BREAKING! Omicron Has Shifted To Using Cathepsins For Cell Entry Via Endosomal Fusion, Impacting Cellular Tropism And Pathogenesis!

We are no longer dealing with the respiratory disease-causing pathogen that debuted in late 2019 in Wuhan but rather the SARS-CoV-2 coronavirus has evolved into a new pathogen which we are referring to as Omicron variant that has done a complete biological about-face of shifting from gaining entry via cell surface fusion following proteolysis by TMPRSS2 to entry via endosomal fusion after activation by the endosomal proteases Cathepsin B or L.


 
This shift will render a lot of things that we come to know through past studies about the SARS-CoV-2 virus as absolute as the shift to using cathepsins instead of TMPRSS2 will cause a total change in cellular tropism and also pathogenesis.

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Yes, the new revelation corroborates that infections with the Omicron variant for the generally healthy populations will result initially in either mild or asymptomatic symptoms but the long-term health implications could be far more devastating!
 
Individuals should understand that there is a difference between the terms: lethality and virulence. In simple language, the Omicron variant might not be as lethal as the previous variants but it is definitely more virulent. It does not kill the human host fast but rather kills it slowly while destroying its cellular functions and pathways more intensely but again slowly!
 
South Africa will hopefully be the best ‘guinea pig farm’ for us to observe this, as despite having a surge that did not kill many, in coming months and years, we will see a whole load of long term heath issues arising, some fatal and the Long COVID or PASC (Post-Acute Sequelae of SARS-CoV-2 infection) burden on the public healthcare system is going to be phenomenal.
 
Scientists from the University of Glasgow Centre for Virus Research along with experts from the NHS Greater Glasgow & Clyde, University of Cambridge, Public Health Scotland. University of St Andrews and the London School of Hygiene and Tropical Medicine in a new study found that the Omicron variant has made a major switch in the cell entry mechanism.
 
The study findings were published as a preprint format and is currently being peer reviewed for publication into a well-known journal.
https://www.gla.ac.uk/media/Media_829360_smxx.pdf
 
https://www.gla.ac.uk/researchinstitutes/iii/cvr/engage/news/headline_829358_en.html
 
The study team found that the Omicron variant of the Sars-CoV-2 has undergone significant biological changes compared to older configurations of the virus, leading to not only the large immune resistance it is now established to have but even seemingly changing the way it infects cells.
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Importantly at the outset, these insights have an implication for the “pathogenesis (the way disease progresses) and clinical severity” of COVID-19 it causes, the clinical severity it exhibits seems to be milder but implications for long term health issues due to its change in pathogenesis is worrisome.
 
This changes however demonstrates the coronavirus’s ability to be very highly adaptive, which means it can still significantly change the way it spreads and sickens us in the future.
 
Lead researcher Dr Brian J. Willett from the MRC-University of Glasgow Centre for Virus Research told Thailand Medical News, “The Omicron variant represents a major change in biological function and antigenicity of Sars-CoV-2 virus… Moreover, our work demonstrates that Sars-CoV-2 exhibits high antigenic and functional plasticity; further fundamental shifts in transmission and disease should be anticipated.”
 
Already emerging data from various open access genomic surveillance platforms such as Nextstrain, GISAID and certain genomic data posted on Github is showing that the Omicron is still aggressively evolving and mutating. https://www.thailandmedical.news/news/warning-omicron-is-still-evolving-the-world-will-pay-dearly-for-assuming-it-is-mild-
 
So called ‘experts’ making claims that Omicron is the last variant or that the COVID-19 pandemic is going to end or that it will become endemic are literally clueless and ignorant and what is coming after Omicron in a matter of months is going to be far worse. https://www.thailandmedical.news/news/warning-sars-cov-2-surges-will-make-the-end-of-2021-far-worse-than-last-year-2022-marks-the-beginning-of-catastrophic-surges-that-will-peak-in-2024
 
The new study findings corroborate two findings that have been reported by several scientists in the last month ie that the variant is very resistant to antibodies from vaccinated people, and it is bad at infecting lung cells. The last factor is among reasons it may be leading to milder disease. https://www.thailandmedical.news/news/good-news-preliminary-unpublished-data-shows-that-omicron-might-not-affect-lungs-much,-rather-your-brains,-heart-and-other-organs-are-targets

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However, more importantly, the new study findings uncover a previously unknown insight into the mechanism by which it infects human cells.
 
Typically, coronaviruses have had two routes by which it does this.
One involves an enzyme called TMRRS2 among the several steps from the point the virus latches on to cells till it fuses with the target. Till now, all variants have favoured this route.
 
Alarmingly the Omicron, however, takes the other route, using enzymes called cathepsins among the many steps of the infection process.
 
The study team warns that the mechanistic difference has several implications.
 
Dr Willett said, “This biological about-face may impact transmission, cellular tropism and pathogenesis. In other words, it changes how it can transmit, which tissues it infects and how it grows in them, and the disease it leads to. We know it transmits faster, grows quickly in some parts of the respiratory systems but not the lungs, and leads to less severe symptoms initially but the long-term health implications are worrisome.”
 
One positive effect however of the mechanistic change is that the variant now no longer leads to the formation of syncitia, or giant cells at all. Even the variant that first spread around Wuhan, the epicenter of the pandemic, led to some syncitia while the Alpha and Delta variants were better at causing it, leading to more initial severe conditions and faster deaths in some cases.
 
The current study findings show that the Omicron is highly evolved to evade both natural and vaccine induced immunity and also highly adapted to disrupt the body’s immune system upon infection hence resulting in asymptomatic or mild symptoms for many, However the disruption and damage of the human host immune system has negative implications as it can make the host more susceptible to secondary or opportunistic infection or even diseases just like in the case of HIV and furthermore it can also it can enhance viral persistence.
 
Thailand Medical News would like to add that with a shift to using Cathepsins for viral entry, we can expect to see more neurological, cardiovascular and gastrointestinal issues in the long-term health implications.
 
It should be also noted that there are still studies underway that will also reveal the Omicron shifting away from the ACE2 receptors to other human host receptors including Dipeptidyl peptidase 4 or DDP4, CD147, Neuropilin‐1, alanyl aminopeptidase (ANPEP), glutamyl aminopeptidase (ENPEP) and angiotensin II receptor type 2 (AGTR2).The preprints for these should be out in a week’s time.
 
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For the latest Omicron Research, keep on logging to Thailand Medical News.
 
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Read Also : https://www.thailandmedical.news/news/breaking-study-alarmingly-shows-omicron-could-be-possibly-evolving-to-shift-its-focus-on-human-receptors-from-ace2-to-ddp-iv,-similar-to-mers