Article ; Online: Adaptive variations in SARS-CoV-2 spike proteins: effects on distinct virus-cell entry stages.
2023 Volume 14, Issue 4, Page(s) e0017123
Abstract: Evolved SARS-CoV-2 variants of concern (VOCs) spread through human populations in succession. Major virus variations are in the entry-facilitating viral spike (S) proteins; Omicron VOCs have 29-40 S mutations relative to ancestral D614G viruses. The ... ...
| Abstract | Evolved SARS-CoV-2 variants of concern (VOCs) spread through human populations in succession. Major virus variations are in the entry-facilitating viral spike (S) proteins; Omicron VOCs have 29-40 S mutations relative to ancestral D614G viruses. The impacts of this Omicron divergence on S protein structure, antigenicity, cell entry pathways, and pathogenicity have been extensively evaluated, yet gaps remain in correlating specific alterations with S protein functions. In this study, we compared the functions of ancestral D614G and Omicron VOCs using cell-free assays that can reveal differences in several distinct steps of the S-directed virus entry process. Relative to ancestral D614G, Omicron BA.1 S proteins were hypersensitized to receptor activation, to conversion into intermediate conformational states, and to membrane fusion-activating proteases. We identified mutations conferring these changes in S protein character by evaluating domain-exchanged D614G/Omicron recombinants in the cell-free assays. Each of the three functional alterations was mapped to specific S protein domains, with the recombinants providing insights on inter-domain interactions that fine-tune S-directed virus entry. Our results provide a structure-function atlas of the S protein variations that may promote the transmissibility and infectivity of current and future SARS-CoV-2 VOCs. IMPORTANCE Continuous SARS-CoV-2 adaptations generate increasingly transmissible variants. These succeeding variants show ever-increasing evasion of suppressive antibodies and host factors, as well as increasing invasion of susceptible host cells. Here, we evaluated the adaptations enhancing invasion. We used reductionist cell-free assays to compare the entry steps of ancestral (D614G) and Omicron (BA.1) variants. Relative to D614G, Omicron entry was distinguished by heightened responsiveness to entry-facilitating receptors and proteases and by enhanced formation of intermediate states that execute virus-cell membrane fusion. We found that these Omicron-specific characteristics arose from mutations in specific S protein domains and subdomains. The results reveal the inter-domain networks controlling S protein dynamics and efficiencies of entry steps, and they offer insights on the evolution of SARS-CoV-2 variants that arise and ultimately dominate infections worldwide. |
|---|---|
| MeSH term(s) | Humans ; COVID-19 ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics ; Virus Internalization ; Endopeptidases |
| Chemical Substances | spike protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Endopeptidases (EC 3.4.-) |
| Language | English |
| Publishing date | 2023-06-29 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 2557172-2 |
| ISSN | 2150-7511 ; 2161-2129 |
| ISSN (online) | 2150-7511 |
| ISSN | 2161-2129 |
| DOI | 10.1128/mbio.00171-23 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.