The virus that causes SARS, SARS-CoV, uses either of two host protease enzymes to break in: TMPRSS2 (pronounced ‘tempress two’) or cathepsin L. TMPRSS2 is the faster route in, but SARS-CoV often enters instead through an endosome — a lipid-surrounded bubble — which relies on cathepsin L. When virions enter cells by this route, however, antiviral proteins can trap them.

SARS-CoV-2 differs from SARS-CoV because it efficiently uses TMPRSS2, an enzyme found in high amounts on the outside of respiratory cells. First, TMPRSS2 cuts a site on the spike’s S2 subunit8. That cut exposes a run of hydrophobic amino acids that rapidly buries itself in the closest membrane — that of the host cell. Next, the extended spike folds back onto itself, like a zipper, forcing the viral and cell membranes to fuse.

The virus then ejects its genome directly into the cell. By invading in this spring-loaded manner, SARS-CoV-2 infects faster than SARS-CoV and avoids being trapped in endosomes, according to work published in April by Barclay and her colleagues at Imperial College London9.

The virus’s speedy entry using TMPRSS2 explains why the malaria drug chloroquine didn’t work in clinical trials as a COVID-19 treatment, despite early promising studies in the lab10. Those turned out to have used cells that rely exclusively on cathepsins for endosomal entry. “When the virus transmits and replicates in the human airway, it doesn’t use endosomes, so chloroquine, which is an endosomal disrupting drug, is not effective in real life,” says Barclay.

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Abstract
A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429), originally detected in California, carries spike glycoprotein mutations S13I in the signal peptide, W152C in the N-terminal domain (NTD), and L452R in the receptor-binding domain (RBD). Plasma from individuals vaccinated with a Wuhan-1 isolate-based mRNA vaccine or convalescent individuals exhibited neutralizing titers, which were reduced 2-3.5 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The L452R mutation reduced neutralizing activity of 14 out of 34 RBD-specific monoclonal antibodies (mAbs). The S13I and W152C mutations resulted in total loss of neutralization for 10 out of 10 NTD-specific mAbs since the NTD antigenic supersite was remodeled by a shift of the signal peptide cleavage site and formation of a new disulphide bond, as revealed by mass spectrometry and structural studies.

The incidence of the B.1.427/B.1.429 lineages is increasing rapidly
The SARS-CoV-2 B.1.427/B.1.429 variant was reported for the first time at the beginning of 2021 in California and as of May 2021 has been detected in 34 additional countries (41, 42). The two lineages B.1.427 and B.1.429 (belonging to clade 20C according to Nextstrain designation) share the same S mutations (S13I, and W152C in the NTD and L452R in the RBD), but harbor different mutations in other SARS-CoV-2 genes (42). Molecular clock analysis suggest that the progenitor of both lineages emerged in May 2020, diverging to give rise to the B.1.427 and B.1.429 lineages in June-July 2020 (42). The fast rise in the number of cases associated with the B.1.427/B.1.429 lineages led to their classification as a VOC by the US Center for Disease Control

These findings show that the three mutations present in the B1.427/B.1.429 S glycoprotein decrease the neutralizing activity of vaccine-elicited and infection-elicited Abs, suggesting that these lineage-defining residue substitutions are associated with immune evasion. However, these data also underscore the higher quality of Ab responses induced by vaccination compared to infection and their enhanced resilience to mutations found in VOC.

Collectively, these findings demonstrate that the S13I and W152C mutations found in the B.1.427/B.1.429 S variant are jointly responsible for escape from NTD-specific mAbs, due to deletion of the SARS-CoV-2 S two N-terminal residues and overall rearrangement of the NTD antigenic supersite. Our data support that the SARS-CoV-2 NTD evolved a compensatory mechanism to form an alternative disulfide bond and that mutations of the S signal peptide occur in vivo in a clinical setting to promote immune evasion. The SARS-CoV-2 B.1.427/B.1.429 S variant therefore relies on an indirect and unusual neutralization-escape strategy.