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Reality Check Marker Profile picture
@RealCheckMarker
Jan 5 • 26 tweets • 10 min read • Read on X
Let's set the record straight on ORF8!
There's virologists venturing beyond their expertise, spewing wild nonsense about ORF8 in SARS-CoV w/o having a grasp of bacteria or ribosomes. Hold tight as we debunk JN.1 chaos and uncover SARS-CoV ribosome frameshifting.
#TEXTBOOKSARS Image
1/ The ribosomal frameshift mechanism in SARS-CoV is crucial for optimizing viral protein synthesis. 🦠🧬A flawed reproduction process allows SARS to produce mRNA viral proteins in specific ratios, enhancing its ability to replicate and propagate.
#BoxOfNails
2/ One consequence of ribosomal frameshifting in coronaviruses is the generation of mRNAs with long 3' untranslated regions (3'UTRs). These extended 3'UTRs can potentially trigger the host NMD (Nonsense-Mediated mRNA Decay) pathway. ⚙️🧬
en.wikipedia.org/wiki/Ribosomal…
3/ NMD is a cellular surveillance mechanism designed to degrade aberrant mRNAs and regulate gene expression. Even if there's no premature termination codon (PTC) in the initial reading frame, certain features like long 3'UTRs can signal NMD. 🕵️‍♂️🧬
en.wikipedia.org/wiki/Nonsense-…
4/ The engagement of NMD becomes significant as it can lead to the degradation of viral transcripts, impacting the virus-host interaction. The delicate balance between optimizing replication and evading host defences adds complexity to this viral strategy. 🦠 Image
5/ While ribosomal frameshifting is essential for SARS protein synthesis, it introduces a potential challenge.
SARS mRNAs with features resembling HOST NMD substrates.
The extended 3'UTR resulting from frameshifting may mimic signals that trigger NMD. 🔄🧬academic.oup.com/bib/article/22…
6/ Viruses like SARS-CoV need to carefully navigate this balance between efficient replication and avoiding host cell defence mechanisms. The interplay between viral strategies and host cellular responses shapes the dynamics of SARS reproduction process.
en.wikipedia.org/wiki/MRNA_surv…
7/ The ribosomal frameshift ability of SARS-CoV is somewhat unique in how viruses exploit host translation machinery for their own benefit. Frameshifting ensures the production of essential proteins, but its consequences involve potential NMD engagement. 🔄 Image
8/ Long 3'UTRs resulting from frameshifting in coronaviruses can act as signals for NMD. This pathway, originally a host defence mechanism, may inadvertently target viral transcripts, impacting the success of the viral life cycle. HCoV reproduction is that bad! ⚠️ Image
9/ In the absence of a PTC in the initial reading frame, the engagement of NMD highlights the complexity of host-virus interactions at the molecular level.
SARS strategy is to hijack the process and intertwine with cellular defense mechanisms. 🧩
ncbi.nlm.nih.gov/pmc/articles/P…
Image
10/ This delicate dance between viruses and host cells involves a flawed human NMD adaptation. Viruses evolve faster strategies like ribosomal frameshifting and humans have not evolved since we were kicked out of the Garden of Eden 15,000 yrs ago. 💃🕺🦠
11/ Coronaviruses (ALL OF THEM) optimized evading host defences due to flawed reproduction. The ribosomal frameshift mechanism in SARS-CoV exemplifies this challenge, introducing potential NMD susceptibility due to features like extended 3'UTRs. 🔄🛡️🧬
en.wikipedia.org/wiki/Coronavir…
12/ Understanding the interplay between ribosomal frameshifting and NMD provides insights into HCoV replication strategies. The intricate molecular dynamics shed light on how HCoVs manipulate human host cellular machinery for their benefit. 🔍🦠🧬
en.wikipedia.org/wiki/Nidoviral…
13/ The consequences of ribosomal frameshifting in HCoVs extend beyond protein synthesis. The resulting transcripts may inadvertently trigger NMD due to features like long 3'UTRs, adding a layer of complexity to SARS-host interactions. ⚙️🧬
en.wikipedia.org/wiki/3C-like_p…
14/ NMD serves as a quality control mechanism for mRNA, ensuring the degradation of aberrant transcripts. We knew decades ago SARS-CoV, utilized frameshifting to introduce a challenge as reproduction transcripts mimicking features of NMD targets. 🕵️‍♂️⚔️🧬
en.wikipedia.org/wiki/SARS-CoV-1
15/ The engagement of NMD in response to frameshifted transcripts represents a host defence mechanism. This intricate dance between viral strategies and human immune responses contributes to the outcomes of infections and the success of viral replication. 💃🦠🕺
16/ Viral subversion of NMD is not "novel" with SARS.
What was novel was the binding mechanism of NMD elimination of transcripts that harbour a PTC giving rise to an abundance of nonfunctional viral proteins and unbalanced truncated proteins (prions).
ncbi.nlm.nih.gov/pmc/articles/P…
17/ If the NMD are stressed from being triggered, then long structures (3’-UTRs), transcriptional errors, defective splicing, translational shifting and even PTCs - form the assortment of free-floating nonsense proteins. #BoxOfNails
gupea.ub.gu.se/handle/2077/74…
Image
18/ SARS-CoV is a master manipulator of hijacked human host cellular machinery. The scientific knowledge of bacterial reproduction such as genetic recombination & ribosomal frameshifting is essential but you won't get that education in high school or virology textbooks. Image
19/ The battle between viruses and host cells at the molecular level is a dynamic and complex process. Recent revelations indicate SARS-CoV has evolved to hijack gut microbiome bacteria in a bacteriophage fashion.
#HijackedChickenCoop

20/ In the world of viruses, bacteria and host cells, the dance continues. To be honest I'd rather eradicate SARS than study it. Nobody will ever convince me we need to sacrifice millions of kids so science advances our understanding of SARS while SARS continues to evolve. Image
21/ So what does ORF8 have to do with this?
OFR8 is the key to histone mimicry.

We've known SARS ORF8 encodes protein that uses histone mimicry to disrupt chromatic regulation during replication, leading to mitochondrial dysfunction.


Image
22/ ORF8-encoded histone mimicry disrupts chromatin regulation that enhances replication means SARS-infected epithelial cells are kept alive by ORF8 as viral sex slaves!
Great thread to explain the many complexities of ORF8 with far less cursing than me:

Image
23/ Often times I refer to ORF8 as the "Lizard's Tail" of SARS. Capable of adding nonsense to the mitochondria's ribosome translation to add immunity evasion/detection, where MHC I and IFN blocking are its primary functions. Image
24/ JN.1 rise can be explained by the Lizard's Tail.

We will continue to see the "Rise and Fall" of ORF8.
Come back and ping me in a year if I'm wrong.
25/ SARS viral replication ribosome frameshift reproduction method is a unique adaptation from ORF8.
This is unique to SARS-2003 & SARS-2019.
This SARS-CoV is not 'novel'.
If you're a virologist and have questions, DM me!
/fin

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More from @RealCheckMarker

Reality Check Marker Profile picture
Jan 5
🔬ELI5: Let's dive into why knowledge about bacteria🦠is super important for understanding how SARS-CoV behaves and grasping the mysteries of #LongCOVID.
#BoxOfNails
#HijackedChickenCoop
en.wikipedia.org/wiki/Bacterial…
1/10 🔬 Scientific Advancement: Our understanding of bacterial evolution has recently evolved. Previously attributed to genetic drift, recent research emphasizes the pivotal role of genetic recombination in shaping bacterial genomes. 🧬
@ejustin46 Image
@ejustin46 2/10 🔄 Genetic Recombination: It's not just mutations! Transformation, transduction, and conjugation are key players in bacterial evolution. These processes drive the exchange of genetic material, influencing adaptability.
#GeneticExchange
en.wikipedia.org/wiki/Genetic_r…
Read 13 tweets
Reality Check Marker Profile picture
Dec 30, 2023
“40% reduction of lies”

Is a 40x2/100 probability of lies.

How the public is being manipulated and deceived currently is a matter of mathematical ignorance.

Anything below “50% reduction” is numerically insignificant. Image
“new research does suggest it could lower the risk of #LongCOVID by around 25%”

This is an absolutely accurate statement about Paxlovid.

Paxlovid has a 25% efficacy rate of prevention of persistent SARS infection. It’s that bad. Image
“95% efficacy with a CI of blah blah blah”

Remember when you were getting pummelled with math in early 2021 about the vaccines ability to prevent severe illness and death?

I need you to remember why efficacy above 80% and “reduction above 80%” matters. Image
Read 5 tweets
Reality Check Marker Profile picture
Dec 28, 2023
@jungleswatcher @DogRiverSA @SolidEvidence Great question!
Yes, HCoV-OC43 is assumed to have evolved from bovine CoV infecting newly civilized primates drinking their unpasteurized milk 15-20,000 years ago. Likely was incredibly deadly during the acute phase for thousands of years but the GI infectivity never faded.
@jungleswatcher @DogRiverSA @SolidEvidence HCoV-OC43 is often suggested to not be able to mutate.

It's perfectly adapted to evade human immunity. It's not presented with immunity obstacles. Any significant CFR during the acute phase will result in self-eradication.
@jungleswatcher @DogRiverSA @SolidEvidence For example, MERS-CoV (camel flu) has a CFR only 30% but outbreaks have resulted in self-eradication since the 1980s.

However, MERS-CoV was not discovered until after the SARS-2003 outbreak. Prior to 2007, there was barely any PCR test to detect CoV infections around the globe.
Read 7 tweets
Reality Check Marker Profile picture
Dec 28, 2023
Mysterious pneumonia outbreaks are overwhelming pediatric hospitals with sick children all around the world.

Was it the Kool-AID or a respiratory viral infection? Of course, it was the Kool-AIDS!
@ClausErnst Schools which have eliminated all forms of Public Health precautions such as masks, testing and isolation are educating tomorrow's future generations to be future minimizers of "just a virus". Image
@ClausErnst "In the lab, COVID is a Level 3 biohazard (yellow fever, West Nile virus, tuberculosis).
In schools, it's no big deal.
I don't think you can reconcile those two statements."
- Colin Furness (infection control epidemiologist) Image
Read 10 tweets
Reality Check Marker Profile picture
Dec 26, 2023
How many studies of child neurological disorders and infant mortality are we going to ignore?

There’s no vaccine for toddlers or updated vaccines for kids >5 but your political leaders have bankrupt future generations banking on a SARS vaccine solution.
#AirborneAIDS
"In the lab, COVID is a Level 3 biohazard (yellow fever, West Nile virus, tuberculosis). In schools, it's no big deal. I don't think you can reconcile those two statements."
- Colin Furness (infection control epidemiologist) Image
"In the lab, COVID is a Level 3 biohazard (yellow fever, West Nile virus, tuberculosis). In schools, it's no big deal. I don't think you can reconcile those two statements."
- Colin Furness (infection control epidemiologist) Image
Read 9 tweets
Reality Check Marker Profile picture
Dec 26, 2023
@mrmickme @_PH___PH_ It’s a combination of several factors which is why each infection has different symptoms and health effects. Image
@mrmickme @_PH___PH_ I’d say “leaky gums” and oral hygiene are a crucial component that’s rarely mentioned. Seroconversion and lymphatic tract infections directly from the mouth are absolutely possible.
@mrmickme @_PH___PH_ Depending upon where the infection occurs, the nasal passages are more common to be the first infected by airborne pathogens. This innate immune response in the olfactory mucosa is critical for determining viral load and therefore severity.
Read 8 tweets

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