Project

Back to overview

Rhinovirus et entérovirus: déterminants génomiques et phénotypes associés

English title Rhinovirus and enterovirus: genomic determinants underlying specific phenotypes
Applicant Tapparel Vu Caroline
Number 146151
Funding scheme Project funding
Research institution Laboratoire de Virologie Service des Maladies Infectieuses Hôpitaux Universitaires de Genève
Institution of higher education University of Geneva - GE
Main discipline Experimental Microbiology
Start/End 01.04.2013 - 31.03.2016
Approved amount 343'960.00
Show all

Keywords (8)

neurotropism; epidemiology; phenotype; rhinovirus; model system; adaptation; diversity; enterovirus

Lay Summary (French)

Lead
Les rhinovirus (RV) et entérovirus (EV) sont caractérisés par une importante variabilité génétique et phénotypique. Les RV infectent les voies respiratoires alors que les EV peuvent disséminer et causent plus de 20 syndromes différents. L’EV71 est le second entérovirus neurotrope après le poliovirus. En plus de leurs différentes pathogenèses, les RVs et la plupart des EVs présentent des phénotypes différents in vitro tels que la température optimale de croissance et la tolérance à l’acide.
Lay summary

- Nous proposons d’investiguer les déterminants génétiques des différents phénotypes observés entre RVs (ou EVs respiratoires) et EVs en créant des chimères entre ces virus et en analysant les phénotypes résultants.

- Après avoir mis en évidence l'acquisition de déterminants neurotropes par l’ EV71 au cours d'une infection disséminée, nous projetons d’étudier leur rôle grâce à expériences fonctionnelles. Nous allons également analyser l’évolution d’EV71 lors d’infections sévères afin de déterminer si l'émergence de nouveaux phénotypes au cours d’une infections est un phénomène fréquent.

-En dehors de ces deux objectifs principaux, nous allons valider l’utilisation d’un système de culture de tissu pour la croissance et l’étude des RV-C, incapable de pousser dans des lignées cellulaires, ce afin de mieux élucider les caractéristiques biologiques de ces virus.

-Finalement, nous allons suivre l’épidémiologie moléculaire des RVs et EVs respiratoires dans la population.

Nous considérons qu’une connaissance approfondie des déterminants génétiques impliqués dans les caractéristiques phénotypiques des EVs et RVs va permettre de mieux comprendre leur pathogenèse. Ceci est particulièrement important du fait de l'absence d'antiviraux ou de vaccins contre ces virus.

 

Direct link to Lay Summary Last update: 04.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Rhinoviruses and Respiratory Enteroviruses: Not as Simple as ABC.
Royston Léna, Tapparel Caroline, Royston Léna, Tapparel Caroline (2016), Rhinoviruses and Respiratory Enteroviruses: Not as Simple as ABC., in Viruses, (1), 1-23.
Chimeric rhinoviruses obtained via genetic engineering or artificially induced recombination are viable only if the polyprotein coding sequence derives from the same species.
Schibler Manuel, Piuz Isabelle, Hao Weidong, Tapparel Caroline, Schibler Manuel, Piuz Isabelle, Hao Weidong, Tapparel Caroline (2015), Chimeric rhinoviruses obtained via genetic engineering or artificially induced recombination are viable only if the polyprotein coding sequence derives from the same species., in Journal of virology, 89(8), 4470-80.
Disseminated rhinovirus C8 infection with infectious virus in blood and fatal outcome in a child with repeated episodes of bronchiolitis.
Lupo Julien, Schuffenecker Isabelle, Morel-Baccard Christine, Bardet Julie, Payen Valérie, Kaiser Laurent, Constant Samuel, Lobrinus Johannes Alexander, Lin-Marq Nathalie, Lina Bruno, Morand Patrice, Tapparel Caroline, Lupo Julien, Schuffenecker Isabelle, Morel-Baccard Christine, Bardet Julie, Payen Valérie, Kaiser Laurent, Constant Samuel, Lobrinus Johannes Alexander, Lin-Marq Nathalie, Lina Bruno, Morand Patrice, Tapparel Caroline (2015), Disseminated rhinovirus C8 infection with infectious virus in blood and fatal outcome in a child with repeated episodes of bronchiolitis., in Journal of clinical microbiology, 53(5), 1775-7.
Human Rhinovirus Types and Association with Respiratory Symptoms During the First Year of Life.
Müller Loretta, Mack Ines, Tapparel Caroline, Kaiser Laurent, Alves Marco P, Kieninger Elisabeth, Frey Urs, Regamey Nicolas, Latzin Philipp, Müller Loretta, Mack Ines, Tapparel Caroline, Kaiser Laurent, Alves Marco P, Kieninger Elisabeth, Frey Urs, Regamey Nicolas, Latzin Philipp (2015), Human Rhinovirus Types and Association with Respiratory Symptoms During the First Year of Life., in The Pediatric infectious disease journal, 34(8), 907-9.
Human three-dimensional engineered neural tissue reveals cellular and molecular events following cytomegalovirus infection.
Cosset Érika, Martinez Yannick, Preynat-Seauve Olivier, Lobrinus Johannes-Alexander, Tapparel Caroline, Cordey Samuel, Peterson Hedi, Petty Tom J, Colaianna Marilena, Tieng Vannary, Tirefort Diderik, Dinnyes Andras, Dubois-Dauphin Michel, Kaiser Laurent, Krause Karl-Heinz, Cosset Érika, Martinez Yannick, Preynat-Seauve Olivier, Lobrinus Johannes-Alexander, Tapparel Caroline, Cordey Samuel, Peterson Hedi, Petty Tom J, Colaianna Marilena, Tieng Vannary, Tirefort Diderik, Dinnyes Andras, Dubois-Dauphin Michel, Kaiser Laurent, Krause Karl-Heinz (2015), Human three-dimensional engineered neural tissue reveals cellular and molecular events following cytomegalovirus infection., in Biomaterials, 53, 296-308.
Molecular Epidemiology of Human Rhinoviruses and Enteroviruses Highlights Their Diversity in Sub-Saharan Africa.
L'Huillier Arnaud G, Kaiser Laurent, Petty Tom J, Kilowoko Mary, Kyungu Esther, Hongoa Philipina, Vieille Gaël, Turin Lara, Genton Blaise, D'Acremont Valérie, Tapparel Caroline, L'Huillier Arnaud G, Kaiser Laurent, Petty Tom J, Kilowoko Mary, Kyungu Esther, Hongoa Philipina, Vieille Gaël, Turin Lara, Genton Blaise, D'Acremont Valérie, Tapparel Caroline (2015), Molecular Epidemiology of Human Rhinoviruses and Enteroviruses Highlights Their Diversity in Sub-Saharan Africa., in Viruses, 7(12), 6412-23.
Vitamin D represses rhinovirus replication in cystic fibrosis cells by inducing LL-37.
Schögler Aline, Muster Ricardo J, Kieninger Elisabeth, Casaulta Carmen, Tapparel Caroline, Jung Andreas, Moeller Alexander, Geiser Thomas, Regamey Nicolas, Alves Marco P, Schögler Aline, Muster Ricardo J, Kieninger Elisabeth, Casaulta Carmen, Tapparel Caroline, Jung Andreas, Moeller Alexander, Geiser Thomas, Regamey Nicolas, Alves Marco P (2015), Vitamin D represses rhinovirus replication in cystic fibrosis cells by inducing LL-37., in The European respiratory journal, 47(2), 520-30.
Lactate dehydrogenase concentration in nasal wash fluid indicates severity of rhinovirus-induced wheezy bronchitis in preschool children.
Cangiano Giulia, Proietti Elena, Kronig Marie Noelle, Kieninger Elisabeth, Sadeghi Christine D, Gorgievski Meri, Barbani Maria Teresa, Midulla Fabio, Tapparel Caroline, Kaiser Laurent, Alves Marco P, Regamey Nicolas, Cangiano Giulia, Proietti Elena, Kronig Marie Noelle, Kieninger Elisabeth, Sadeghi Christine D, Gorgievski Meri, Barbani Maria Teresa, Midulla Fabio, Tapparel Caroline, Kaiser Laurent, Alves Marco P, Regamey Nicolas (2014), Lactate dehydrogenase concentration in nasal wash fluid indicates severity of rhinovirus-induced wheezy bronchitis in preschool children., in The Pediatric infectious disease journal, 33(12), 1285-7.
Survival of rhinoviruses on human fingers.
L'Huillier A G, Tapparel C, Turin L, Boquete-Suter P, Thomas Y, Kaiser L, L'Huillier A G, Tapparel C, Turin L, Boquete-Suter P, Thomas Y, Kaiser L (2014), Survival of rhinoviruses on human fingers., in Clinical microbiology and infection : the official publication of the European Society of Clinical M, 21(4), 381-5.
Growth and characterization of different human rhinovirus C types in three-dimensional human airway epithelia reconstituted in vitro.
Tapparel Caroline, Sobo Komla, Constant Samuel, Huang Song, Van Belle Sandra, Kaiser Laurent, Tapparel Caroline, Sobo Komla, Constant Samuel, Huang Song, Van Belle Sandra, Kaiser Laurent (2013), Growth and characterization of different human rhinovirus C types in three-dimensional human airway epithelia reconstituted in vitro., in Virology, 446(1-2), 1-8.

Collaboration

Group / person Country
Types of collaboration
Prof. E.Zdobnov, Department of Genetic Medicine and Development, University of Geneva Medical School Switzerland (Europe)
- Publication
Dr. N. Regamey, Division of Pediatric Pulmonary Medicine, University Hospital of Bern, Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Epithelix SARL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Industry/business/other use-inspired collaboration
Dr. Rogier Van Doorn, Oxford University Clinical Research Unit (OUCRU) Vietnam (Asia)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Life science research:3R Applications Talk given at a conference “Differential pathogenesis of the most common respiratory viruses in reconstituted human airway epithelia” 02.10.2015 Genève, Switzerland Tapparel Vu Caroline;
Europics 2014 Talk given at a conference Artificial and non replicative recombination as tools to assess the viability of Rhinovirus intra- and interspecies chimeras. 09.03.2014 Blankenberge, Belgium Tapparel Vu Caroline; Meister Simon; Kaiser Laurent;
European Congress of Virology 2013 Talk given at a conference Growth and Characterization of different Human Rhinovirus C Types in 3D Human Airway Epithelia Reconstituted in Vitro 11.09.2013 Lyon, France Sobo Komla;
SSM meeting Interlaken Talk given at a conference Enterovirus diversity and acquisition of new phenotypic characteristics 26.06.2013 Interlaken, Switzerland Tapparel Vu Caroline; Kaiser Laurent;


Self-organised

Title Date Place
Swiss virology meeting 2016 02.02.2016 Thun, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: radio, television Il business del raffreddore RTSI Italian-speaking Switzerland 2016
Media relations: radio, television Le rhume dans tous ses états CQFD, RTS1 Western Switzerland 2016
Media relations: radio, television Faut-il encore faire des tests sur les animaux? RTS: 36.9 Western Switzerland 2015
Media relations: radio, television La route du rhume Antenne 2 International 2015

Awards

Title Year
Prix E. Naef pour la recherche in vitro 2016
Prix Leenaards pour la recherche tranlationnelle 2016
Prix Bizot pour la meilleure thèse de Privat Docent 2015

Associated projects

Number Title Start Funding scheme
113426 Rhinoviruses associated with lower respiratory diseases: genetic variability and replications site 01.01.2007 Project funding
166218 Viral and host factors modulating rhinovirus and enterovirus disease severity 01.04.2016 Project funding
127159 Picornavirus respiratoires: variabilité génomique et adaptation 01.01.2010 Project funding

Abstract

Rhinoviruses (RVs) and enteroviruses (EVs) are leading causes of infections in humans. Although closely related and classified within the Enterovirus genus of the Picornaviridae family, they are characterized by an important genetic variability, illustrated by the existence of more than 280 different types. New types and species, including viruses unable to grow in standard cell lines such as the recently described RV species C, are continuously identified thanks to the development of sophisticated molecular detection tools. This genetic diversity is paralleled by an important phenotypic diversity. RV infection is mostly restricted to the respiratory tract, whereas EVs can cause viremia, spread to multiple body sites, and have been associated with over 20 clinically recognized syndromes. The two most virulent EVs are poliovirus and enterovirus 71 (EV-71). Thanks to efforts in poliovirus eradication, wild-type poliovirus remains endemic only in few countries. In contrast, EV-71 is becoming an important threat for human health, causing major hand-foot-and-mouth diseases (HFMD), such as those recently reported in Asia-Pacific countries, which involved meningo-encephalitis complications and deaths. Besides these different in vivo pathogeneses, RVs and EVs display different in vitro phenotypes, such as optimal growth temperature, acid tolerance and cell tropism. However, some EVs exhibit specific respiratory tropism and thus have properties similar to RVs both in vivo and in vitro. The genomic features involved in these distinct phenotypes have not been elucidated yet. In our previous investigations (FNS grant N° 310030-127159), we aimed to explore the two main driving factors of Enterovirus diversity: mutations and recombination. We identified natural intraspecies recombinants, and showed, using reverse genetic tools, that 5’UTR interspecies exchanges lead to viable chimeras. We then analysed the ability of RVs and EVs to adapt according to time or site during infection in humans. Remarkably, we observed acquisition of neurotropism determinants in the course of a natural EV-71 disseminated infection. In the current proposal, we aim to further dissect the functional relevance of these neurotropism determinants in cell culture models and in vitro virus binding assays. We will also investigate whether the emergence of new phenotypes during EV-71 infections is a common process, by searching for similar virus modifications in Vietnamese children suffering from HFMD with severe neurological complications. Another important objective of this proposal is the identification of the genomic regions implicated in the differential sensitivity to temperature or acid conditions, as well as cell tropism observed during the growth of RVs (or respiratory EVs) and EVs. To address this objective, we will generate chimeras between EV types that belong to a common species, are highly genetically related but display distinct in vitro and in vivo phenotypes (e.g. EV-68 and -94), and assess their growth potential in cell cultures. Aside from these two main objectives, we will, in collaboration with the Epithelix company, develop and validate a standardized tissue culture system enabling growth of different RV types from species C, and compare virus growth in tissues isolated from patients suffering from different comorbidities. These studies will gain insights into these newly discovered and poorly characterized viruses. Finally, and as initiated in FNS grant N° 310030-127159, we will pursue the molecular characterization of respiratory RV and EV strains circulating in the population, potentially associated with specific diseases and/or representing unusual new variants.Taken together, these investigations address unanswered questions on the genetic determinants involved in specific EV and RV pathogenic features. This research area is essential in the perspective of development of antivirals and/or vaccine against these highly common infectious agents.
-