Since the first report of SARS-CoV-2 from Wuhan, back in December 2019, the pandemic has ravaged the world with ever-evolving different variants-with changing dominance patterns. Different variant of concerns (alpha, beta, gamma, delta and kappa) with corresponding spike mutations, rendering evasion of the immune system and making them varyingly resistant to different vaccines (1). Presently, the delta variant (B.1.617.2) has outcompeted the other variants of concern and is globally the most intimidatingly dominant one.
The furin cleavage of polybasic motif, 681PRRAR685/↓S imparts high infectivity and transmissibility to SARS-CoV-2 with the deletion of the motif showing attenuated pathogenesis in humanised ACE2 mice and hamster models (2). Interestingly, P681H/R mutation in the motif was found only in the highly transmissible variants of concern (B.1.1.7, B.1.617 and it’s allied siblings). The 681residue substitution to arginine (R in delta variant) from proline (R), makes it more basic and similar to classic furin cleavage sites, than to histidine (H in alpha variant). The ensuing increased basicity makes it more recognisable for furin to cleave the S protein.
The increased S protein cleavage in delta variants in comparison to alpha variants (and other variants), is known to account for enhanced viral replication and fusogenicity, which could contribute to heightened transmissibility and infectious nature of the variant (3,4). The side chain of R682 and R685 residues of spike protein (in infected pneumocytes) getting exposed on the surface, facilitates furin cleavage and further known to activate the scramblase TMEM16F, leading to cell fusion/syncytia formation and T cell exhaustion (5). In conjunction, TMEM16F promotes cell death by enabling phosphatidylserine (PS) exposure on outer leaflet of cells, which is used as a scaffold for coagulation factors, helping in thrombin generation for blood clotting phenomena (6).With GSDM-N terminal fragment known to have propensity for binding phospholipids (like PS) – to enhance it’s pore forming capacity (7), TMEM16F activation could lead to heightened cell death by GSDM-N involvement. The flipping of PS residue to outer leaflet of plasma membrane can activate the alternate complement system (8)- which can further be responsible for the hypercoagulability phenotype in COVID-19. Indeed, complement system has been shown to be activated in the disease too (9).
It is noteworthy to say – the apocalyptic surge in India observed during April/May in which a large population of patients reported of sudden lowered oxygenation status coupled with higher mortality, could be an aftermath of aberrant blood clottings, thrombus formations and cell death (ensuing in impaired alveolar gaseous exchange) due to enhanced furin cleavage (P681R) by B.1.617 variant. The sudden huge demand of oxygen cylinders and oxygen concentrators in the country made people direly helpless and clueless. The B.1.617 variant, first identified in India caused a mayhem with 4,00,000 new infections and 4,000 deaths per day in the month of April/May in India (2nd wave) reflecting a near partial collapse of health infrastructure system. The numbers might be under-represented too, with many childrens becoming orphans and many aging parents losing their children. The funeral pyres kept burning incessantly with corpses out-numbering the near and dear ones who come to bid adieu. People unable to find places for burning corpses made their own pyres or even let it go to the Ganges river. Yes indeed, the country was in total shambles, with the second wave targeting the young and middle aged population, in comparison to the aged population – who were vulnerable during the first wave. But what went wrong? The virus mutated to a more virulent strain and we underestimated it and dropped down our guards to allow large populated gatherings- Assembly elections, Kumbh Mela and unrestricted personal convocations. The outcome was dreadful with vaccine roll out not started in full swing with primarily the aged population receiving their doses- leaving the young and middle aged population vulnerable.
The delta variant is also much less potent to antibody neutralization in comparison to other variants, making it a more infectious candidate (10). Hence, enhanced furin cleavage by P681R mutation in delta variant could lead culmination of events like: enhanced viral replication, syncytia formation, cell death, blood coagulations coupled with evading neutralizing antibodies – making it the most transmissible variant. Equally, these events can well be responsible for the Indian catastrophic second wave, attributed to P681R mutation harbouring B.1.617 variant.
Ethical Approval and Consent to participate- Not applicable
Consent for publication-Yes
Availability of supporting data-Literature survey.
Competing interests-I don’t have any competing interests
Funding- The study hasn’t received any funding as yet
Authors’ contributions- Rahul conceptualized the study and wrote the manuscript.
Acknowledgement: Rahul is very grateful to Dr Katherine Fitzgerald and Dr Douglas Golenbock (UMass Chan Medical School) for the initial insightful discussions. Very thankful to Biorender for providing me the free version for making the artwork
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