A detailed comparison of the spike protein across six SARS-CoV-2 variants shows that Delta’s spike is especially good at membrane fusion, allowing the virus to get into cells quickly.
The Delta variant of SARS-CoV-2 has swept the planet, becoming the dominant variant within just a few months. A new study from Boston Children’s Hospital, published in Science, explains why Delta spreads so easily and infects people so quickly. It also suggests a more targeted strategy for developing next-generation COVID-19 vaccines and treatments.
Last spring, study leader Bing Chen, PhD, showed how several earlier SARS-CoV-2 variants (alpha, beta, G614) became more infectious than the original virus. Each variant acquired a genetic change that stabilized the spike protein on the virus’s surface, the protein on which current vaccines are based.
But the Delta variant, which emerged soon after, is the most infectious variant known to date. Chen and colleagues set out to understand why.
For SARS-CoV-2 to infect our cells, its spikes must first attach to a receptor called ACE2. The spikes then dramatically change shape, folding in on themselves. This jackknifing motion fuses the virus’s outer membrane with the membrane of our cells, allow the virus to gain entry, according to a press release from Children’s Hospital.
Using two kinds of cell-based assays, Chen and colleagues demonstrated that Delta’s spike protein is especially adept at membrane fusion. This allowed a simulated Delta virus to infect human cells much more quickly and efficiently than the other five SARS-CoV-2 variants. Delta had the advantage especially when cells had relatively low amounts of the ACE2 receptor.
The Delta variant’s spike proteins fused to cell membranes far more rapidly than those of the five other variants.
Chen and colleagues also investigated how mutations in the variants affect the spike protein’s structure. Using cryo-electron microscopy, which has resolution down to the atomic level, they imaged spike proteins from the Delta, Kappa, and Gamma variants, and compared them to spikes from the previously characterized G614, Alpha, and Beta variants.
All six variants showed changes in two key parts of the spike protein that our immune system recognizes: the receptor-binding domain (RBD), which binds to the ACE2 receptor, and the N-terminal domain (NTD). Mutations in either domain can make our neutralizing antibodies less able to bind to the spike and contain the virus.
