The M2 protein of live, attenuated influenza vaccine encodes a mutation that reduces replication in human nasal epithelial cells.
Identifieur interne : 000264 ( Main/Exploration ); précédent : 000263; suivant : 000265The M2 protein of live, attenuated influenza vaccine encodes a mutation that reduces replication in human nasal epithelial cells.
Auteurs : Nicholas Wohlgemuth [États-Unis] ; Yang Ye [États-Unis] ; Katherine J. Fenstermacher [États-Unis] ; Hsuan Liu [États-Unis] ; Andrew P. Lane [États-Unis] ; Andrew Pekosz [États-Unis]Source :
- Vaccine [ 1873-2518 ] ; 2017.
Descripteurs français
- KwdFr :
- Cellules cultivées, Cellules épithéliales (immunologie), Cellules épithéliales (virologie), Grippe humaine (), Génétique inverse, Humains, Locus génétiques, Mutation, Nez (immunologie), Nez (virologie), Phénotype, Protéines de la matrice virale (génétique), Protéines de la matrice virale (immunologie), Réplication de l'ADN (génétique), Réplication virale (génétique), Vaccins antigrippaux (administration et posologie), Vaccins antigrippaux (immunologie), Vaccins atténués (administration et posologie), Vaccins atténués (génétique), Vaccins atténués (immunologie), Virus de la grippe A (), Virus de la grippe A (génétique), Virus de la grippe A (immunologie).
- MESH :
- administration et posologie : Vaccins antigrippaux, Vaccins atténués.
- génétique : Protéines de la matrice virale, Réplication de l'ADN, Réplication virale, Vaccins atténués, Virus de la grippe A.
- immunologie : Cellules épithéliales, Nez, Protéines de la matrice virale, Vaccins antigrippaux, Vaccins atténués, Virus de la grippe A.
- virologie : Cellules épithéliales, Nez.
- Cellules cultivées, Grippe humaine, Génétique inverse, Humains, Locus génétiques, Mutation, Phénotype, Virus de la grippe A.
English descriptors
- KwdEn :
- Cells, Cultured, DNA Replication (genetics), Epithelial Cells (immunology), Epithelial Cells (virology), Genetic Loci, Humans, Influenza A virus (chemistry), Influenza A virus (genetics), Influenza A virus (immunology), Influenza Vaccines (administration & dosage), Influenza Vaccines (immunology), Influenza, Human (prevention & control), Mutation, Nose (immunology), Nose (virology), Phenotype, Reverse Genetics, Vaccines, Attenuated (administration & dosage), Vaccines, Attenuated (genetics), Vaccines, Attenuated (immunology), Viral Matrix Proteins (genetics), Viral Matrix Proteins (immunology), Virus Replication (genetics).
- MESH :
- chemical , administration & dosage : Influenza Vaccines, Vaccines, Attenuated.
- chemistry : Influenza A virus.
- genetics : DNA Replication, Influenza A virus, Vaccines, Attenuated, Viral Matrix Proteins, Virus Replication.
- immunology : Epithelial Cells, Influenza A virus, Influenza Vaccines, Nose, Vaccines, Attenuated, Viral Matrix Proteins.
- prevention & control : Influenza, Human.
- virology : Epithelial Cells, Nose.
- Cells, Cultured, Genetic Loci, Humans, Mutation, Phenotype, Reverse Genetics.
Abstract
The influenza A virus components of the live, attenuated influenza vaccine (LAIV) encode the HA and NA gene segments from a circulating virus strain and the remaining gene segments from the cold-adapted master donor virus, A/Ann Arbor/6/1960 (H2N2). The master donor virus imparts at least three phenotypes: temperature-sensitivity (ts), attenuation (att), and cold-adaption (ca). The genetic loci responsible for the att and ts phenotypes of LAIV were mapped to PB1, PB2, and NP by reverse genetics experiments using immortalized cell lines. However, some in vivo studies have demonstrated that the M segment, which acquired an alanine (Ala) to serine (Ser) mutation at M2 position 86 during cold adaption - a mutation found in no other influenza A virus strain - contributes to the att phenotype. Prior studies have shown this region of the M2 cytoplasmic tail to be critical for influenza virus replication. Using reverse genetics, we demonstrate that certain amino acid substitutions at M2 positions 83 and 86 alter the replication of influenza A/Udorn/307/72 (H3N2). Importantly, substitution of a Ser at M2 position 86 reduces A/Udorn/307/72 replication in differentiated primary human nasal epithelial cell (hNECs) cultures, but does not considerably affect replication in MDCK cells. When a Ser was substituted for Ala at M2 86 in LAIV, the virus replicated to higher titers and with faster kinetics in hNEC cultures, implicating this amino acid change as contributing to LAIV attenuation. Increased replication also resulted in increased production of IFN-λ. These data indicate the LAIV associated Ser mutation at M2 position 86 contributes to the att phenotype and is associated with a differential regulation of interferon in LAIV infection.
DOI: 10.1016/j.vaccine.2017.10.018
PubMed: 29079099
Affiliations:
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Le document en format XML
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Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</wicri:regionArea><wicri:noRegion>MD</wicri:noRegion></affiliation></author><author><name sortKey="Ye, Yang" sort="Ye, Yang" uniqKey="Ye Y" first="Yang" last="Ye">Yang Ye</name><affiliation wicri:level="1"><nlm:affiliation>W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</wicri:regionArea><wicri:noRegion>MD</wicri:noRegion></affiliation></author><author><name sortKey="Fenstermacher, Katherine J" sort="Fenstermacher, Katherine J" uniqKey="Fenstermacher K" first="Katherine J" last="Fenstermacher">Katherine J. Fenstermacher</name><affiliation wicri:level="1"><nlm:affiliation>W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>W. 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Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Environmental Health Sciences, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD</wicri:regionArea><wicri:noRegion>MD</wicri:noRegion></affiliation></author></analytic><series><title level="j">Vaccine</title><idno type="eISSN">1873-2518</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cells, Cultured</term><term>DNA Replication (genetics)</term><term>Epithelial Cells (immunology)</term><term>Epithelial Cells (virology)</term><term>Genetic Loci</term><term>Humans</term><term>Influenza A virus (chemistry)</term><term>Influenza A virus (genetics)</term><term>Influenza A virus (immunology)</term><term>Influenza Vaccines (administration & dosage)</term><term>Influenza Vaccines (immunology)</term><term>Influenza, Human (prevention & control)</term><term>Mutation</term><term>Nose (immunology)</term><term>Nose (virology)</term><term>Phenotype</term><term>Reverse Genetics</term><term>Vaccines, Attenuated (administration & dosage)</term><term>Vaccines, Attenuated (genetics)</term><term>Vaccines, Attenuated (immunology)</term><term>Viral Matrix Proteins (genetics)</term><term>Viral Matrix Proteins (immunology)</term><term>Virus Replication (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Cellules cultivées</term><term>Cellules épithéliales (immunologie)</term><term>Cellules épithéliales (virologie)</term><term>Grippe humaine ()</term><term>Génétique inverse</term><term>Humains</term><term>Locus génétiques</term><term>Mutation</term><term>Nez (immunologie)</term><term>Nez (virologie)</term><term>Phénotype</term><term>Protéines de la matrice virale (génétique)</term><term>Protéines de la matrice virale (immunologie)</term><term>Réplication de l'ADN (génétique)</term><term>Réplication virale (génétique)</term><term>Vaccins antigrippaux (administration et posologie)</term><term>Vaccins antigrippaux (immunologie)</term><term>Vaccins atténués (administration et posologie)</term><term>Vaccins atténués (génétique)</term><term>Vaccins atténués (immunologie)</term><term>Virus de la grippe A ()</term><term>Virus de la grippe A (génétique)</term><term>Virus de la grippe A (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Influenza Vaccines</term><term>Vaccines, Attenuated</term></keywords><keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Vaccins antigrippaux</term><term>Vaccins atténués</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>DNA Replication</term><term>Influenza A virus</term><term>Vaccines, Attenuated</term><term>Viral Matrix Proteins</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines de la matrice virale</term><term>Réplication de l'ADN</term><term>Réplication virale</term><term>Vaccins atténués</term><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Cellules épithéliales</term><term>Nez</term><term>Protéines de la matrice virale</term><term>Vaccins antigrippaux</term><term>Vaccins atténués</term><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Epithelial Cells</term><term>Influenza A virus</term><term>Influenza Vaccines</term><term>Nose</term><term>Vaccines, Attenuated</term><term>Viral Matrix Proteins</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Influenza, Human</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Cellules épithéliales</term><term>Nez</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Epithelial Cells</term><term>Nose</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cells, Cultured</term><term>Genetic Loci</term><term>Humans</term><term>Mutation</term><term>Phenotype</term><term>Reverse Genetics</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cellules cultivées</term><term>Grippe humaine</term><term>Génétique inverse</term><term>Humains</term><term>Locus génétiques</term><term>Mutation</term><term>Phénotype</term><term>Virus de la grippe A</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The influenza A virus components of the live, attenuated influenza vaccine (LAIV) encode the HA and NA gene segments from a circulating virus strain and the remaining gene segments from the cold-adapted master donor virus, A/Ann Arbor/6/1960 (H2N2). The master donor virus imparts at least three phenotypes: temperature-sensitivity (ts), attenuation (att), and cold-adaption (ca). The genetic loci responsible for the att and ts phenotypes of LAIV were mapped to PB1, PB2, and NP by reverse genetics experiments using immortalized cell lines. However, some in vivo studies have demonstrated that the M segment, which acquired an alanine (Ala) to serine (Ser) mutation at M2 position 86 during cold adaption - a mutation found in no other influenza A virus strain - contributes to the att phenotype. Prior studies have shown this region of the M2 cytoplasmic tail to be critical for influenza virus replication. Using reverse genetics, we demonstrate that certain amino acid substitutions at M2 positions 83 and 86 alter the replication of influenza A/Udorn/307/72 (H3N2). Importantly, substitution of a Ser at M2 position 86 reduces A/Udorn/307/72 replication in differentiated primary human nasal epithelial cell (hNECs) cultures, but does not considerably affect replication in MDCK cells. When a Ser was substituted for Ala at M2 86 in LAIV, the virus replicated to higher titers and with faster kinetics in hNEC cultures, implicating this amino acid change as contributing to LAIV attenuation. Increased replication also resulted in increased production of IFN-λ. These data indicate the LAIV associated Ser mutation at M2 position 86 contributes to the att phenotype and is associated with a differential regulation of interferon in LAIV infection.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Wohlgemuth, Nicholas" sort="Wohlgemuth, Nicholas" uniqKey="Wohlgemuth N" first="Nicholas" last="Wohlgemuth">Nicholas Wohlgemuth</name></noRegion><name sortKey="Fenstermacher, Katherine J" sort="Fenstermacher, Katherine J" uniqKey="Fenstermacher K" first="Katherine J" last="Fenstermacher">Katherine J. Fenstermacher</name><name sortKey="Lane, Andrew P" sort="Lane, Andrew P" uniqKey="Lane A" first="Andrew P" last="Lane">Andrew P. Lane</name><name sortKey="Liu, Hsuan" sort="Liu, Hsuan" uniqKey="Liu H" first="Hsuan" last="Liu">Hsuan Liu</name><name sortKey="Pekosz, Andrew" sort="Pekosz, Andrew" uniqKey="Pekosz A" first="Andrew" last="Pekosz">Andrew Pekosz</name><name sortKey="Ye, Yang" sort="Ye, Yang" uniqKey="Ye Y" first="Yang" last="Ye">Yang Ye</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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