tetano
Editor, Senior Moderator
Cell Rep
. 2022 Aug 3;111220.
doi: 10.1016/j.celrep.2022.111220. Online ahead of print.
SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity
Bo Meng[SUP] 1 [/SUP], Rawlings Datir[SUP] 2 [/SUP], Jinwook Choi[SUP] 3 [/SUP], CITIID-NIHR Bioresource COVID-19 Collaboration; John R Bradley[SUP] 4 [/SUP], Kenneth G C Smith[SUP] 2 [/SUP], Joo Hyeon Lee[SUP] 5 [/SUP], Ravindra K Gupta[SUP] 6 [/SUP]
Collaborators, Affiliations
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants of concern (VOCs). Here, we examine the contribution of the NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus. We find that the Delta NTD on a Kappa or wild-type (WT) background increases S1/S2 cleavage efficiency and virus entry, specifically in lung cells and airway organoids, through use of TMPRSS2. Delta exhibits increased cell-cell fusogenicity that could be conferred to WT and Kappa spikes by Delta NTD transfer. However, chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD do not show more efficient TMPRSS2 use or fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions in a spike context-dependent manner, and allosteric interactions may be lost when combining regions from more distantly related VOCs.
Keywords: CP: Microbiology; Delta; NTD; Omicron; Organoid; SARS-CoV-2; TMPRSS2; entry; fusogenicity; spike.
. 2022 Aug 3;111220.
doi: 10.1016/j.celrep.2022.111220. Online ahead of print.
SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity
Bo Meng[SUP] 1 [/SUP], Rawlings Datir[SUP] 2 [/SUP], Jinwook Choi[SUP] 3 [/SUP], CITIID-NIHR Bioresource COVID-19 Collaboration; John R Bradley[SUP] 4 [/SUP], Kenneth G C Smith[SUP] 2 [/SUP], Joo Hyeon Lee[SUP] 5 [/SUP], Ravindra K Gupta[SUP] 6 [/SUP]
Collaborators, Affiliations
- PMID: 35963244
- PMCID: PMC9346021
- DOI: 10.1016/j.celrep.2022.111220
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants of concern (VOCs). Here, we examine the contribution of the NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus. We find that the Delta NTD on a Kappa or wild-type (WT) background increases S1/S2 cleavage efficiency and virus entry, specifically in lung cells and airway organoids, through use of TMPRSS2. Delta exhibits increased cell-cell fusogenicity that could be conferred to WT and Kappa spikes by Delta NTD transfer. However, chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD do not show more efficient TMPRSS2 use or fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions in a spike context-dependent manner, and allosteric interactions may be lost when combining regions from more distantly related VOCs.
Keywords: CP: Microbiology; Delta; NTD; Omicron; Organoid; SARS-CoV-2; TMPRSS2; entry; fusogenicity; spike.