BREAKING NEWS! Study Confirms P681R Mutation Found On Delta Variant Has Special Infection Strategy And Can Evade Immunity Induced By Vaccination Or Natural Infection!
: Japanese scientists have conducted a new research in which the findings show that the B.1.617 lineage of the SARS-CoV-2 coronavirus that emerged in India has evolved a unique strategy to facilitate infection and evade the immunity induced by vaccination or natural infection.
Numerous mutations have been accumulated in the viral genome, and at least five variants of concerns (VOCs) have been considered as the hazardous SARS-CoV-2 variants to the human society.
The newly emerged VOC, the B.1.617.2 lineage (delta variant), closely associates with a huge COVID-19 surge in India in Spring 2021. However, its virological property remains unclear.
The study team shows that the B.1.617 variants are highly fusogenic and form prominent syncytia. Bioinformatic analyses reveal that the P681R mutation in the spike protein is highly conserved in this lineage. Although the P681R mutation decreases viral infectivity, this mutation confers the neutralizing antibody resistance. Notably, we demonstrate that the P681R mutation facilitates the furin-mediated spike cleavage and enhances and accelerates cell-cell fusion. Our data suggest that the P681R mutation is a hallmark characterizing the virological phenotype of this newest VOC, which may associate with viral pathogenicity.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.06.17.448820v1
Alarmingly, the SARS-CoV-2 virus, responsible for the COVID-19, continues to threaten global public health and the worldwide economy.
Detailed bioinformatic analysis revealed that the mutation P681R
is highly conserved in the viral spike protein of the B.1.617 lineage. The spike protein mediates the initial stage of the infection process when its receptor-binding domain (RBD) attaches to the host cell receptor angiotensin-converting enzyme 2 (ACE2).
The study team showed that the presence of P681R significantly enhanced the efficacy of viral fusion, promoted cell-to-cell infection, and was associated with the formation of prominent syncytia. Syncytia are multinucleated cells that arise through the fusion of uninuclear cells.
The team says that the P681R-mediated kinetics of viral fusion may not only contribute to immune escape but also more severe disease among individuals exposed to SARS-CoV-2.
Dr Kei Sato from the University of Tokyo told Thailand Medical News, “Our data suggest that the P681R mutation is a hallmark characterizing the virological phenotype of this newest variant of concern, which may be associated with viral pathogenicity.”
After the identification of the original SARS-CoV-2 virus in Wuhan, China in late December 2019, a new strain harboring the spike mutation D614G quickly became predominant due to its increased infectivity, fitness, and transmissibility.
Ever since then, numerous containing multiple mutations have emerged, at least five of which have been classified as variants of concern. These include the
B.1.1.7 lineage that emerged in the UK, the B.1.351 lineage that arose in South Africa, and the P.1 (Brazil), B.1.427/429 (United States), and B.1.617.2 (India) lineages.
Research has shown that B.1.1.7, B.1.351, P.1, and B.1.427/429 are differentially resistant to neutralizing antibodies (nAbs) derived from COVID-19 convalescents and vaccinees. Since the spike RBD is immunodominant, approximately 90% of the nAbs present in anti-SARS-CoV-2 sera target this domain.
Interestingly at the end of 2020, the emergence of B.1.617 in India was associated with a huge surge in COVID-19 prevalence, with the incidence of new SARS-CoV-2 infections peaking at 400,000 per day.
This dangerous lineage comprises three sublineages (B.1.617.1, B.1.617.2, and B.1.617.3) and sublineage B.1.617.2 has been categorized as the most recent variant of concern.
The Public Health England has suggested that B.1.617.2 may be associated with an increased risk of hospitalization, compared with the B.1.1.7 lineage.
A recent study also showed that the B.1.617.2 variant exhibits resistance to the nAbs elicited by vaccination.
Importantly, a unique mutation called the P681R mutation has been identified in the spike protein of the B.1.617 lineage that has not yet been identified in any other variants of concern.
Dr Sato added, “Because the P681R mutation is located in the proximity of the furin cleavage site (FCS) of the SARS-CoV-2 S protein, it is possible that this substitution affects viral replication dynamics and potentially determines the virological characteristics of the B.1.617 variants
The study team downloaded and analyzed 1,761,037 SARS-CoV-2 genomes from the Global Initiative on Sharing All Influenza Data (GISAID) database.
The team found that the P681R mutation was highly conserved in B.1.617 and was the most representative mutation (99.3%) in this lineage.
They conducted experiments using Vero cells infected with either B.1.617.1, B.1.617.2, or a D614G-bearing B.1.1 isolate.
The study team found that levels of viral RNA were 150 times lower following infection with B.1.617.1 and B.1.617.2, compared with B.1.1 infection.
Alarmingly however, infection with the B.1.617.1 and B.1.617.2 viruses formed syncytia that were 2.3 and 2.7 times larger, respectively, than those formed following B.1.1 infection.
The study team says the findings show that the B.1.617 lineages form syncytia and favor cell-to-cell infection, compared with the D614G-containing B.1.1 virus.
The team also said that the presence of P681R significantly increased spike cleavage.
The western blotting of HIV-1-based pseudoviruses carrying the P681R mutation revealed that the presence of P681R significantly increased cleavage of subunit 2 of the SARS-CoV-2 spike protein, suggesting that the mutation facilitates furin-mediated spike cleavage.
In addition, neutralizing assays of sera obtained from vaccinees who received two doses of the Pfizer BioNTech COVID-19 vaccine revealed that a D614G/P681R pseudovirus was significantly more resistant to vaccine-induced nAbs than a D614G pseudovirus.
Dr Sato further added, “Although the P681R mutation is not located in the RBD of the SARS-CoV-2 spike protein, it rendered resistance to nAbs targeting the RBD.”
The study team also says the study findings suggest that the B.1.617 lineage has acquired a unique strategy to facilitate infection and evade antiviral immunity.
The study findings show that the P681R mutation enhances the cleavage of SARS-CoV-2 spike, enhances viral fusion, and promotes cell-to-cell infection.
The study team warns, “Switching of the viral infection mode by the P681R mutation may be associated with the severity of viral infection. SARS-CoV-2 variants harboring the P681R mutation should therefore be surveyed in-depth.”
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