Coronavirus non-structural protein 1 is a major pathogenicity factor: implications for the rational design of coronavirus vaccines.
Identifieur interne : 003741 ( Main/Exploration ); précédent : 003740; suivant : 003742Coronavirus non-structural protein 1 is a major pathogenicity factor: implications for the rational design of coronavirus vaccines.
Auteurs : Roland Züst [Suisse] ; Luisa Cervantes-Barragán ; Thomas Kuri ; Gjon Blakqori ; Friedemann Weber ; Burkhard Ludewig ; Volker ThielSource :
- PLoS pathogens [ 1553-7374 ] ; 2007.
Descripteurs français
- KwdFr :
- ADN viral, Animaux, Cellules cultivées, Conception de médicament, Données de séquences moléculaires, Délétion de gène, Extinction de l'expression des gènes, Facteurs de virulence (immunologie), Foie (anatomopathologie), Foie (métabolisme), Foie (virologie), Humains, Hépatite virale animale (), Hépatite virale animale (immunologie), Interféron de type I (déficit), Interféron de type I (génétique), Modèles animaux de maladie humaine, Protéines recombinantes (immunologie), Protéines virales non structurales (génétique), Protéines virales non structurales (immunologie), Protéines virales non structurales (métabolisme), Réplication virale, Souris, Souris de lignée C57BL, Souris knockout, Séquence nucléotidique, Vaccins antiviraux (immunologie), Vaccins atténués (immunologie), Virus de l'hépatite murine (immunologie), Virus de l'hépatite murine (pathogénicité).
- MESH :
- anatomopathologie : Foie.
- déficit : Interféron de type I.
- génétique : Interféron de type I, Protéines virales non structurales.
- immunologie : Facteurs de virulence, Hépatite virale animale, Protéines recombinantes, Protéines virales non structurales, Vaccins antiviraux, Vaccins atténués, Virus de l'hépatite murine.
- métabolisme : Foie, Protéines virales non structurales.
- pathogénicité : Virus de l'hépatite murine.
- virologie : Foie.
- ADN viral, Animaux, Cellules cultivées, Conception de médicament, Données de séquences moléculaires, Délétion de gène, Extinction de l'expression des gènes, Humains, Hépatite virale animale, Modèles animaux de maladie humaine, Réplication virale, Souris, Souris de lignée C57BL, Souris knockout, Séquence nucléotidique.
English descriptors
- KwdEn :
- Animals, Base Sequence, Cells, Cultured, DNA, Viral, Disease Models, Animal, Drug Design, Gene Deletion, Gene Silencing, Hepatitis, Viral, Animal (immunology), Hepatitis, Viral, Animal (prevention & control), Humans, Interferon Type I (deficiency), Interferon Type I (genetics), Liver (metabolism), Liver (pathology), Liver (virology), Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Murine hepatitis virus (immunology), Murine hepatitis virus (pathogenicity), Recombinant Proteins (immunology), Vaccines, Attenuated (immunology), Viral Nonstructural Proteins (genetics), Viral Nonstructural Proteins (immunology), Viral Nonstructural Proteins (metabolism), Viral Vaccines (immunology), Virulence Factors (immunology), Virus Replication.
- MESH :
- chemical , deficiency : Interferon Type I.
- chemical , genetics : Interferon Type I, Viral Nonstructural Proteins.
- chemical , immunology : Recombinant Proteins, Vaccines, Attenuated, Viral Nonstructural Proteins, Viral Vaccines, Virulence Factors.
- chemical , metabolism : Viral Nonstructural Proteins.
- chemical : DNA, Viral.
- immunology : Hepatitis, Viral, Animal, Murine hepatitis virus.
- metabolism : Liver.
- pathogenicity : Murine hepatitis virus.
- pathology : Liver.
- prevention & control : Hepatitis, Viral, Animal.
- virology : Liver.
- Animals, Base Sequence, Cells, Cultured, Disease Models, Animal, Drug Design, Gene Deletion, Gene Silencing, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Virus Replication.
Abstract
Attenuated viral vaccines can be generated by targeting essential pathogenicity factors. We report here the rational design of an attenuated recombinant coronavirus vaccine based on a deletion in the coding sequence of the non-structural protein 1 (nsp1). In cell culture, nsp1 of mouse hepatitis virus (MHV), like its SARS-coronavirus homolog, strongly reduced cellular gene expression. The effect of nsp1 on MHV replication in vitro and in vivo was analyzed using a recombinant MHV encoding a deletion in the nsp1-coding sequence. The recombinant MHV nsp1 mutant grew normally in tissue culture, but was severely attenuated in vivo. Replication and spread of the nsp1 mutant virus was restored almost to wild-type levels in type I interferon (IFN) receptor-deficient mice, indicating that nsp1 interferes efficiently with the type I IFN system. Importantly, replication of nsp1 mutant virus in professional antigen-presenting cells such as conventional dendritic cells and macrophages, and induction of type I IFN in plasmacytoid dendritic cells, was not impaired. Furthermore, even low doses of nsp1 mutant MHV elicited potent cytotoxic T cell responses and protected mice against homologous and heterologous virus challenge. Taken together, the presented attenuation strategy provides a paradigm for the development of highly efficient coronavirus vaccines.
DOI: 10.1371/journal.ppat.0030109
PubMed: 17696607
Affiliations:
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Animal</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Foie</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Liver</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Base Sequence</term><term>Cells, Cultured</term><term>Disease Models, Animal</term><term>Drug Design</term><term>Gene Deletion</term><term>Gene Silencing</term><term>Humans</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Molecular Sequence Data</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>ADN viral</term><term>Animaux</term><term>Cellules cultivées</term><term>Conception de médicament</term><term>Données de séquences moléculaires</term><term>Délétion de gène</term><term>Extinction de l'expression des gènes</term><term>Humains</term><term>Hépatite virale animale</term><term>Modèles animaux de maladie humaine</term><term>Réplication virale</term><term>Souris</term><term>Souris de lignée C57BL</term><term>Souris knockout</term><term>Séquence nucléotidique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Attenuated viral vaccines can be generated by targeting essential pathogenicity factors. We report here the rational design of an attenuated recombinant coronavirus vaccine based on a deletion in the coding sequence of the non-structural protein 1 (nsp1). In cell culture, nsp1 of mouse hepatitis virus (MHV), like its SARS-coronavirus homolog, strongly reduced cellular gene expression. The effect of nsp1 on MHV replication in vitro and in vivo was analyzed using a recombinant MHV encoding a deletion in the nsp1-coding sequence. The recombinant MHV nsp1 mutant grew normally in tissue culture, but was severely attenuated in vivo. Replication and spread of the nsp1 mutant virus was restored almost to wild-type levels in type I interferon (IFN) receptor-deficient mice, indicating that nsp1 interferes efficiently with the type I IFN system. Importantly, replication of nsp1 mutant virus in professional antigen-presenting cells such as conventional dendritic cells and macrophages, and induction of type I IFN in plasmacytoid dendritic cells, was not impaired. Furthermore, even low doses of nsp1 mutant MHV elicited potent cytotoxic T cell responses and protected mice against homologous and heterologous virus challenge. Taken together, the presented attenuation strategy provides a paradigm for the development of highly efficient coronavirus vaccines.</div></front></TEI><affiliations><list><country><li>Suisse</li></country></list><tree><noCountry><name sortKey="Blakqori, Gjon" sort="Blakqori, Gjon" uniqKey="Blakqori G" first="Gjon" last="Blakqori">Gjon Blakqori</name><name sortKey="Cervantes Barragan, Luisa" sort="Cervantes Barragan, Luisa" uniqKey="Cervantes Barragan L" first="Luisa" last="Cervantes-Barragán">Luisa Cervantes-Barragán</name><name sortKey="Kuri, Thomas" sort="Kuri, Thomas" uniqKey="Kuri T" first="Thomas" last="Kuri">Thomas Kuri</name><name sortKey="Ludewig, Burkhard" sort="Ludewig, Burkhard" uniqKey="Ludewig B" first="Burkhard" last="Ludewig">Burkhard Ludewig</name><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name><name sortKey="Weber, Friedemann" sort="Weber, Friedemann" uniqKey="Weber F" first="Friedemann" last="Weber">Friedemann Weber</name></noCountry><country name="Suisse"><noRegion><name sortKey="Zust, Roland" sort="Zust, Roland" uniqKey="Zust R" first="Roland" last="Züst">Roland Züst</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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