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Effect of P681H spike mutation in SARS-CoV-2 alpha variants




In a recent study published in Bio Rxiv*Preprint server, Researchers have demonstrated the relevance of the P681H spike (S) mutation in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) alpha variant.

STUDY: The P681H mutation in the spike glycoprotein bypasses IFITM restriction and is required for type I interferon resistance in SARS-CoV-2 alpha variants. Image Credit: Lightspring/Shutterstock
study: The P681H mutation in the spike glycoprotein bypasses IFITM restriction and is required for type I interferon resistance in SARS-CoV-2 alpha variantsImage Credit: Lightspring/Shutterstock


The emergence of novel predominant variants of concern (VOCs) of SARS-CoV-2 challenges the response to the global coronavirus disease 2019 (COVID-19) pandemic. In the first half of 2021, B.1.1.7, also known as an alpha version of SARS-CoV-2, first emerged across the United Kingdom (UK) and dominated North America and much of Europe.

Numerous studies have revealed that alpha is more contagious among people. glycoprotein There were two deletions and seven mutations, including the P681H mutation in the polybasic cleavage region, which may have improved S cleavage.

There is growing evidence that VOCs have evolved to evade the immune response in humans, and much attention has focused on mutations throughout the S protein that evade neutralizing antibody responses. Nonetheless, successful viral infection and replication relies on resistance to host non-specific immune responses.

About research

In this study, the authors demonstrated that the modified cleavage domain of SARS-CoV-2 VOCs with mutations in the furin cleavage site (FCS) could affect susceptibility to interferon-I (IFN-I) and IFN induction. I hypothesized that there is. transmembrane protein (IFITM).

The team distinguished the susceptibility of the entrance of the full-length S-pseudotyped lentiviral vector (PLV) of the SARS-CoV-2 VOC currently circulating near the IFITM protein. They generated the D614GΔCT mutant and evaluated the infectivity of these PLVs in A549-angiotensin-converting enzyme 2 (ACE2) cells compared to full-length D614GS as PLV, showing that deletion of the last 19 amino acids resulted in an IFITM phenotype. to see if it affects the The researchers examined her IFITM susceptibility to AlphaΔCT to determine whether ΔCT mutations were sufficient to overcome her IFITM2 resistance seen in the Alpha S protein.

The researchers aimed to confirm that PLV and native alphavirus behave similarly in IFITM-expressing cells. They investigated the theory put forward by others that alpha is more immune to the effects of IFNβ. and Delta mutants entered by the same pathway.

Additionally, scientists determined the importance of the P681H mutation in conferring IFNβ and IFITM resistance on alpha VOCs. Finally, they assessed whether reversion of the P681H mutation sensitized the alpha variant to her IFNβ and IFITM.


Our results showed that among SARS-CoV-2 alpha, gamma, beta, delta, omicron, and kappa variants, only alpha S is immune to IFITM restriction in A549-ACE2-IFITM cells. Furthermore, the team demonstrated that the ΔCT mutation, frequently used to increase the infectivity of SARS-CoV-2 PLV, masked by increasing her IFITM resistance to alpha PLV. Cathepsins reliance. Furthermore, they showed that reversing the P681H mutation abolished the alpha variant resistance of Calu-3 and A549-ACE2 cells to her IFNβ.

Researchers have shown that alpha S protein confers some resistance to the effects of IFNβ in human lung epithelial cells. This observation corresponds to her apparent enhancement of IFITM3-mediated infection and resistance to IFITM2-induced entry restriction. A major determinant of this was the change from proline to histidine at position 681 in S near the FCS, which the team had previously shown to modulate IFITM2 sensitivity.

Moreover, the P681H mutation in the alpha S protein was required for both context-dependent resistance to IFITM and resistance to IFN. Yet, reversion of the P681H mutation does not reduce the particle incorporation of cleaved S, even though it appears to confer an altered susceptibility to endosomal protease inhibition associated with increased cell surface entry. Implying downstream functions. This reasoning indicates that structural changes in S after cleavage altered the viral entry mechanism and, consequently, IFN susceptibility.

In sum, the study results highlight the dynamic properties of SARS CoV-2 S during adaptation to both adaptive and innate immunity across human populations.


The results of this study show that the SARS-CoV-2 alpha VOC is significantly more resistant to type 1 IFN than the parental Wuhan-like strain. This observation is associated with resistance to IFITM2, an antiviral protein that prevents virus entry into target cells, and its paralog IFITM3.

P681H modifies the SARS-CoV-2 cell entry pathway on the alpha S glycoprotein, reducing the virus’ dependence on endosomal proteases, in contrast to other SARS-CoV-2 VOCs. The team found that changing position 681 of the alpha S-containing virus back to proline was sufficient to restore IFITM2 and IFN sensitivity without diminishing furin-promoted S cleavage.

The authors suggest that mutations associated with the SARS-CoV-2 VOC, apart from conferring adaptive immune escape, may provide a replication or transmission advantage through adaptation to withstand non-specific host immune processes. concluded that it is possible.

*Important Notices

bioRxiv publishes non-peer-reviewed, preliminary scientific reports and should not be considered conclusive, to guide clinical practice/health-related actions, or to be treated as established information .




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