Project

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Picornavirus respiratoires: variabilité génomique et adaptation

English title Respiratory picornaviruses: genomic variability and adaptation
Applicant Tapparel Vu Caroline
Number 127159
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 Medical Microbiology
Start/End 01.01.2010 - 31.12.2012
Approved amount 331'000.00
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Keywords (11)

rhinovirus; respiratory enterovirus; adaptation; innate immunity; reverse genetics; enterovirus; variants; genotype; phenotype; adaptations; epidemiology

Lay Summary (English)

Lead
Lay summary
Human rhinoviruses (HRV) and enteroviruses (HEV) are the most frequent causes of respiratory infections. These viruses are characterized by a huge diversity and frequent discovery of new strains such as the HRV-C lineage identified recently.HRVs and HEVs share identical genome organization. However significant phenotypic characteristics differentiate them. In vivo, rhinoviruses are restricted to the respiratory tract, whereas enteroviruses infect the gastrointestinal tract and can spread to other sites such as the central nervous system. In vitro, HRVs and HEVs differ by their optimal growth temperature, acid tolerance and cell tropism. Our previous investigations revealed that some HRVs are more related to enteroviruses than to other HRV at the genome level, which is surprising given the different phenotypes. The basis underlying these contradictory observations is not fully understood. Our goals is to define the genomic regions supporting these differences. Using representative rhino- and enteroviral strains with distinct phenotypes, we will characterize features such as temperature, acid sensitivity, and interferon induction/sensitivity. We also plan to construct an HRV-C infectious clone to characterize this newly discovered virus.This part of the project will be complemented by a molecular epidemiology survey of circulating rhino- and enteroviruses. This approach has allowed us to identify an previously unknown enterovirus genotype (EV104) adapted to the respiratory tract. We plan to genotype circulating strains, to assess the incidence of EV104 and to identify other new variants. Through different collaborations, we have access to specimens collected from transplant recipients chronically infected with rhinoviruses. We will sequence the genomes of such samples collected at different times and from different sites to study in-host adaptation. We will then compare viral adaptation in immunocompromised versus immunocompetent patients. Comparison with viral adaptation under in vitro conditions, such as cell cultures, will also be performed. These investigations will shed some light on the diversity of HRV and HEV genomes and could highlight key features shaping the phenotypes of these viruses. This is of importance since HRVs and HEVs have a high propensity to mutate and could generate new genotypes with phenotypes of unexpected severity. A better understanding of the regions defining phenotypic features and of those implicated in viral adaptation may help to anticipate the phenotype of new variants and to develop antivirals targeting areas less prone to generate resistant mutants.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Family outbreak of an infection with a recombinant Coxsackie A virus in eastern Switzerland
Butsch R., Tapparel C., Keller P., Herzog K., Krause M., Wunderli W., Kaiser L., Bossart W. (2013), Family outbreak of an infection with a recombinant Coxsackie A virus in eastern Switzerland, in INFECTION, 41(1), 231-235.
Critical analysis of rhinovirus RNA load quantification by real-time reverse transcription-PCR.
Schibler Manuel, Yerly Sabine, Vieille Gaël, Docquier Mylène, Turin Lara, Kaiser Laurent, Tapparel Caroline (2012), Critical analysis of rhinovirus RNA load quantification by real-time reverse transcription-PCR., in Journal of clinical microbiology, 50(9), 2868-72.
Experimental human rhinovirus and enterovirus interspecies recombination.
Schibler Manuel, Gerlach Daniel, Martinez Yannick, Belle Sandra Van, Turin Lara, Kaiser Laurent, Tapparel Caroline (2012), Experimental human rhinovirus and enterovirus interspecies recombination., in The Journal of general virology, 93(Pt 1), 93-101.
High Rhinovirus Burden in Lower Airways of Children With Cystic Fibrosis
Kieninger Elisabeth, Singer Florian, Tapparel Caroline, Alves Marco P., Latzin Philipp, Tan Hui-Leng, Bossley Cara, Casaulta Carmen, Bush Andrew, Davies Jane C., Kaiser Laurent, Regamey Nicolas (2012), High Rhinovirus Burden in Lower Airways of Children With Cystic Fibrosis, in CHEST, 143(3), 782-790.
Identification of site-specific adaptations conferring increased neural cell tropism during human enterovirus 71 infection.
Cordey Samuel, Petty Tom J, Schibler Manuel, Martinez Yannick, Gerlach Daniel, van Belle Sandra, Turin Lara, Zdobnov Evgeny, Kaiser Laurent, Tapparel Caroline (2012), Identification of site-specific adaptations conferring increased neural cell tropism during human enterovirus 71 infection., in PLoS pathogens, 8(7), 1002826-1002826.
Picornavirus and enterovirus diversity with associated human diseases.
Tapparel Caroline, Siegrist Fredy, Petty Tom J, Kaiser Laurent (2012), Picornavirus and enterovirus diversity with associated human diseases., in Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in i, epub-epub.
Astrovirus infection in hospitalized infants with severe combined immunodeficiency after allogeneic hematopoietic stem cell transplantation.
Wunderli Werner, Meerbach Astrid, Güngör Tayfun, Guengoer Tayfun, Berger Christoph, Greiner Oliver, Caduff Rosmarie, Trkola Alexandra, Bossart Walter, Gerlach Daniel, Schibler Manuel, Cordey Samuel, McKee Thomas Alexander, Van Belle Sandra, Kaiser Laurent, Tapparel Caroline (2011), Astrovirus infection in hospitalized infants with severe combined immunodeficiency after allogeneic hematopoietic stem cell transplantation., in PloS one, 6(11), 27483-27483.
Rhinovirus genome variation during chronic upper and lower respiratory tract infections.
Tapparel Caroline, Cordey Samuel, Junier Thomas, Farinelli Laurent, Van Belle Sandra, Soccal Paola M, Aubert John-David, Zdobnov Evgeny, Kaiser Laurent (2011), Rhinovirus genome variation during chronic upper and lower respiratory tract infections., in PloS one, 6(6), 21163-21163.
T lymphocytes promote the antiviral and inflammatory responses of airway epithelial cells.
Jornot Lan, Cordey Samuel, Caruso Assunta, Gerber Christine, Vukicevic Marija, Tapparel Caroline, Kaiser Laurent, Burger Danielle, Roosnek Eddy, Lacroix Jean Silvain, Rochat Thierry (2011), T lymphocytes promote the antiviral and inflammatory responses of airway epithelial cells., in PloS one, 6(10), 26293-26293.
Proposals for the classification of human rhinovirus species C into genotypically assigned types.
Simmonds Peter, McIntyre Chloe, Savolainen-Kopra Carita, Tapparel Caroline, Mackay Ian M, Hovi Tapani (2010), Proposals for the classification of human rhinovirus species C into genotypically assigned types., in The Journal of general virology, 91(Pt 10), 2409-19.
Rhinovirus genome evolution during experimental human infection.
Cordey Samuel, Junier Thomas, Gerlach Daniel, Gobbini Francesca, Farinelli Laurent, Zdobnov Evgeny M, Winther Birgit, Tapparel Caroline, Kaiser Laurent (2010), Rhinovirus genome evolution during experimental human infection., in PloS one, 5(5), 10588-10588.
Upper and lower respiratory tract viral infections and acute graft rejection in lung transplant recipients.
Soccal P M, Aubert J-D, Bridevaux P-O, Garbino J, Thomas Y, Rochat T, Rochat T S, Meylan P, Tapparel C, Kaiser L (2010), Upper and lower respiratory tract viral infections and acute graft rejection in lung transplant recipients., in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 51(2), 163-70.

Collaboration

Group / person Country
Types of collaboration
Université de Genève, Département de pathologie et immunologie Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Fasteris SA Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
University of Queensland Australia (Oceania)
- Publication
National Institute for Health and Welfare Finland (Europe)
- Publication
University of Edinburgh Great Britain and Northern Ireland (Europe)
- Publication
Institut Suisse de Bioinformatique et Université de Genève Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Université de Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Hôpitaux universitaires de Lausanne Switzerland (Europe)
- Publication
University of Virginia United States of America (North America)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
3rd Swiss Workshop in Fundamental Virology Talk given at a conference Rhinovirus Genome Evolution during Human Infections 03.06.2012 Thun, Switzerland Tapparel Vu Caroline;
Europic 2012 Talk given at a conference Identification of site-specific adaptations conferring increased neural cell tropism during human enterovirus 71 infection 03.06.2012 St-Raphaël, France Kaiser Laurent; Tapparel Vu Caroline;
Europic 2010 Talk given at a conference Rhinovirus genome evolution in immunocompromised hosts with chronic upper and lower respiratory tract infections 11.09.2010 Genève, Great Britain and Northern Ireland Tapparel Vu Caroline;


Associated projects

Number Title Start Funding scheme
184777 Factors modulating rhinovirus and enterovirus pathogenicity 01.04.2019 Project funding
166218 Viral and host factors modulating rhinovirus and enterovirus disease severity 01.04.2016 Project funding
146151 Rhinovirus et entérovirus: déterminants génomiques et phénotypes associés 01.04.2013 Project funding
113426 Rhinoviruses associated with lower respiratory diseases: genetic variability and replications site 01.01.2007 Project funding

Abstract

Human rhinoviruses (HRV) and enteroviruses (HEV) are the most frequent causes of respiratory infections. These two picornaviruses are characterized by the existence of approximately 100 serotypes, but their diversity expands well beyond these predefined serotypes and encompasses also previously unrecognized genotypes. As an example, a new HRV lineage named HRV-C was recently identified.HRVs and HEVs share an identical genome organization, have similar functional RNA secondary structures, and are classified within the same genus because of their high sequence homology. Despite their common genomic features, significant phenotypic characteristics differentiate these two groups of viruses. In vivo, rhinoviruses are restricted to the respiratory tract, whereas enteroviruses infect primarily the gastrointestinal tract and can spread to other sites such as the central nervous system. In vitro, most HRVs and HEVs differ by their optimal growth temperature, acid tolerance, receptor usage and cell tropism. In addition, some HRV and HEV serotypes cannot be grown in cell culture. Our previous investigations revealed that HRV-B are more related to enteroviruses than to HRV-A at the global genome level, which is surprising given the different phenotypes. The genomic basis underlying these different and apparently contradictory observations is not yet fully understood. One of our goals is to define more precisely the genomic regions supporting these differences. Using a panel of representative rhino- and enteroviral strains with distinct phenotypes, we will first characterize features such as temperature and acid sensitivity, as well as interferon induction/sensitivity. The latter assessment may explain why some strains can be isolated in cell culture whereas others cannot, such as the HRV-C viruses. We plan to construct an infectious clone from an HRV-C strain to better characterize its replicative ability in vitro including its interferon susceptibility and, potentially, to determine its receptor usage.This part of the project will be complemented by a molecular epidemiology survey of circulating rhino- and enteroviruses using strains routinely identified in our clinical laboratory or within cohort studies conducted by our group. This approach has allowed us to identify a previously unknown enterovirus genotype (EV104) adapted to the respiratory tract. We plan to conduct this systematic genotyping of circulating strains over several years, first to assess the incidence of this newly discovered EV104, and second to identify other potential new variants. Through different established collaborations, we have access to precious samples such as specimens collected from transplant recipients chronically infected with rhinoviruses. Whenever possible, we will systematically complete the genomes of such samples collected at different times and from different sites to study in-host genome adaptation. We will then compare viral adaptation in immunocompromised patients versus immunocompetent volunteers experimentally infected with HRVs. Comparison with viral adaptation under in vitro conditions, such as cell cultures, will also be performed. Taken together, these investigations will shed some light on the diversity of HRV and HEV genomes and could highlight the key genomic features shaping the phenotypes of these viruses. This is likely of importance since HRVs and HEVs have a high propensity to mutate and could thus generate new genotypes with phenotypes of unexpected severity. A better understanding of the regions defining phenotypic features and of those implicated in viral adaptation may help first to anticipate the phenotype of new variants and second, to develop potent antivirals targeting areas less prone to generate resistant mutants.
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