tetano
Editor, Senior Moderator
Nat Commun
. 2023 Feb 28;14(1):1141.
doi: 10.1038/s41467-023-36754-z.
Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase
Sebenzile K Myeni[SUP] 1 [/SUP], Peter J Bredenbeek[SUP] 2 [/SUP], Robert C M Knaap[SUP] 2 [/SUP], Tim J Dalebout[SUP] 2 [/SUP], Shessy Torres Morales[SUP] 2 [/SUP], Igor A Sidorov[SUP] 2 [/SUP], Marissa E Linger[SUP] 2 [/SUP], Nadia Oreshkova[SUP] 2 [/SUP], Sophie van Zanen-Gerhardt[SUP] 3 [/SUP], Serge A L Zander[SUP] 3 [/SUP], Luis Enjuanes[SUP] 4 [/SUP], Isabel Sola[SUP] 4 [/SUP], Eric J Snijder[SUP] 2 [/SUP], Marjolein Kikkert[SUP] 5 [/SUP]
Affiliations
Abstract
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-CoV[SUB]MA[/SUB] 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-CoV[SUB]MA[/SUB] 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-CoV[SUB]MA[/SUB] 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.
. 2023 Feb 28;14(1):1141.
doi: 10.1038/s41467-023-36754-z.
Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase
Sebenzile K Myeni[SUP] 1 [/SUP], Peter J Bredenbeek[SUP] 2 [/SUP], Robert C M Knaap[SUP] 2 [/SUP], Tim J Dalebout[SUP] 2 [/SUP], Shessy Torres Morales[SUP] 2 [/SUP], Igor A Sidorov[SUP] 2 [/SUP], Marissa E Linger[SUP] 2 [/SUP], Nadia Oreshkova[SUP] 2 [/SUP], Sophie van Zanen-Gerhardt[SUP] 3 [/SUP], Serge A L Zander[SUP] 3 [/SUP], Luis Enjuanes[SUP] 4 [/SUP], Isabel Sola[SUP] 4 [/SUP], Eric J Snijder[SUP] 2 [/SUP], Marjolein Kikkert[SUP] 5 [/SUP]
Affiliations
- PMID: 36854765
- DOI: 10.1038/s41467-023-36754-z
Abstract
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-CoV[SUB]MA[/SUB] 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-CoV[SUB]MA[/SUB] 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-CoV[SUB]MA[/SUB] 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.