Project

Back to overview

Viral and host factors modulating rhinovirus and enterovirus disease severity

English title Viral and host factors modulating rhinovirus and enterovirus disease severity
Applicant Tapparel Vu Caroline
Number 166218
Funding scheme Project funding (Div. I-III)
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Experimental Microbiology
Start/End 01.04.2016 - 31.03.2019
Approved amount 474'000.00
Show all

Keywords (8)

rhinovirus; enterovirus; genotype; phenotype; neurotropism; virulence; respiratory; 3D tissue culture system

Lay Summary (French)

Lead
Les rhinovirus (RV) et entérovirus (EV) sont des causes majeures d’infections chez l’homme. Ces virus, classés dans le genre Entérovirus et la famille des Picornaviridae, sont très proches génétiquement mais présentent d’importantes différences phénotypiques. Les RV ont un tropisme limité aux voies respiratoires, sont sensibles à l’acidité et ont une température optimale de croissance de 33°C alors que les EV répliquent majoritairement dans le tractus gastro-intestinal, résistent à l’acidité et aux températures corporelles plus élevées. Ces derniers peuvent donc disséminer et ont été associés à plus de 20 maladies différentes dont les plus sévères sont les infections du système nerveux. Les déterminants de ces différentes pathogénèses ne sont pas encore élucidés.
Lay summary

Contenu et objectifs du travail de recherche :

  • Nous proposons d’investiguer les déterminants génétiques des phénotypes spécifiques aux RV et aux EV grâce à des chimères représentant des hybrides entre ces 2 types de virus. Nous allons comparer les sensibilités à l’acidité et à la température de ces chimères ainsi que leur tropisme dans des modèles de tissus 3D respiratoires et nerveux. Ceci permettra d’identifier les régions génomiques responsables des phénotypes propres aux RV et EV.
  • Nous avons mis en évidence deux mutations dans la protéine de capside de l’Entérovirus 71 (EV71), un important pathogène humain, et montré que ces mutations conféraient  un meilleur attachement et un avantage réplicatif dans des cellules neurales. Nous projetons d’étudier l’implication de ces mutations dans :

    - l’utilisation d’un récepteur spécifique aux cellules neurales

    - une capacité de croissance accrue dans des tissus nerveux

    - la composition protéique des particules virales

    Ceci nous permettra de mieux comprendre les déterminants du neurotropisme de l’EV71.

  • Nous allons comparer la pathogénèse de virus respiratoires dans des tissus 3D sains ou dérivés de patients avec co-morbidités. Nous allons également étudier les interactions de ces virus avec d’autres pathogènes respiratoires.
  • Nous allons caractériser des EV ou RV associés à des maladies sévères pour identifier des facteurs de virulence.

Contexte scientifique et social du projet de recherche

Cette recherche permettra d'améliorer la connaissance des déterminants génomiques associés à des traits phénotypiques tels que la virulence et le neurotropisme, ainsi que la manière dont les RV et EV interagissent avec leurs hôtes et avec d'autres agents pathogènes. Cette connaissance est essentielle dans le contexte du développement de médicaments et de vaccins contre ces virus.

Direct link to Lay Summary Last update: 05.04.2016

Responsible applicant and co-applicants

Employees

Publications

Collaboration

Group / person Country
Types of collaboration
Dr S. Constant/Epithelix Compagny SARL, Genève Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. K-H Krause/Departement of Pathology and Immunology; Medical Faculty; UNIGE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. L. Kaiser/Head of the Service of Infectious Diseases from the University Hospitals of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. E. Zdobnov/Department of Genetic, Medicine and Development, Medical Faculty, UNIGE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events



Self-organised

Title Date Place
Europic Meeting Les Diablerets 04.09.2016 Les Diablerets, Switzerland

Associated projects

Number Title Start Funding scheme
146151 Rhinovirus et entérovirus: déterminants génomiques et phénotypes associés 01.04.2013 Project funding (Div. I-III)
184777 Factors modulating rhinovirus and enterovirus pathogenicity 01.04.2019 Project funding (Div. I-III)
127159 Picornavirus respiratoires: variabilité génomique et adaptation 01.01.2010 Project funding (Div. I-III)

Abstract

Rhinoviruses (RVs) and enteroviruses (EVs) are important respiratory and neurotropic pathogens with a high prevalence in the human population. However, no vaccines (except against poliovirus [PV]) or antivirals are available. These viruses, classified in the Enterovirus genus in the Picornaviridae family, are closely related at the nucleotide level, but they present important differences in vitro and in vivo. RVs (and respiratory EVs) have a restricted respiratory tropism, are acid labile, and grow better at 33°C, the temperature of the upper respiratory tract. EVs grow better at 37°C, resist acidity, and replicate in the gastrointestinal tract from where they can disseminate and infect a wide range of different organs, including the central nervous system. The determinants of these different pathogeneses are not elucidated yet. Previously, we have studied the adaptation and evolution of these viruses by mutation and recombination. Our investigations highlighted that recombination in the polyprotein coding sequence gives rise to viable chimeras only if the parental genomes belong to the same species. Furthermore, we found that non-replicative RNA recombination is highly efficient in cell culture and represents a powerful tool to generate viral chimeras. We were also able to calculate mutation frequency during human acute and chronic infections. More importantly, we found out that a VP1 capsid mutation occurred in the course of a disseminated infection with EV-A71 - the most important neurotropic EV after PV - which provided the virus with increased neural cell tropism. More recently, we validated the use of artificially engineered respiratory epithelia and neural tissues as relevant model systems for the study of respiratory and neurotropic viruses, respectively. In this proposal we will use the results of our past investigations to address clinically relevant questions: First, we aim at identifying which viral functions present in EVs, but not in RVs (or respiratory EVs), confer the ability to resist the gastrointestinal acidic environment, replicate at high body temperature, and disseminate. Based on our RV recombination studies, we will generate chimeras between respiratory and typical EVs from the same species (EV-D68 and EV-D94) and assess their preferred growth temperature, acid lability, and cell tropism. We will compare the growth of the chimeras and the parental viruses in our validated respiratory and neural tissue systems. Second, we will try to elucidate how the identified EV-A71 capsid mutation leads to changes in viral tropism. Three approaches will be taken: i) we will analyze the binding of the EV-A71 virus, with or without the capsid mutation, in cell lines where the two derivatives present differential growth and knocked down for EV-A71 known receptors; ii) we will investigate the ability of the two variants to grow in engineered neural tissues and characterize the molecular and cellular events following the infection; iii) we will assess whether EV-A71 packs cellular proteins in its mature capsid and if the packed proteins differ in the presence of the capsid mutation in a cell-specific manner. Third, we will use human airway epithelia reconstituted from healthy subjects or subjects with co-morbidities to compare the in vitro pathogenesis of the most clinically relevant respiratory viruses, as well as the way RVs modulate viral and bacterial super-infections. This latter point will be achieved through simultaneous and successive infections with RVs and selected respiratory pathogens. For all these infections, the replication level, specific cell tropism, tissue toxicity, and cytokine/chemokine induction will be measured. Finally, we will characterize strains from RV and EV infections associated with diseases of unexpected severity to determine if they have specific virulence features. Taken together, these translational investigations will improve knowledge of the genomic determinants associated with specific phenotypic traits, such as virulence and neurotropism, as well as the way in which RVs and EVs interact with the host and with other pathogens. This knowledge is essential not only for optimal patient handling, but also in the context of drug and vaccine development.
-