Keys to mild vs severe Coronavirus illness start to come into view

[halbhh]

Why some become severely ill, and others have mild cases --

Scientists Uncover Biological Signatures of the Worst Covid-19 Cases
Studies of patients with severe cases of Covid-19 show the immune system lacks its usual coordinated response.

...
In certain patients, according to a flurry of recent studies, the virus appears to make the immune system go haywire.

Unable to marshal the right cells and molecules to fight off the invader, the bodies of the infected instead launch an entire arsenal of weapons — a misguided barrage that can wreak havoc on healthy tissues, experts said.
...
Researchers studying these unusual responses are finding patterns that distinguish patients on the path to recovery from those who fare far worse.
...
When a more familiar respiratory infection, like a flu virus, tries to gain a foothold in the body, the immune response launches a defense in two orchestrated acts. First, a cavalry of fast-acting fighters flocks to the site of infection and tries to corral the invader, buying the rest of the immune system time to mount a more tailored attack.

Much of the early response depends on signaling molecules called cytokines that are produced in response to a virus. Like microscopic alarms, cytokines can mobilize reinforcements from elsewhere in the body, triggering a round of inflammation.

Eventually, these cells and molecules leading the initial charge will stand down, making way for antibodies and T cells — specialized assassins built to home in on the virus and the cells it has infected.

But this coordinated handoff seems to break down in people with severe Covid-19.
...

...Many who struggle to recover from their illness seem to harbor the pathogen long after other patients have purged it, perhaps goading the immune system into prolonging its frantic inflammatory siege.

Plenty of other viruses, including those that cause AIDS and herpes, have evolved tricks to elude the immune system. Recent evidence hints that the new coronavirus might have a way of delaying or muffling interferon, one of the earliest cytokine defenses the body mounts.
...
Scientists Uncover Biological Signatures of the Worst Covid-19 Cases

(you can read I think several free articles a month at the New York Times if you register your email)

 

[Onoma]

I can offer some interesting insight here

When the genome was first published online, I began to study it using available data

It runs out there is a part of the viral genome that interferes with the cellular immune response that normally tips off the innate immune system there is an invader

This is the Open Read Frame 10 ( ORF10 )

This prevents the infected cell from releasing Interferon I that normally binds to Interferon II that is expressed by natural killer T lymphocytes that roam the body looking for pathogens

It essentially interferes with nuclear export in the cell,( RAE1 ) preventing the alarm ( Interferon I ) from being released to the bloodstream and neighboring cells

Specifically, it hijacks the cell's nuclear export factor and instead of the cell passing Interferon I through it's membrane, it begins passing assembled virions

This is why you get asymptomatic carriers

It allows the virus to take hold in the body without triggering an alarm

Coincidentally, this ORF10 protein is also found in the genome of Herpesvirus-8, which is an oncovirus ( cancer virus ) that normally shows up in the bodies of late stage HIV patients that have developed AIDS ( Kaposi's Sarcoma )

It's a very tricky virus

 

[sun rise]

Now I've read everything on RF --- an informative exposition of the biology of COVID-19. THANKS.

 

[Onoma]

I can't help but be interested, mom was a virologist and fostered in me, the love of science

Have you guys been following Nextstrain ?

auspice

That link is a mapping of all the different genomes of the virus ( 4,000 + mutations so far )

 

[Secret Chief]

I can't help but be interested, mom was a virologist and fostered in me, the love of science

Have you guys been following Nextstrain ?

auspice

That link is a mapping of all the different genomes of the virus ( 4,000 + mutations so far )

Care to do any crystal ball gazing?

 

[Onoma]

I haven't really kept up with the published papers lately, but I have noticed that the ORF10 has had almost zero mutations, at least according to nextstrain's data

I recall reading a few months back that the way that particular protein folds, makes it very stable, so this would make it highly unlikely that this part of the viral genome mutates with what is called a " gain of function " mutation or " loss of function " mutation, ( Due to errors in transcription when the virions are being assembled )

If you expand the bar in the 3rd section down on the nextstrain page ( By clicking on and dragging the little black triangle markers left or right ) you can see how few mutations have occurred in this protein, compared to the rest of the genome ( ORF10 is the last bar to the right )

Coronaviruses are prone to high rates of mutation ( Hence the 4,000+ genomes in ~6 months ), so compared to Influenza viruses, ( About 130+ serotypes to date ), it may greatly complicate vaccine developments in that new vaccines would have to be routinely made to keep up with all the various mutations ( Like we have to do with Influenza currently every year-new vaccines )

So based on that alone, I would expect that asymptomatic transmission will continue to be a problem

Couple that with the fact this is usually a lower respiratory infection, and micro-aerosols are created in the alveoli just by normal breathing, and that the virions produced in the type II alveolar epithelial cells are conveniently encapsulated in pulmonary surfactant ( Initiated in the lungs by mechanical stretch receptors ) into little structures known as " micelles " ( A micelle is basically a little spherical shell ) that dry in the air ( rapidly ) when exhaled and travel vast distances with a slight breeze, ....this just means long distance aerosol transmission will continue to be a risk as well

About 80% of the moisture you breath out is actually pulmonary surfactant that's secreted in the alveoli to help get rid of dust and other particulates ( Because they have an effect on the gas exchange rates if left unchecked )

Most folks didn't bother to read the early papers being published on the Lancet's website back in the beginning of the year, but they specifically said " airborne aerosolized pathogen ", which means exactly what it says

There was a lot of talk about this virus becoming endemic, back a few months ago, and I think that may also turn out to be the case, so there would be yearly vaccinations like there are with Influenza

Now, we may get lucky like we did with the SARS virus in 2003, which had a " loss of function " mutation in the tip of the spike protein that binds to ACE2, and the mutation made the protein fold in such a way that it lost much of it's binding potential, which meant it became far less likely that were you to inhale / ingest the virus, that it actually be able to become established, because it lost most of its ability to " stick to " ACE2

I would expect that out of the 130+ vaccines in development right now ( Using a wide variety of approaches ), at least a few will turn out to be promising

( At least I hope )

 

[Rational Agnostic]

Why some become severely ill, and others have mild cases --

Scientists Uncover Biological Signatures of the Worst Covid-19 Cases
Studies of patients with severe cases of Covid-19 show the immune system lacks its usual coordinated response.

...
In certain patients, according to a flurry of recent studies, the virus appears to make the immune system go haywire.

Unable to marshal the right cells and molecules to fight off the invader, the bodies of the infected instead launch an entire arsenal of weapons — a misguided barrage that can wreak havoc on healthy tissues, experts said.
...
Researchers studying these unusual responses are finding patterns that distinguish patients on the path to recovery from those who fare far worse.
...
When a more familiar respiratory infection, like a flu virus, tries to gain a foothold in the body, the immune response launches a defense in two orchestrated acts. First, a cavalry of fast-acting fighters flocks to the site of infection and tries to corral the invader, buying the rest of the immune system time to mount a more tailored attack.

Much of the early response depends on signaling molecules called cytokines that are produced in response to a virus. Like microscopic alarms, cytokines can mobilize reinforcements from elsewhere in the body, triggering a round of inflammation.

Eventually, these cells and molecules leading the initial charge will stand down, making way for antibodies and T cells — specialized assassins built to home in on the virus and the cells it has infected.

But this coordinated handoff seems to break down in people with severe Covid-19.
...

...Many who struggle to recover from their illness seem to harbor the pathogen long after other patients have purged it, perhaps goading the immune system into prolonging its frantic inflammatory siege.

Plenty of other viruses, including those that cause AIDS and herpes, have evolved tricks to elude the immune system. Recent evidence hints that the new coronavirus might have a way of delaying or muffling interferon, one of the earliest cytokine defenses the body mounts.
...
Scientists Uncover Biological Signatures of the Worst Covid-19 Cases

(you can read I think several free articles a month at the New York Times if you register your email)

Someone needs to figure out why age is such a strong predictor of mortality rate. Did you know that only 42 people under the age of 15 and 244 people under the age of 25 have died in the US of the virus? Compare that with 135,000-150,000 people above the age of 25. There is obviously something about the immune systems of children and young adults that is different from others that the medical community should be looking into to try to help more vulnerable patients.

See:

https://data.cdc.gov/widgets/9bhg-hcku

 

[Onoma]

Someone needs to figure out why age is such a strong predictor of mortality rate. Did you know that only 42 people under the age of 15 and 244 people under the age of 25 have died in the US of the virus? Compare that with 135,000-150,000 people above the age of 25. There is obviously something about the immune systems of children and young adults that is different from others that the medical community should be looking into to try to help more vulnerable patients.

See:

https://data.cdc.gov/widgets/9bhg-hcku

afaik, ( from what reading I did ) this is perhaps because of things like copper serum levels in infants and children ( A deficiency of Cu in infants is known to lead to higher susceptibility to infections, for example ) Last time I read any papers they were mentioning the roles of Copper (Cu), zinc (Zn), and iron (Fe) in the Covid infections because of how blood chemistry is affected

 

[halbhh]

I can offer some interesting insight here

When the genome was first published online, I began to study it using available data

It runs out there is a part of the viral genome that interferes with the cellular immune response that normally tips off the innate immune system there is an invader

This is the Open Read Frame 10 ( ORF10 )

This prevents the infected cell from releasing Interferon I that normally binds to Interferon II that is expressed by natural killer T lymphocytes that roam the body looking for pathogens

It essentially interferes with nuclear export in the cell,( RAE1 ) preventing the alarm ( Interferon I ) from being released to the bloodstream and neighboring cells

Specifically, it hijacks the cell's nuclear export factor and instead of the cell passing Interferon I through it's membrane, it begins passing assembled virions

This is why you get asymptomatic carriers

It allows the virus to take hold in the body without triggering an alarm

Coincidentally, this ORF10 protein is also found in the genome of Herpesvirus-8, which is an oncovirus ( cancer virus ) that normally shows up in the bodies of late stage HIV patients that have developed AIDS ( Kaposi's Sarcoma )

It's a very tricky virus

An interesting question to me at the moment is whether being infected and having a good immune response and resolution to any of the various strains of sars-cov2 will confer immunity to all (or almost all?) of the other strains. This came up as I was reading this, where it seems (not my field, so I'm trying to infer the meaning) possible that variants with a mutated orf10 could spread, and wondering at the possible implication --
https://www.journalofinfection.com/article/S0163-4453(20)30186-9/fulltext
A question in my mind: it seems that we are putting selection pressure to select more mild variants (if there are such variants), because we isolate those with severe illness, so if the severe illness is caused significantly from orf10(?), then we'd be putting (some, or in some countries) selection pressure for a milder strain (such as by quarantining all nearby contacts before they test positive via contract tracing and required quarantine), and if orf10 could mutate to be milder(?), that would be significant. Just speculative questions, since it's not a field I've read much in. More questions in my mind at the moment -- such as could one engineer a near identical virus but without the orf10, and then have an immune response to a more mild virus that does not interfere with Interferon I, and would that then confer immunity to the more dangerous strains?

 

[halbhh]

Someone needs to figure out why age is such a strong predictor of mortality rate. Did you know that only 42 people under the age of 15 and 244 people under the age of 25 have died in the US of the virus? Compare that with 135,000-150,000 people above the age of 25. There is obviously something about the immune systems of children and young adults that is different from others that the medical community should be looking into to try to help more vulnerable patients.

See:

https://data.cdc.gov/widgets/9bhg-hcku

Yes, this question has been so interesting since near the beginning when it was clear children were much less affected in China.

 

[Onoma]

An interesting question to me at the moment is whether being infected and having a good immune response and resolution to any of the various strains of sars-cov2 will confer immunity to all (or almost all?) of the other strains. This came up as I was reading this, where it seems (not my field, so I'm trying to infer the meaning) possible that variants with a mutated orf10 could spread, and wondering at the possible implication --
https://www.journalofinfection.com/article/S0163-4453(20)30186-9/fulltext
A question in my mind: it seems that we are putting selection pressure to select more mild variants (if there are such variants), because we isolate those with severe illness, so if the severe illness is caused significantly from orf10(?), then we'd be putting (some, or in some countries) selection pressure for a milder strain (such as by quarantining all nearby contacts before they test positive via contract tracing and required quarantine), and if orf10 could mutate to be milder(?), that would be significant. Just speculative questions, since it's not a field I've read much in. More questions in my mind at the moment -- such as could one engineer a near identical virus but without the orf10, and then have an immune response to a more mild virus that does not interfere with Interferon I, and would that then confer immunity to the more dangerous strains?

First off, thanks for posting the paper, that's an interesting one for sure !

As far as developing an immunity...this is tricky, especially with this virus

I'd have to check my notes to make sure, but I believe that the genome contains a rather long sequence that is associated with severe immune response, ( Small interfering RNA (siRNA). More or less, as I understand it, you can be infected once by something, then on second exposure it will provoke a far more severe immune response

If the sequence is under something like 10 amino acids, the response is not severe, and then anything approaching 15+ acids will provoke severe response ( This is well known in the field of vaccine development, iirc )

So basically, you might be infected and only have a short and mild illness, then months down the road, you are exposed again and the body's immune system responds with a very severe response ( which is actually the body waging war on it's own tissues, where the invaders reside )

The immune system always remembers a pathogen and keeps a library of protein sequences handy in case of future run-ins, so in the case of this virus, a second infection might actually provoke a response that is akin to killing a gnat with a sledgehammer

But, with that said, there are so many possible variables to consider

Medications, blood chemistry, genetics, the list is rather large

Personally, what I find most disturbing is the link between air pollution and high infection rates, this has been quietly swept under the rug, yet is perhaps the largest contributor to high rates of infection

 

[halbhh]

First off, thanks for posting the paper, that's an interesting one for sure !

As far as developing an immunity...this is tricky, especially with this virus

I'd have to check my notes to make sure, but I believe that the genome contains a rather long sequence that is associated with severe immune response, ( Small interfering RNA (siRNA). More or less, as I understand it, you can be infected once by something, then on second exposure it will provoke a far more severe immune response

If the sequence is under something like 10 amino acids, the response is not severe, and then anything approaching 15+ acids will provoke severe response ( This is well known in the field of vaccine development, iirc )

So basically, you might be infected and only have a short and mild illness, then months down the road, you are exposed again and the body's immune system responds with a very severe response ( which is actually the body waging war on it's own tissues, where the invaders reside )

The immune system always remembers a pathogen and keeps a library of protein sequences handy in case of future run-ins, so in the case of this virus, a second infection might actually provoke a response that is akin to killing a gnat with a sledgehammer

But, with that said, there are so many possible variables to consider

Medications, blood chemistry, genetics, the list is rather large

Personally, what I find most disturbing is the link between air pollution and high infection rates, this has been quietly swept under the rug, yet is perhaps the largest contributor to high rates of infection

Hmmm, the last part makes me wonder if air pollution degrades some natural barrier in the sinuses/lungs to be less of a barrier, then one could wonder if perhaps younger people have more of that barrier naturally too, so that if they get infected, it's with fewer virus particles initially (which being fewer particles at the outset allows the immune system extra time to respond before the virus has grown into a high level).

 

[Onoma]

Hmmm, the last part makes me wonder if air pollution degrades some natural barrier in the sinuses/lungs to be less of a barrier, then one could wonder if perhaps younger people have more of that barrier naturally too, so that if they get infected, it's with fewer virus particles initially (which being fewer particles at the outset allows the immune system extra time to respond before the virus has grown into a high level).

It's directly attributed to nitrogen dioxide ( weakens cell membranes and allows the virus to enter cells much faster )

Back before the WHO director finally acknowledged it publically on Twitter, I had actually done a comparative analysis between nitrogen dioxide concentrations ( From various sources like Industrial pollution, internal combustion engines, volcanoes, etc ) and infection hotspots and noticed a very obvious linear relationship

Then I just read a stack of papers on the role that NO2 plays in lung infections ( There is much published work on this )

You can actually see the linear relationships with US infections here in this graphic I came up with ( I did them for the entire world map too, especially in China where the NO2 pollution is through the roof, specifically Wuhan.... )

 

[Onoma]

Here are several more panels I made to illustrate the relationship

The first 5 are focused on the air quality in Wuhan

The 6th shows NO2 concentrations compared to a map of infection hotspots ( as of 3 months ago )

The 7th panel shows the air quality in those areas hit hardest by infections ( as of 3 months ago )

 

[Onoma]

Here's a recently published paper ( august 3rd ) discussing the potential for dain bramage after Covid infections

Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study

 

[halbhh]

Here's a recently published paper ( august 3rd ) discussing the potential for dain bramage after Covid infections

Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study

Well, there's an extra motivator to make even more effort to wear a good mask consistently.

 

[Onoma]

Well, there's an extra motivator to make even more effort to wear a good mask consistently.

There had been some evidence that the first SARS virus exhibited what's called " viral neurotropism " in some patients, which was specifically in the brain stem, making it very difficult to deal with

It would mean that because the body won't attack the brain stem ( Unless you have immune disorder ), when a person's antibody levels fell off with time, the virus could actually re-emerge and cause another infection or even possibly the severe reaction I mentioned earlier ( In rare cases I would assume )

I'm really shocked that many people are not taking this seriously, considering the wide range of possible problems, many of which seem to be permanent scarring and loss of function of organs ( even in mild to moderate cases )

Even the scarring to the lungs is something to take seriously, it's permanent, for life, and permanently lowers your ability to breath because of the scar tissue

Not wearing a mask is playing a dangerous game of roulette where you have no idea what you will win

Not a great idea to gamble in that scenario

 

[Secret Chief]

Finally happened. I know someone who has got covid. Been in hospital weeks. Heart damaged. Chronic lack of energy. No underlying health condition.

Keep your masks on.

 

[halbhh]

Finally happened. I know someone who has got covid. Been in hospital weeks. Heart damaged. Chronic lack of energy. No underlying health condition.

Keep your masks on.

This may happen to more and more people -- someone they know personally. So far about 160,000 have died, about 1 in 2,000 Americans. But I wonder also what is the total that have survived with lasting problems.

 

[lostwanderingsoul]

Fake news. Hoax. There is no virus. No one has died. It is a plan by the drug companies to make money. We should be more worried about getting pregnant from dreaming about aliens. That's real.