le, McMahon Dino P., Palmarini Massimo, Thiel Volker, Marz Manja (2018), Virologists—Heroes need weapons, in PLOS Pathogens, 14(2), e1006771-e1006771.
Inactivation of Zika virus in human breast milk by prolonged storage or pasteurization
Pfaender Stephanie, Vielle Nathalie J., Ebert Nadine, Steinmann Eike, Alves Marco P., Thiel Volker (2017), Inactivation of Zika virus in human breast milk by prolonged storage or pasteurization, in Virus Research, 228, 58-60.

Collaboration

Group / person Country
Types of collaboration
Dr. Remy Bruggmann, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Esteban Domingo, Universidad Autonoma, Madrid Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Christian Drosten, University of Bonn Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Daniel Ruzek, Academy of Sciences of the Czech Republic Czech Republic (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Luis Enjuanes, Spanish National Center for Biotechnology Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Tosso Leeb, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

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 2018 Talk given at a conference Organotypic culture slices of rat cerebellum to study antivirals against tick-borne encephalitis virus 29.08.2018 Lausanne, Switzerland Ackermann Rahel; Leib Stephen L.; Lenz Nicole;
Founding of the European Virus Bioinformatics Center (EVBC) Individual talk elected as Member of the EVBC Board of Directors 08.03.2017 Jena, Germany Thiel Volker;


Self-organised

Title Date Place

Communication with the public

Communication Title Media Place Year
Print (books, brochures, leaflets) Annual report Spiez Laboratory Western Switzerland German-speaking Switzerland 2018
Other activities Kinderuniversität; Vortrag über Viren für Kinder im Alter von 8-12 Jahren German-speaking Switzerland 2017

Associated projects

Number Title Start Funding scheme
173085 Host innate immune responses to viral RNA 01.09.2017 Project funding
170108 Host cell invasion by Lassa virus 01.01.2017 Project funding
149746 Host cell invasion by Lassa virus 01.01.2014 Project funding
149784 Host innate immune responses to viral RNA 01.04.2014 Project funding
143754 Immunoengineering a synthetic vaccine against emerging human pathogenic viruses 01.10.2012 Interdisciplinary projects
189136 Shedding light on the pathophysiology of pneumococcal and listeric meningitis by complementary disease models and non- invasive methods to evaluate novel therapeutics 01.10.2019 Project funding
183376 Biocontained Confocal Microscopy Platform Lausanne University Hospital 01.10.2019 R'EQUIP

Abstract

During the past years, numerous novel viruses of zoonotic origin, including flavi-, corona-, and arenaviruses have emerged as causative agents of severe incurable human diseases posing important public health problems. A hallmark of emerging pathogenic human RNA viruses is their low-fidelity mechanism of replication, resulting in high mutation rates and consequent high genetic diversity. Actual RNA virus populations are therefore comprised of swarms of genetic variants with high information content referred to as quasispecies. The quasispecies nature of RNA viruses allows for rapid adaptation to dynamic environments, including changing hosts and tissues during zoonotic transmission and evading host immune responses. In our present project, we will apply cutting edge next generation sequencing (NGS) technologies for a comprehensive real-time analysis of quasispecies dynamics underlying viral plasticity of major emerging viruses in relevant experimental paradigms in vitro and in vivo. We will combine our complementary expertise on highly pathogenic coronaviruses (Thiel), neurotropic flaviviruses (Leib, Gäumann), and hemorrhagic arenaviruses (Kunz) to study the genetic basis of viral plasticity underlying the tropism and innate immune evasion. Importantly, our studies will be performed in natural target cells, such as primary human airway epithelium (HAE, Thiel), organotypic culture slices of brain tissue (OCS, Leib, Gäumann), and primary human endothelial cell cultures (Kunz). These systems recapitulate major features of living tissue in vivo, are biologically highly relevant, and provide well-controlled infection paradigms that, combined with NGS, allow us to track temporal dynamics of genetic changes in viral quasispecies as a function of virus-host cell interaction and adaptation to a changed environment. Upon spill-over into the human population, viruses are subject to strong selective pressure leading to positive selection of viral attachment proteins able to use human receptors and selection of viral proteins involved in cell interactions at later steps of the viral life cycle. Importantly, the subject of selective pressure is not the individual viral variant but the entire quasispecies population, involving complex interactions between variants. The selection of specific viral variants within a population is thus impossible to predict by biocomputational models and an experimental approach is needed. In our first aim, we will use an unbiased approach based on NGS analysis of the entire quasispecies population during passage in organotypic tissue cultures. We hypothesize that alterations in the viral quasispecies are important indicators and requirements for viral adaptation including host and target cell tropism.Innate anti-viral immunity, in particular the interferon (IFN)-I system, represents a powerful first line of defense against RNA viruses. In our second aim, we will treat organotypic tissue cultures with recombinant IFN-I in order to modulate the innate immune status of cells . We hypothesize that selection by innate immune pressure will induce changes in the viral quasispecies that will pinpoint general mechanisms of innate immune evasion. Finally, in our third aim, we will use of a wide panel of functional assays, reverse genetic systems, in vitro and in vivo systems to phenotypically analyze the most interesting virus mutants identified in aims 1 and 2, and we hypothesize that the use of primary organotypic culture systems and in vivo disease models will validate biologically relevant phenotypes present in the viral quasispecies.Using a comparative approach at the level of viral population genetics, streamlined experimental approaches and technologies (aim 4), our studies on coronaviruses, flaviviruses, and arenaviruses will reveal important commonalities and differences, allowing the definition of general principles of viral plasticity in the context of tropism and innate immune evasion. The results of our study could help to predict the risk of zoonotic transmission, adding to our preparedness. By combining cutting-edge technology with an important scientific question our project will address an unmatched problem of high relevance for the infectious disease community at large.
-