Detailed dive into zoonosis (long read)

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  • Sat, Aug 08, 2020 - 01:42pm

    #1
    Dr. Jurgen Mayer

    Dr. Jurgen Mayer

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    Detailed dive into zoonosis (long read)

I wanted to make a post to provide some clarification about comparing coronaviruses that are potentially related to SARS-CoV (2002).

First, we will start with SARS-CoV. It is imperative to understand that are dealing with a zoonotic adapted virus. We need to gain a better understanding of that process in order to continue. The host animal is likely infected with numerous viruses. Bats can be natural reservoirs of dozens of viruses. As these viruses are not causing harm to the host, the viruses will interact, make adaptations and mutations. The potential results of any of those changes are impossible to determine. Think of this like throwing 20 viruses in a soup, put that in a container and walk away for 10 years. Perhaps some of the viruses have interacted causing breakdowns. We will use Ebola as an example. Ebola likely finds a way to adapt various parts from other viruses. Are these positive or negative changes to Ebola? Within the bat host, they should be considered neutral. So this is a roll of the dice type of situation. Just understand that these viruses will evolve over time. The bat host will likely unintentionally pass many of these viruses to other bats.

To recap, if we have a bat that is infected with coronavirus version 1 since the bat has many co-infections, the coronavirus will be version 50+ by the time it passes the virus to the second host.

A tangent point while speaking of passing a virus to a second host. I need to be crystal clear that no bat coronavirus has ever directly infected human ACE2. Dr. Shi used Gain of Function research to prove that this was theoretically correct and that we should prepare for this eventual evolution of coronaviruses from bats. Back in 2002, if the origin SARS-CoV bat urinated directly into your mouth ensuring that you have a high viral dose of SARS, your cells would not get infected. Now, this is a virion, not a virus as it has not infected your cells. The virion particles contain instruction manuals about how to infect and replicate. None of that is occurring since this virion lacks the knowledge to directly dock to your cells. Let’s say these virions circulate in your body for 3 days. You would not have any symptoms and you would not be contagious. This is a very important part. During the initial outbreak reporting for hCoV-2019, many news agencies were reporting that the novel virus came from a bat and that people in China eating bats caused the outbreak. There is quite literally zero known instances of this happening in world history. Again, Dr. Shi hypothesized that eventuality was indeed possible, but we have still never seen this happen in nature.

Now we move to the secondary host. For the case of SARS-CoV this was determined to be a Palm Civet (cat). So we have two roads we can take. Either the civet was healthy before being infected by the bat or the civet had co-infections which helped make further changes to the virus. For clarification, certain animals have more tolerance for viruses. Immunity is not the correct word here. Immunity would try and wipe out the virus. Think of this as co-existence. Civets’ have very interesting digestive systems and have a higher tolerance to co-exist with viruses. It is the co-existence ability that makes it more probable that the civet had co-infections. Although a series of civets were tested I am unaware of co-infections being sequenced and published. So the original state of this virus within the bat is unknown. Scientists were able to determine a high probability that a horseshoe bat infected the civet but there is no specific bat to speak of. No isolated genome to point to, just a series of closely related genomes. I should also make the point that we never determined patient zero among the civets. SARS was found in a number of civets as they were infecting each other. The virus within each was near identical, with minor mutations. These gaps are what causes problems. I cannot tell you the viral genome from the origin host bat or the secondarily infected civet. That is a vital missing component. It is of great value to see the bat virus and compare it with the civet virus. This would allow us to see exact mutations that occurred while in the civet. However, this is only relevant if we can sequence every co-existing virus in the civet. By now you are likely starting to see how messy all of this is and how many questions cannot actually be answered.

But how do we know that the bat did not infect the humans and then the humans infected the civets?! This is where viral mutation evolution is the smoking gun. As a virus mutates it also adapts and “adds” function, by doing so, it is creating more “information”, which means the source code will be longer. Simply put, as you continue to edit a Microsoft Word document, the (data) file size increases. It is that simple. So the smaller the data size, the earlier the version of that file.

Without getting into biochemistry we will be using nucleotides. This will help. Nucleic acids strung together = nucleotides. Nucleotides convert to amino acids. Amino acids strung together are Peptide chains. Peptide chains convert to active proteins. Good enough for now! When I reference base pair (bp), just think of this as the file size of a document. What data is in the document is not relevant right now, we are simply trying to version track with some guesswork.

SARS-CoV in humans is 29,751bp

Palm civet subject 20 is 29,683bp (68bp less than humans)

Palm civet subject 7 is 29,540bp (211bp less than humans)

Palm civet subject 10 is 29,518bp (233bp less than humans)

Subject 10 has less information than subject 20 which has less information than the human. So there is our history. Clearly the virus gained information as it mutated in humans. This firmly means the virus was circulating in the civets prior to humans. If the humans infected civets, we would expect the civet numbers to be 29,000+

 

Here is an example of humans infecting an animal with a coronavirus.

hCoV-2019 in humans is 29,903bp (2019 Wuhan strain, L clade)

Mink subject MT457401 is 29,891bp (July NED sample, G clade)

Over time hCoV-2019 has mutated and formed various strain groups. Ineffective features were removed and effective features were removed. The current (relevant) strain is around 29,837, so comparing July (human) to July (mink), the mink has 54 more basepairs than in humans. Which means humans infected the minks, then the virus continued to mutate/evolve within humans.

Another point of clarification is that every patient is going to have slightly different base pair counts. This is mainly because there are different strains of the virus around the world but also comes down to testing. Some (bad) testing leaves GAPS in the genome, which results in sequences like 29,504bp. That is a pretty garbage sample on the face of it, but there is still a lot of valuable information we can pull from that sequence.

 

In summary, we can see the exact differences between civet and human SARS-CoV and determine that it was civets that infected humans. We cannot see the bat genomes to determine what the original virus looked like. The recipe is a mutated virus in co-infected bat + co-infected civet mutates virus + healthy human gets infected by the civet. The virus in humans then adapts and evolves for efficiency.

We need to be very careful about attempting to compare primary host viruses to tertiary host viruses. As an example, even if RaTG13 is 96% similar to hCoV-2019 it would be a mistake to compare these side-by-side. This is like comparing an apple to an orange. Their properties are similar, so there are more similarities than dissimilarities but an apple cannot become an orange. As coronaviruses in bats cannot directly infect human cells we MUST use a secondary host, then infect the human, which then changes the virus even further.

pCoV-MP789 is a great example of the complexity of zoonosis. Pangolin (subject 08) was riddled with co-infections including coronaviruses. How long had it been infected with the coronavirus? With other viruses? How different is the coronavirus compared to within the unknown host animal? There is much we cannot answer.

 

I wanted to write this out to help people understand that we are dealing with complicated systems. I get the feeling that people are looking at zoonosis from too basic a view. Assumption: a healthy bat has 1 infection, a SARS-like coronavirus. There is a healthy pangolin with zero infections. The bat then infects the pangolin. The virus slightly mutates. The pangolin then passes the virus on to the human host. The virus mutates again. This is absolutely not what is happening. Reality: Both the bat and pangolin are riddled with co-existing viruses. The co-existing viruses are mutating the coronavirus within the bat. Once the coronavirus reaches the pangolin, the co-existing viruses further mutate the virus. The healthy human is infected with the release to market product. The virus then adapts to better fit its new host. The original virus in the bat may be 85%+ similar to what we find in the human host, that is how much change could have occurred over this transfer span.

 

  • Sat, Aug 08, 2020 - 05:46pm

    #2
    robie robinson

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    Detailed dive into zoonosis (long read)

Probabilities that normal viral transmission between mammals results in gain of function? I suppose if there are sufficient numbers and sufficient [concentration]?

somebody has been stirring the soup.

I wear a mask.

  • Sat, Aug 08, 2020 - 05:49pm

    #3
    robie robinson

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    awesome dive

into viral zoonosis.

Much Thanks for your efforts.

  • Sun, Aug 09, 2020 - 07:31am

    #4
    Mohammed Mast

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    Detailed dive into zoonosis (long read)

Thanks Jurgen.

Interestingly Friday night I had a dream of Mers mixing with SC2. I had no idea if that was possible. It seems from your post that it is very possible. MERS is still with us. It is not as transmissible in humans as SC2 but it is apparently more lethal.

It would be a very bad combination.

I was just going to post a question about this and then there it is. So various mutations and combinations could be going on all the time.

Thanks again

  • Mon, Aug 24, 2020 - 06:51am

    #5
    tbp

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    Reply To: Detailed dive into zoonosis (long read)

Back in 2002, if the origin SARS-CoV bat urinated directly into your mouth ensuring that you have a high viral dose of SARS, your cells would not get infected.

Good to know!

I wanted to write this out to help people understand that we are dealing with complicated systems. I get the feeling that people are looking at zoonosis from too basic a view. Assumption: a healthy bat has 1 infection, a SARS-like coronavirus. There is a healthy pangolin with zero infections. The bat then infects the pangolin. The virus slightly mutates. The pangolin then passes the virus on to the human host. The virus mutates again. This is absolutely not what is happening. Reality: Both the bat and pangolin are riddled with co-existing viruses. The co-existing viruses are mutating the coronavirus within the bat. Once the coronavirus reaches the pangolin, the co-existing viruses further mutate the virus. The healthy human is infected with the release to market product. The virus then adapts to better fit its new host. The original virus in the bat may be 85%+ similar to what we find in the human host, that is how much change could have occurred over this transfer span.

So virus mutations are greatly affected by co-existing viruses? For example, could a pathogenic influenza virus influence hCoV-2019 mutation speed and types? What about innocuous ones like the 4 commmon hCoVs, or dormant ones like shingles-causing varicella?

 

  • Tue, Aug 25, 2020 - 04:31pm

    #6
    Dr. Jurgen Mayer

    Dr. Jurgen Mayer

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    Detailed dive into zoonosis (long read)

So virus mutations are greatly affected by co-existing viruses? For example, could a pathogenic influenza virus influence hCoV-2019 mutation speed and types? What about innocuous ones like the 4 commmon hCoVs, or dormant ones like shingles-causing varicella?

There are many factors involved such as host, length of time each virus is active in the host, and how the viruses can interact within said host. In the case of horseshoe bats, it is seen that various active viruses can mutate with each other. For example, we infect a bat with a SARS-related beta coronavirus and Ebola. If we let those viruses site and naturally mutate over a certain (indeterminant) period of time it is possible that the RxRR cleavage site of Ebola could make its way into the SARS-like beta coronavirus. I want to caution that this example is HIGHLY improbable and requires perfect conditions over said indeterminate period of time to possibly even occur. These types of cross mutations are very specific to natural host animals as opposed to unnatural hosts, such as homo sapiens. If we infect a human with the SARS-like beta coronavirus and Ebola, these two viruses would not cross mutate. This is because both of these viruses would theoretically be able to dock to cells within the human host and therefore are busy doing their jobs of replication. Back to the bats. Whilst inside of the bat the virus is sitting there, unable to “impact” the cells of the bat so it has no need to “adapt” mutations in a way to make itself more powerful. These mutations occurring within the bat should be considered as random and rolling of the dice. Whereas the mutations occurring in humans are more specific. Think of these as rolls of the dice but the virus is specifically trying to pick a lock to better infect cells or new pathways.

In terms of zoonosis, the existence of co-infections is more relevant in the secondary animal. Why? If the primary host is a bat that contains SARS, as previously mentioned, the mutations occurring to the SARS virus are mainly random and likely have no impact when being passed to the secondary animal. But let’s look at that secondary animal. Let’s use the palm civet (SARS 2002). This animal is an unnatural host for SARS or any major viruses such as Zika or Ebola. This animal is a natural host for lesser viruses such as mono or chlamydia. When the bat transmits the SARS virus to the civet, what happens next greatly depends on the health of the civet. If the civet is very healthy and has no (relevant) co-infections, then the SARS virus would remain largely unchanged before being passed to the human host. However, that is where timing comes in. Given enough time, months, or years, the virus in the civet would naturally mutate to further infect the civet.

How long the virus has sat in the civet is very important

What relevant co-infections the civet may have had is even more important. Given that the civet is not a natural host for SARS or Ebola, IF we craft a situation where poor civet is infected with Ebola and then has the misfortunate to also become infected with SARS, via the bat, IF the civet can survive long enough, the chances of Ebola recombination with SARS becomes more and more probable. By the time this is successful the civet would likely be nearly dead and most anyone would notice that the civet is sick and would be stupid to kill and eat it. That is where China marketplaces come into play since they do not seem to care.

 

For clarification. Can Ebola and SARS mix within a bat? Yes, but it is very improbable, even over an extended period of time. Can Ebola and SARS mix within a non-natural hosting animal? Yes, this is highly probable IF the right conditions are met, including enough time to have passed where natural mutations and cross-mutations would occur. For example, if we infect said civet with both viruses tomorrow, there is a zero percent chance that by next week or next month these two viruses have interacted/traded.

For the other parts of your question, no, this does not apply to dormant viruses. Yes, this does apply to hCoV viruses but would need to occur within a human host. For example, if we infect a house cat with hCoV-HKU1 there are components of the virus that will have no impact on the cat, so the virus would shed part of its build and work on docking with the cells of the cat. The ORF1ab would drastically change but lose information as the job has now changed. Let’s say the ORF1ab NT count for humans is 2,500. Once it properly infects the cat it would be down around 2,300. That also means it becomes LESS probable for that cat to properly infect a human since the virus has adapted itself for infection in cats. This is the case with the Netherland minks. We can scientifically show that humans infected the minks, the ORF1ab shrank, as did the Spike, but the overall count NT was similar, since it adapted.

  • Wed, Aug 26, 2020 - 10:46am

    #7
    Mpup

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    Picking the lock

One might ask,  what is it within the virus that allows it to “pick the lock”   Or asked another way,  if not random, what is it within the virus that drives it to seek a means to further infect?  Could AI help solve  the puzzle?

After re-reading the initial post by Dr. Mayer another question arises.  What is it, or what is the process or means that allows the virion to become a virus?  If that process was identified, might there be a way to reverse or prevent the viral cycle?  Knowing that certain animal species are the vectors, should consideration be given to affecting the virion/virus in the original hosts?  Will the man-God attempts to alter “nature” be our final downfall?  “Accidents” happen.

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