Why B.1.617 Variant Of SARS-CoV-2 Is Highly Transmissible Than Others? (Biology)

There are many variants of SARS-CoV-2, the virus which causes COVID-19, but why is B.1.617 variant of SARS-CoV-2 virus is highly transmissible among all others? Recent study done by Wendy Barclay and colleagues now answered this question. They provided experimental evidence that virus of the B.1.617 variant has enhanced spike (S) cleavage and this cleavage is enhanced by P681R monobasic mutant or by an enzyme furin. Their study recently appeared in bioRxiv.

Unlike SARS-CoV, the SARS-CoV-2 spike (S) protein contains a furin cleavage site at S1/S2 junction (as shown in figure above) that enhances SARS-CoV-2 replication in airway cells and contributes to virus pathogenicity and transmissibility. The Lineage B.1.617, also known as G/452R.V3, is one of the known variants of SARS-CoV-2, the virus that causes COVID-19. It was first identified in Maharashtra, India on 5 October 2020. As of May 2021, three sublineages/subvariants have been found. Despite its name, B.1.617.3 was the first sublineage of this variant to be detected, in October 2020 in India. This sublineage has remained relatively uncommon compared to the two other sublineages, B.1.617.1 and B.1.617.2, both of which were first detected in December 2020.

Now, Barclay and colleagues investigated whether the spike (S) protein of B.1.617 undergoes a higher degree of post translational cleavage at S1/S2 than previously circulating strains. In order to know, they isolated several B.1.617 lineage viruses (1 x B.1.617.1 and 2 x B.1.617.2) and compared their S1/S2 cleavage to that of a previously circulating strain of lineage B.1.238, which contains only D614G. They found that, B.1.617 lineage S proteins were all more highly cleaved (≥50% cleaved), with a higher proportion of cleaved S2 and a lower proportion of full-length S detectable than the control virus (~33% cleaved) (Figure 1 below).

Figure 1 – P681R results in enhanced furin cleavage of the SARS-CoV-2 B.1.617 spike protein: (left panel) Western blot analysis of spike cleavage of concentrated B.1.238 (D614G) and B.1.617 (P681R containing) SARS-CoV-2 isolates. Levels of nucleocapsid (N) protein shown as loading control. Right panel: Densitometry analysis of the western blot from part (b). Densitometry measured using J. Points indicate two technical repeats from the same concentrated virus stocks. © Barclay et al.

They also characterised which amino change in the B.1.617 S is responsible for its enhanced cleavage and suggested that P681R alone is responsible for the enhanced S cleavage seen in the B.1.617 lineages viruses.

They then performed assays to determine whether the optimised cleavage site found in the B.1.617 S enables better cleavage directly by furin (an enzyme that in humans is encoded by the FURIN gene). They showed that, P681R significantly enhanced the ability of furin to cleave the peptide confirming that the arginine substitution is responsible for the enhanced cleavage of the B.1.617 spike protein.

“The virus of the B.1.617 lineage has enhanced S cleavage, that enhanced processing of an expressed B.1.617 spike protein in cells is due to P681R, and that this mutation enables more efficient cleavage of a peptide mimetic of the B.1.617 S1/S2 cleavage site by recombinant furin.  Together, these data demonstrate viruses in this emerging lineage have enhanced S cleavage by furin which we hypothesise could be enhancing transmissibility and pathogenicity.”

Finally, they concluded that, enhanced S1/S2 cleavage seen in B.1.617 and B. 1.1.7, may be contributing to the enhanced transmissibility of these SARS-CoV-2 variants. As well as B.1.1.7 and B.1.617, several other emerging variants contain mutations in the furin cleavage site. They advise that these lineages be kept under close monitoring for any early evidence of more rapid transmission or higher pathogenesis.

Reference: Thomas P. Peacock, Carol M. Sheppard, Jonathan C. Brown, Niluka Goonawardane, Jie Zhou, Max Whiteley, PHE Virology Consortium, Thushan I. de Silva, Wendy S. Barclay, “The SARS-CoV-2 variants associated with infections in India, B.1.617, show enhanced spike cleavage by furin”, bioRxiv 2021.05.28.446163; doi: https://doi.org/10.1101/2021.05.28.446163

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