Scientists Warn That SARS-CoV-2 Spike Exhibits Extreme Plasticity And Will Continue To Adopt Shape-Shifting Strategies For Immunity Escape.

COVID-19 News: While some ‘experts’ have recently said that there is only up to a certain level to which the SARS-CoV-2 virus can evolve for immune escape and even for viral fitness, a latest study by scientist from Janssen Pharmaceuticals has revealed that the spike proteins of the SARS-CoV-2 virus exhibits extreme plasticity and is able to adopt a variety of never-ending shape-shifting strategies for immunity escape. The study findings have serious implications in terms of all the strategies that have been proposed with regards to ending the COVID-19 crisis including herd immunity, hybrid immunity and the current vaccine strategies etc.


 
The world has been grappling with the SARS-CoV-2 virus for several years now. This tenacious virus, the cause of COVID-19, continues to evolve and spread globally, posing a significant challenge to our collective health and wellbeing.
 
To better understand and combat this virus, researchers focused on its 'spike' protein. This protein, much like a key, allows the virus to unlock and invade our cells, causing infection. All currently approved vaccines target this 'spike' because it triggers our immune system to produce neutralizing antibodies, which can prevent the virus from infecting our cells.
 
However, SARS-CoV-2 has a cunning trick up its sleeve. It's capable of changing, or 'reshaping,' its spike protein, which can potentially render some of our current vaccines and immune therapies less effective.
 
The study team from Janssen Pharmaceuticals delved into spike proteins of the SARS-CoV-2 virus and explored how it manages to elude our immune defenses by reshaping its spike protein, with a focus on two specific virus isolates from Brazil and Peru.
 
SARS-CoV-2 has a component called the N-terminal domain (NTD) in its spike protein. It's an important region that our immune system recognizes and targets. However, researchers have noticed something unusual in the Brazilian and Peruvian isolates. These isolates possess unusually large deletions (missing parts) in the NTD. This remodeling of the NTD interferes with the binding of NTD-specific antibodies, which are crucial in neutralizing the virus.

Furthermore, one of the isolates exhibited a unique escape mechanism involving a shift in the spike protein's cleavage site, a spot where the protein is cut during its formation. This shift leads to a significant structural change, resulting in the loss of a disulfide-bridge, an important link in the protein structure.
 
Although these specific changes are rare, they have independently appeared in several other viral strains, suggesting that this might be a strategy the virus could utilize more broadly in the future. It highlights the remarkable adaptability or 'plasticity' of the virus, which could pave the way for it to evade our immune system as it continues spawn newer sub-lineages and spread.
 
The spike protein of SARS-CoV-2 is a complex structure. It's made up of different subunits and domains, each with a specific role in the virus's life cycle. Among these, the NTD has been identified as an 'immunodominant' domain. This means it's a prime target for our immune system and can bind to antibodies with high neutralizing and protective potential. Despite this, the exac t function of NTD and how it aids the virus remains unclear.
 
The Brazilian and Peruvian isolates, despite the significant deletions in the NTD, showed surprising resilience. The spike proteins in these isolates maintained their overall fold and function, including their ability to bind to human cells. However, the structural changes in the NTD led to a complete loss of antibody binding to the NTD supersite, a region considered vital for immune recognition.
 
The virus's ability to reshape its spike protein is not limited to these deletions. It can also modify its NTD supersite by shifting its signal peptide cleavage site, a process enabled by certain mutations. This strategy further underscores the virus's cunning ability to escape our immune response.
 
These mutations, along with the deletions, have been found in different geographical locations and various lineages of the virus. In fact, one such variant, B.1.640.2, recently emerged in Southern France, while another sub-lineage, BA.2.3.21, is spreading globally, initially seen in the Philippines and the United States, and now also present in Australia and several Southeast Asian countries.
 
Over the past few years, the NTD domain of the SARS-CoV-2 spike protein has been a hotspot for changes, specifically deletions. Interestingly, these deletions aren't random. They appear to cluster around specific sites in the NTD, suggesting some sort of strategic advantage for the virus.
 
The ability to delete portions of the NTD, combined with the ability to reshape the remaining portions, allows the virus to remodel its 'identity' - the NTD supersite. This remodeling essentially gives the virus a 'new face,' making it harder for our immune system to recognize and target it.
 
This sneaky strategy of reshaping the spike protein has evolved independently in multiple branches of the virus's family tree. This suggests that such a strategy could be a recurring theme in future variants of concern. Furthermore, the variability in the NTD's structure could play a role in optimizing the virus's function, increasing its ability to evade our immune system, and adapting to new hosts.
 
Indeed, this seems to be the case with the Omicron variant and its newer sub-lineages and recombinant variants and their sub-lineages, which shows signs of significant immune evasion as reported by various studies and COVID-19 News coverages.
 
It's plausible that future variants might use similar strategies, such as large deletions in the NTD and the reshaping of the spike protein. These changes are already evident in some of the later Delta and Omicron variants, which have become globally dominant.
 
The study findings concluded that the SARS-CoV-2 virus is a shapeshifter, continuously evolving to ensure its survival. Its plasticity is a testament to the tenacity of life, even at its most microscopic. As we continue to battle this pandemic, understanding these shifting strategies will be key in developing effective countermeasures and ultimately overcoming this global health challenge.
 
The study findings were published in the peer reviewed journal: PLOS Pathogens.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011308
 
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