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How our immune system struggles with corona

Jerome Marot

Well-known member
An interesting article from the Nieuwe Rotterdamsche Courant summarizing the present knowledge about covid-19. Fascinating read.

The article (in Dutch) can be found here: https://www.nrc.nl/nieuws/2020/10/09/hoe-onze-afweer-worstelt-met-corona-a4015405 Readers should refer to this link if they are interested to the source and links to scientific studies.

As few members of this forum are fluent in Dutch, I used https://www.deepl.com/translator to translate the article to English. First half of translation below, rest in the next message:

Immunology Why does one person become deathly ill from corona while another hardly notices the infection?

As if one falls in the middle of a dramatic film, without having seen the beginning. That is the feeling that medical immunologist Jacques van Dongen from the LUMC in Leiden has when he tries in his research to unravel the reaction of the immune system against the coronavirus SARS-CoV-2. "In people who test positive for the virus, the infection has already taken place at least four days before. Patients who end up in hospital with corona have suffered from the virus for much longer. All this time, the immunological process has been on its way. But I am so curious to see how the immune system reacts when the virus arrives".
Intentionally infecting volunteers with the potentially dangerous corona virus to see what happens in the first part of the film is considered unethical. Van Dongen tries to piece together the puzzle by superimposing the immune images he sees in different people. This is tricky, because the severity of the infection varies enormously from person to person. Van Dongen: "Some people get better quickly, others end up with serious respiratory problems in intensive care, and lie in hospital for weeks.
The way the immune system reacts to this new coronavirus sometimes goes against all expectations. New surprising insights regularly appear in the scientific literature. Scientists do their best to reconcile it with their existing knowledge. But the story is not yet unambiguous, everyone puts a different emphasis from their own background.
Van Dongen emphasizes the importance of good antibodies, which target the part of the spike protein with which the virus invades human cells. His colleague at the UMC Groningen, vaccinologist and immunologist Debbie van Baarle, sees a leading role for the defence based on T-cells. And virologist Lia van der Hoek of the Amsterdam UMC emphasizes the virus' box of tricks, with which it escapes the immune system.

The dose of the virus that someone ingests can also influence the severity of the disease. "That certainly plays a role," says Van Dongen. "But you really get a lot of virus if you are immediately coughed up by a patient. That sometimes happened at the beginning of the first corona wave, but that is less common now of course".
Reduced exposure to virus is also a side effect of coronary measures such as keeping distance, sufficient ventilation and wearing a mouth mask, some doctors think. Infection may not be preventable, but at least it attenuates the severity of the disease, they reason. Hard evidence for this is still lacking.
Because the immune system intervenes late, the virus gets the chance to multiply, which can aggravate the course of the disease. "SARS-CoV-2 knows how to enter without being seen", says virologist Lia van der Hoek. "Once it is in the host cells, it can multiply. The new generation of virus particles that are released from it spread to other cells for a new cycle".
Only when tissue damage occurs does the immune system realize that there is an intruder, and pieces of the virus are presented to the immune cells so that they can react to it (B cells with antibodies and T cells through a targeted action against cells infected with the virus).
Coronaviruses know how to bypass the immune system as the best, according to an overview article of Chinese virologists in the trade journal Viruses. They pull out all kinds of tricks. In the cells they infect, they shield their genetic material, which would betray the presence of a virus. When they have made hundreds of copies of themselves in that cell, they leave the cell without letting it burst open. In this way they prevent early detection by the immune system. This makes it difficult to get rid of the viruses quickly, but they can also easily spread to the next victim due to the coughing stimulus that the tissue damage induces in their host.

Exhaustion of T-cells

There are also indications that the virus can actively hinder the development of an adequate immune system. In a publication in Immunity in early August, Hong Kong doctors write how SARS-CoV-2 blocks a good immune response during the acute phase of the infection by eliminating crucial immune cells. And later in the infection, especially in people who have become seriously ill, white blood cells appear to be almost absent (lymphocytopenia). What exactly causes this, exhaustion of the T-cells or even infection of the white blood cells themselves, is not well known yet. Most Covid-19 patients who die have such a collapsed T-cell defense.
In severely ill patients, the immune response can become so severe that they are in acute danger of death. But according to Van Dongen the picture is not correct that the immune system then desperately uses all means to get rid of the virus. "A cytokine storm is precisely a sign of a weak immune reaction, not a strong one," he says. "It's precisely when the body can't quickly produce the right antibodies that the system derails.
Meanwhile, the immune cells of the innate immune system continue to fight the virus. That system reacts to tissue damage in the lungs. These immune cells penetrate into the lung tissue in the interstitium of the lung vesicles. This is normally a wafer-thin layer of tissue over which the gas exchange between the lung vesicles and the blood flow must take place. However, if the interstitial tissue becomes thicker as a result of the inflammation, the patient soon runs out of breath.
To prevent this, patients are given early corticosteroids, such as dexamethasone. "This allows you to muffle this process at an early stage," says Van Dongen, "but at the same time it also muffles the antigen presentation and the activation of B-cells, making them less able to form antibodies against the virus. That's why we almost have to titrate the antigen - not too little, but certainly not too much either".

Young brothers with corona

In addition, a person's genetic predisposition influences how well the immune system can fight the viral infection. Researchers from Radboudumc in Nijmegen found a hereditary cause of a more serious course in July, after two brothers in two families shortly after each other ended up in the ICU and had to undergo artificial respiration. Because this is unusual for young people, the researchers went looking for a hereditary cause. They soon found one: in both families the brothers appeared to have a rare mutation in the gene for the Toll-like receptor 7, or TLR7 for short. This gene is located on the X-chromosome, and because males only have one of these, a second gene copy is missing that can compensate for the error. TLR7 seems essential for the first defense against SARS-CoV-2. It initiates the production of so-called interferons: signal proteins that are essential for attracting additional defence auxiliaries. Without the TLR7 alarm, the virus would have had free rein with the four brothers.
Possibly this discovery also explains why Covid-19 is relatively more severe in men than in women. Even with an intact TLR7 gene, men have only one copy, women have two copies.
The importance of this first defense against the virus via interferon also came to the fore in two recent studies in Science. One study concludes that a genetic error can impede the correct production of interferon. And the other study surprisingly discovered a new autoimmune disorder: in 10 percent of critically ill Covid-19 patients, the antibodies were not directed against the virus, but against their own interferon. And another strange thing: almost all patients with this disorder (95 percent) were men. Although the origin of this adverse reaction is not yet known, it may also explain the relatively high proportion of men among critically ill Covid-19 patients, including an increased mortality risk.
According to immunologist Van Dongen, the role of heredity not only involves rare mutations in genes involved in the immune system, but may also affect normal genetic variation: "Between two people there can be a factor of a hundred difference in the amount of antibodies that their immune system can produce. Our body is capable of making one trillion (1012) to one hundred billion (1014) different antibodies. Compare that with someone who can only make 1010 antibodies. The first one is a hundred times more likely to make a good antibody against the spike protein of the coronavirus. By the time a person with a weaker immune system is that far, that person may already have ended up in intensive care.

Jerome Marot

Well-known member

People who have had a corona infection become immune, but for how long? Virologist Lia van der Hoek expects that this protection is not permanent, based on her research into infections with the four relatively innocent cold coronaviruses. Van der Hoek and her team measured the antibodies in the blood of ten participants in a large-scale study into HIV in Amsterdam. These people did not have HIV themselves, but belonged to the control group. Blood samples and health data were collected from them over a period of 20 to 35 years, which provided a unique picture of recontamination with cold coronaviruses.
The study appeared in Nature Medicine last month. In total, more than one hundred coronavirus infections were measured in the ten participants, and this showed that normally healthy people experience recontaminations, sometimes after six months with the same coronavirus. "We saw this pattern of regular recontamination for all four cold coronaviruses without exception," says Van der Hoek, "and I do not expect SARS-CoV-2 to behave differently.
With other cold viruses, such as rhinoviruses, it is each time a different strain that causes the infection. Influenza, too, circulates different variants every year, causing people to become infected again. "But with coronaviruses, exactly the same virus succeeds in infecting someone over and over again," Van der Hoek observes. "After every infection you see the concentration of antibodies in the blood quickly drop again. The B-cell memory of the immune system is still there, but apparently that can't prevent someone from being re-infected by the same virus".
Research has shown that antibodies quickly disappear from the blood again with SARS-CoV-2. According to Debbie van Baarle this is normal: "It drops back to a stable low level. But the bone marrow still contains the memory cells, which ensure that the antibodies are quickly back up to the same level in the event of a new infection".
Nevertheless, there have already been reported patients who, confirmed by genetic analysis of the virus, became infected with SARS-CoV-2 for a second time. At the end of August, a study appeared on a 33-year-old man in Hong Kong who had already been hospitalized at the end of March with Covid-19, which was not very serious, and who tested positive again after a business trip to Europe in a mandatory coronary test at Hong Kong airport. The second infection, with a genetically distinct virus, was asymptomatic.
In the days following that news, there suddenly followed reports of similar recontaminations from Belgium (1) and the Netherlands (4). Since then, they have also been reported in patients in Ecuador (1) the US (2) and India (6). On average there was two weeks between the two infections, with a spread of twelve days to four months. They were male and female, young and old.
These reports quickly raise the question whether everyone who has had corona is at risk of becoming ill for the second time? According to immunologists Van Dongen and Van Baarle, reinfection is a rare phenomenon. The fact that it sometimes does happen is possibly due to the patient's weak immune system during the first infection, which gave the virus a second chance in their case.
"In my opinion, the fact that we have now seen a number of re-infections is due to the fact that we are so on top of them, which has never been the case with other infections", says Van Baarle. "It doesn't mean that everyone who has had Covid-19 will be susceptible to SARS-CoV-2 again after a while".

Lia van der Hoek is less optimistic about this. "I do expect that most people will be susceptible again after a while, but we simply haven't been able to see massive recontamination yet because we are still in the first six months after the start of the pandemic. At the same time, I expect that the second and subsequent infections may be milder, and that offers hope.
And antibodies are only half the story; T-cells also have a memory for viruses they've dealt with before. Another special feature of T-cells is that they not only focus on proteins on the outside of the virus, but also on structures of internal proteins of the virus. Because they are less variable than the outside, T-cells sometimes react almost as strongly to groups of related viruses, something immunologists call cross-reactivity.
Indeed, American researchers this spring found T-cells reacting to SARS-CoV-2 in about half of the people who never experienced Covid-19 in their blood. Probably this was cross-reactivity, which was induced by infections with cold coronaviruses. This pre-existing T-cell immunity to other coronaviruses could also be one of the reasons that SARS-CoV-2 causes only mild symptoms in many people.
But 100 percent protection against re-infections does not give that immunity, the same American researchers write in a follow-up article. This is because this immune memory is largely limited to T-helper cells. In case of a second infection, or an infection after vaccination, people might get less sick from it, but they would still be able to pass on the virus to others. Therefore, the limited T-cell immunity does not provide group protection.

Defense in the mucous membranes

What does all the new knowledge gained about SARS-CoV-2 immunology mean for the corona vaccine that everyone is now hoping for? Nearly all vaccines under development focus on the spiking proteins. Ideally, a vaccine should generate "mucosal immunity" to the virus, i.e. immunity that is already active in the mucous membranes. "That is exactly where the virus is trying to penetrate," says Van Dongen. "For that you want strong antibodies of the IgA type. That's the best type of antibody against respiratory viruses, because IgA can survive in the mucous membranes of both the airways and the intestine".

Van Baarle thinks that a good vaccine should not only generate antibodies against the virus, but should also create a good T-cell reaction. "We see more and more indications for this in the literature. The antibodies in patients who are very ill rise to the highest levels, without it appearing to have a good dampening effect. At the same time, there are studies showing that people with T-cells present have milder infections".
We can no longer eradicate this virus - not even with a vaccine, says Van der Hoek. "Not only is it spread too widely around the world for that, but the virus is now also present in animal reservoirs. Just like minks and cats, a large number of wild animals are susceptible to the virus. So we won't get rid of it even if we succeed in vaccinating the entire world population".
Twenty years ago, SARS could hardly be eradicated, because of the serious complaints every infected person could be recognized and outbreaks could be detected and extinguished more easily. His successor SARS-CoV-2 is more insidious.

Probably the common cold coronaviruses once started in the same way. Gradually these viruses have become milder, until they only cause colds. "Inevitably SARS-CoV-2 will become the fifth coronavirus", says Van der Hoek, "That may take fifty years or may have happened within two years. But there is no turning back."

Asher Kelman

OPF Owner/Editor-in-Chief
Wow: excellent report, Jérôme,

You’re a wizard finding such a coherent translation too!

It’s impressive.

Add to that previous BCG vaccination against Tuberculous, Bacillus Calmette-Guernica, and plausibly pneumococcus vaccine, are both general immune stimulants that are now being considered and tested against SARS-CoV-2. The BCG study is already underway trans-nationally.

I went and got my pneumococcal vaccine, (plausibly by my wild guess, worth perhaps a reduction in hospitalization by about 15% or so).

It’s free from any pharmacy. But you can’t say you want it for SARS-CoV-2, LOL!

I will try to get another BCG shot as my last one was as a child!

Also, certain genes inherited by Asians and Caucasians from Neanderthals seem to increase lethality. With all these factors influencing outcome, experts to look at individuals could be valuable to optimizing our chance of remaining healthy.

It could be the beginning of a new profession in SARS CoV-2 counseling!


Asher Kelman

OPF Owner/Editor-in-Chief
So, who has gotten the pneumococcal vaccine? Is it hard to get hold of where you are?

And who already had the immune stimulant, BCG! That is worth looking at too!