Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase
© 2023. The Author(s)..
Coronaviruses express a papain-like protease (PLpro) that is required for replicase polyprotein maturation and also serves as a deubiquitinating enzyme (DUB). In this study, using a Middle East respiratory syndrome virus (MERS-CoV) PLpro modified virus in which the DUB is selectively inactivated, we show that the PLpro DUB is an important MERS-CoV interferon antagonist and virulence factor. Although the DUB-negative rMERS-CoVMA replicates robustly in the lungs of human dipeptidyl peptidase 4 knock-in (hDPP4 KI) mice, it does not cause clinical symptoms. Interestingly, a single intranasal vaccination with DUB-negative rMERS-CoVMA induces strong and sustained neutralizing antibody responses and sterilizing immunity after a lethal wt virus challenge. The survival of naïve animals also significantly increases when sera from animals vaccinated with the DUB-negative rMERS-CoVMA are passively transferred, prior to receiving a lethal virus dose. These data demonstrate that DUB-negative coronaviruses could be the basis of effective modified live attenuated vaccines.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 28. Feb., Seite 1141 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Myeni, Sebenzile K [VerfasserIn] |
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| Links: |
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| Themen: |
COVID-19 Vaccines |
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| Anmerkungen: |
Date Completed 02.03.2023 Date Revised 11.03.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-36754-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM353607908 |
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| 245 | 1 | 0 | |a Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase |
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| 520 | |a © 2023. The Author(s). | ||
| 520 | |a Coronaviruses express a papain-like protease (PLpro) that is required for replicase polyprotein maturation and also serves as a deubiquitinating enzyme (DUB). In this study, using a Middle East respiratory syndrome virus (MERS-CoV) PLpro modified virus in which the DUB is selectively inactivated, we show that the PLpro DUB is an important MERS-CoV interferon antagonist and virulence factor. Although the DUB-negative rMERS-CoVMA replicates robustly in the lungs of human dipeptidyl peptidase 4 knock-in (hDPP4 KI) mice, it does not cause clinical symptoms. Interestingly, a single intranasal vaccination with DUB-negative rMERS-CoVMA induces strong and sustained neutralizing antibody responses and sterilizing immunity after a lethal wt virus challenge. The survival of naïve animals also significantly increases when sera from animals vaccinated with the DUB-negative rMERS-CoVMA are passively transferred, prior to receiving a lethal virus dose. These data demonstrate that DUB-negative coronaviruses could be the basis of effective modified live attenuated vaccines | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a Deubiquitinating Enzymes |2 NLM | |
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| 700 | 1 | |a Bredenbeek, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Knaap, Robert C M |e verfasserin |4 aut | |
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| 700 | 1 | |a Morales, Shessy Torres |e verfasserin |4 aut | |
| 700 | 1 | |a Sidorov, Igor A |e verfasserin |4 aut | |
| 700 | 1 | |a Linger, Marissa E |e verfasserin |4 aut | |
| 700 | 1 | |a Oreshkova, Nadia |e verfasserin |4 aut | |
| 700 | 1 | |a van Zanen-Gerhardt, Sophie |e verfasserin |4 aut | |
| 700 | 1 | |a Zander, Serge A L |e verfasserin |4 aut | |
| 700 | 1 | |a Enjuanes, Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Sola, Isabel |e verfasserin |4 aut | |
| 700 | 1 | |a Snijder, Eric J |e verfasserin |4 aut | |
| 700 | 1 | |a Kikkert, Marjolein |e verfasserin |4 aut | |
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