SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

Meng, B.; Datir, R.; Choi, J.; Baker, S.; Dougan, G.; Hess, C.; Kingston, N.; Lehner, P. J.; Lyons, P. A.; Matheson, N. J.; Owehand, W. H.; Saunders, C.; Summers, C.; Thaventhiran, J. E. D.; Toshner, M.; Weekes, M. P.; Maxwell, P.; Shaw, A.; Bucke, A.; Calder, J.; Canna, L.; Domingo, J.; Elmer, A.; Fuller, S.; Harris, J.; Hewitt, S.; Kennet, J.; Jose, S.; Kourampa, J.; Meadows, A.; O'Brien, C.; Price, J.; Publico, C.; Rastall, R.; Ribeiro, C.; Rowlands, J.; Ruffolo, V.; Tordesillas, H.; Bullman, B.; Dunmore, B. J.; Fawke, S.; Graf, S.; Hodgson, J.; Huang, C.; Hunter, K.; Jones, E.; Legchenko, E.; Matara, C.; Martin, J.; Mescia, F.; O'Donnell, C.; Pointon, L.; Shih, J.; Sutcliffe, R.; Tilly, T.; Treacy, C.; Tong, Z.; Wood, J.; Wylot, M.; Betancourt, A.; Bower, G.; Cossetti, C.; De Sa, A.; Epping, M.; Gleadall, N.; Grenfell, R.; Hinch, A.; Jackson, S.; Jarvis, I.; Krishna, B.; Nice, F.; Omarjee, O.; Perera, M.; Potts, M.; Richoz, N.; Romashova, V.; Stefanucci, L.; Strezlecki, M.; Turner, L.; De Bie, E. M. D. D.; Bunclark, K.; Josipovic, M.; Mackay, M.; Allison, J.; Butcher, H.; Caputo, D.; Clapham-Riley, D.; Dewhurst, E.; Furlong, A.; Graves, B.; Gray, J.; Ivers, T.; Le Gresley, E.; Linger, R.; Meloy, S.; Muldoon, F.; Ovington, N.; Papadia, S.; Phelan, I.; Stark, H.; Stirrups, K. E.; Townsend, P.; Walker, N.; Webster, J.; Scholtes, I.; Hein, S.; King, R.; Bradley, J. R.; Smith, K. G. C.; Lee, J. H.; Gupta, R. K.

doi:10.1016/j.celrep.2022.111220

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.