Susan Weiss writes:
I just listened to TWIV 688 and have some comments
PLP or PLpro
Trivial fact- MHV actually has two PLPs (as we called them then)
The nsp3 protease and deubiquitinase (DUB) are activities that can be separated, at least for MHV. Susan Baker had a paper on this last year (Deng et al J,Virol). This is important because in the paper you talked about if they mutated the protease and the DUB how can they separate the effects of poor replication on innate immunity from those of the DUB? I would think inactivating the protease completely would be lethal .
More generally there are so many conserved host antagonist activities encoded in ORF1a/ORF1b (for example, ExoN, EndoU, nsp1, Macrodomain, capping enzymes). Then there are the accessory proteins that differ among the sublineages of Betacoronaviruses (SARS and SARS 2 are similar, MERS completely different as is MHV). These replicase proteins have sometimes overlapping activities and sometime additive activities with accessory proteins- for example in MERS, EndoU reduces dsRNA accumulation and NS4b protects dsRNA. In MHV both EndoU and NS2 phosphodiesterase must be active to prevent RNase L activation. These viruses are very clever and it is difficult to point to one activity as a major indicator of host antagonism . We have a paper in revision now where we found maybe surprisingly that SARS2 activates RNase L and PKR pathways while weakly including IFN; in contrast MERS completely shuts down all these pathways. We haven’t worked on SARS1 because it is a select agent and we do not have approval,
RE the RNA paper. IF these mRNAs are indeed in lipid bound vesicles, they should also have genome RNA in them. If you stain cells for genome and mRNA genome is near ER/DMVs but mRNA is cytoplasmic, presumable being translated. I would expect more genome than mRNAs. It is really too bad that they didn’t more broadly do some biological experiments. Remember too that in MHV we see RNA (genome and mRNA) persists in the brain in noninfectious form. Nobody has figured out how this happens.
All this gets back to protection of viral RNA from cytoplasmic sensors, a question far beyond CoVs. While viruses protect their RNAs during replication, some of it is sensed by MDA5, PKR, OAS etc., I don’t remember if you have discussed Eric Snijder’s paper showing that the DMVs (MHV I think) have channels so they are not completely closed and things can move in and out – although they don’t know what yet.
Keep up the great TWIVs
Susan
Rich writes:
Hi twivvers again!
A followup from my previously covered email…
This article illustrates the travel of the virus & droplets around rooms, looking at 3 case studies.
It mostly illustrates what I was getting at in my initial email to you.
But i guess we now think that ‘COVID-19 clouds’ or ‘COVID-19 fog’ might be likely, so amply fresh air purging the rooms will really help by diluting the droplets/virus in the air, reducing the likely dose others could receive in any given amount of time.
Thanks again for providing us with high specificity, very accurate and adjuvanted informational booster shots twice a week! The side effect: grumpiness, wears off quickly. Efficacy is proving to be exceptionally good!
Cheers,
Rich.
Still on our little island in Bali, where our very much outdoorsy lives and sea breeze might be helping us a bit! 29°C and mostly sunny. Tho wet season is looming up early it seems.
Bob writes:
Hello TWiV:
Thank-you for your amazing podcast. I have put many other podcasts on hold to give yours top priority!
Near the beginning of TWiV 687 with guest Peter Hotez, he and your team acknowledged several motives for various groups to be involved in anti-vax campaigns. Conspicuously missing among them, or from Peter’s recent related paper that was linked in the show notes, was actual vaccine injury, though you did touch on vaccine injury later in the show. The few people that I personally know that are anti-vaxxers claim to have experienced vaccine injury, including death of loved ones. They were not anti-vaxxers prior to the injury (or else, they wouldn’t have received the vaccine), but they are very strong voices, and their stories get tremendous traction in the movement(s).
In this kind of discussion, how can we especially make sure that those that are legitimately injured by vaccines are not thrown under the bus with all those sporting the nefarious motives you appropriately listed?
TWiV has acknowledged vaccine injury in previous episodes e.g. the Cutter Incident. I also recall Vincent stating in a previous podcast “I am not an anti-vaxxer” prior to listing some statistics for vaccine injury, such as the historical death rate due to smallpox. So let me also say that I am not an anti-vaxxer: this year, on turning 60, I pursued and received 3 different vaccines.
A related question: Could you discuss in some more detail the AstraZeneca cases that caused the two pauses to their trial? So far on TWiV, you had briefly acknowledged that those conducting the trial had concluded that the incidents were not related to the vaccine, and you have also acknowledged the truth that trial participants can co-incidentally suffer from some disease unrelated to the vaccine they had received. But given Dr. Paul Offit’s comments at https://ca.reuters.com/article/idUSL1N2HB19Z, a deeper dive is warranted: “Transverse myelitis, which the study volunteer is believed to have developed, typically occurs at a rate of 1-in-200,000 people, Offit said, so it would be unusual to see it in a trial of 9,000 individuals.”
Those odds above are less than the typical p-value used for significance (0.05), but they are most especially so when the odds of appearing in a time frame close to the vaccine administration are taken into account. I have taken a crack at such a calculation that incorporates timing, and would be very interested in yours. When the process of how vaccines cause injury is not well understood, theoretical discussion about how the injury could or couldn’t happen should not trump statistically significant data. That is, an assumption that the event is related to the vaccine should be upheld. Besides the obvious prime compelling motive to prevent harm, safer vaccines are also a very important way to help keep the most powerful stories (the true ones) from joining the ranks of the anti-vaxxers, which would cause yet more harm.
I always look forward to your podcasts,
Bob
Drumbo, Ontario, Canada
Niall writes:
An application for Rich’s Chernobyl fungi
Hello again,
I thought you might get a kick out of this, i found i quite exciting:
Humans on the moon and Mars would face the problem of damaging space radiation.
But new research suggests one possible solution to the fact that “Space wants to kill you,” according to CNET:
To protect astronauts, scientists have been studying an unusually hardy organism, discovered in one of the most radioactive places on the planet: Chernobyl… In some parts of the plant, the level of radiation spiked so high that exposure would kill a human in about 60 seconds. But several species of fungi have been discovered in the reactor. And they’re thriving, “feeding” on the extreme levels of radiation. A new study, yet to undergo peer review, was published on the pre-print repository bioRxiv on July 17 and examines one of these species, Cladosporium sphaerospermum. It suggests the fungi could be used as a self-healing, self-replicating shield to protect astronauts in deep space…
Researchers placed the fungi aboard the ISS for 30 days and analyzed its ability to block radiation… The proof-of-concept study showed that the fungi were able to adapt to microgravity and thrive on radiation. It was able to block some of the incoming radiation, decreasing the levels by almost 2%. One of the major advantages, the researchers write, is the fungi self-replicate from microscopic amounts. You would only need to send a small amount to orbit, give it some nutrients and let it replicate, forming a biological radiation shield. With some tweaking, the fungi could be used to shield bases on the moon or Mars.
It’s a long while until we put boots on the red planet, but the groundwork is being laid now.
Hope you enjoy,
—
Niall
Abby writes:
Just listened to the last episode.
As a practicing urgent care pediatrician the NEED for a central message with good information is so evident. People Have No Idea!
Just in the last week I had patients who were sent to school with cough and congestion (developed fever at school).
Another mom asked for the curative med to treat Covid for her kid. Her internist had prescribed a zpack for the mom and said it will cure her.
Another dad said his son has severe headache and fatigue, and wondered if there’s any illness going around.
My whole family still has elevated resting heart rates, we aren’t all better and we had this in March. (And most doctors are still gaslighting people like us).
We are in trouble pretending we can control this without more national education on every level.
I’m trying a few patients at a time. (And , no, I did Not prescribe the Zithromax)
Thanks for all the updates.
Abby Siegel MD