The secret of the vulnerability of some to COVID-19

COVID-19 has struck down healthy young people in their twenties, and many more men than women. It still devastates some people and, strangely, leaves others almost unharmed. Scientists were quickly intrigued by the fact that some apparently healthy individuals seemed more vulnerable than others to this infection which never ceases to amaze us. They quickly hypothesized that particular genetic factors were probably behind these differences in the disease.

An international project called COVID Human Genetic Effort involving more than 50 sequencing centers and hundreds of hospitals around the world, including the Research Institute of the McGill University Health Center (IRCUSM), has just discovered the biological and genetic factors that are responsible for the severity of the disease. infection in many people without a medical history. This discovery is the subject of two articles in the journal Science.

“It was first discovered that the infected people whose condition deteriorated to the point of threatening their lives were mostly seniors and men with other health problems, such as heart disease or kidney disease. Then, we noticed that some young people without any of these risk factors also fell seriously ill. We then wondered why these people in particular were at greater risk of dying from COVID-19, “says Dr.r Donald Vinh, clinical researcher at IRCUSM, who is the only Canadian to contribute to this international consortium of researchers.

The Consortium first found that all of these people who were particularly vulnerable to COVID-19 had an immune system defect that had remained invisible until then.

When SARS-CoV-2 affects human cells, one of the immediate actions of the immune system (innate immune response) is to attack the virus using a family of cytokines called type 1 interferons. found that in more than 13.5% of people suffering from a severe form of COVID-19, no type 1 interferon was detected during the acute phase of their infection, whereas those infected, but not very ill , produced abundantly. While looking for the cause of this anomaly, they discovered that a protein (an auto-antibody) present in the blood of these severely affected people neutralized interferon type 1. “Antibodies are proteins that are produced. naturally to fight germs that enter our body, but in some cases, such as lupus, an autoimmune disease, the body produces autoantibodies that attack tissues within the body itself, such as type 1 interferon in this case ”, explains Dr Vinh.

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“In more than 10% of severely ill patients, the autoantibodies attacked the immune system cytokine that was needed at the onset of infection to fight viruses. And their action was so effective that we could no longer detect it in the blood of patients, “says Dr.r Vinh, who is among the authors of the article by Science which relates this discovery.

The researchers also found that in another group of patients, representing 3.5% of those severely affected by COVID-19, neither type 1 interferon nor autoantibodies were found in their blood. When the scientists sequenced the genome of the 659 critically ill patients and 534 individuals with mild or asymptomatic infection who participated in the study, they noticed that 3.5% of patients carried genetic mutations (described in Science) which compromised the production of type 1 interferon, and that these mutations were carried mainly by young patients.

On the other hand, they observed that the patients who presented autoantibodies were mainly elderly men. “Over 90% of the patients with autoantibodies were elderly men. For the first time, we can explain why this category of people is more severely affected by COVID-19 “, enthuses Dr.r Vinh who is on the lookout for new mutations in other genes possibly related to type 1 interferon that could be the cause of the severity of the infection in a different percentage of patients.

To explain the fact that it is mainly men who tend to produce autoantibodies, the researchers suspect that the presence of a mutation in a gene on the X chromosome of men may be at the origin of this abnormality which induces the production of autoantibodies.

Over 90% of the patients with autoantibodies were elderly men. For the first time, we can explain why this category of people is more severely affected by COVID-19.

And why is it mostly older men who produce autoantibodies? “Over the course of life, various events and factors, such as our diet, the infections we contract, the environment in which we live, our lifestyles, such as smoking, modify the expression of our genes. And so, probably with age, there are epigenetic changes that influence genes that are suspected of producing autoantibodies that normally would not induce a particular disease, but which upon exposure to SARS-CoV-2, cause serious illness, ”explains the researcher.

Unfortunately, people who are victims of this immune system disorder do not have other characteristics that would allow them to be recognized. “The majority of people who have been found to have mutations or autoantibodies have no history of serious infections, no health problems that could lead us to suspect this disorder. There really does appear to be a unique link to COVID-19. The latter seems to be the only infection to be associated with it, ”says Dr.r Vinh.

Useful for prognosis

These important findings will help screen people who are at greater risk of developing life-threatening COVID-19 through simple blood tests, says Dr.r Vinh.

“We can make a prognosis by taking a blood test and looking for autoantibodies against type 1 interferon in elderly men living in a CHSLD who have tested positive for COVID-19 as a result of a screening test. We will be able to hospitalize those in whom we detect autoantibodies in order to monitor them more closely given their increased risk of developing a severe form ”, specifies the researcher.

Another way will be to measure the serum level of type 1 interferon. “However, we do not currently have the necessary equipment and sufficient resources in Quebec to perform this measurement, but with the support of the government, we could provide an institution, like the MUHC, to do so. If by this test we do not detect interferon in an infected person, it will help us establish a prognosis which will prompt us to hospitalize it, ”he continues.

Could we do a genetic test that would tell us if the person has mutations that prevent type 1 interferon production? “In theory, it would be possible, but it takes time to receive the results of these tests. We could possibly try to accelerate their execution during the pandemic, “says the researcher.

Orient the treatment

The discovery will also help provide more adequate treatment for patients with type 1 interferon deficiency, says Dr.r Vinh. “Forms of type 1 interferons have long been used as drugs for other diseases. Two categories of type 1 interferon already exist on the market: on the one hand, alpha interferon (Intron A) that we use to treat viral infections other than COVID-19 and which was formerly used to treat hepatitis C and some cancers; on the other hand, beta interferon which is an old drug that was prescribed to treat multiple sclerosis, ”he says.

These two drugs could be given to people who do not synthesize type 1 interferon because of the genetic mutations they carry, as well as to those who produce autoantibodies to type 1 interferon.

Another treatment, plasmapheresis, which involves removing autoantibodies from the blood of an infected person, may also be offered to vulnerable patients who produce this type of antibody. “However, if a person produces autoantibodies directed specifically against interferon alpha, which is most commonly seen, they may be given interferon beta and, vice versa, if an individual has autoantibodies. targeting interferon beta, he may be offered alpha interferon. But if a person unfortunately has antibodies against both forms (alpha and beta) of type 1 interferon, plasmapheresis could help them fight infection, “says Dr.r Vinh.

The consortium of researchers is now working to set up clinical trials that will aim to validate the use of a blood test to measure the levels of type 1 interferon in elderly men who have tested positive for COVID-19 , as a prognostic tool.

Another clinical trial will examine whether infected people in whom no type 1 interferon could be detected would benefit from the administration of alpha or beta interferon. These clinical trials are a necessary step before recommending this method of prognosis and these therapeutic approaches to the medical community, says Dr.r Vinh.

“Our findings published Thursday in Science target the very onset of infection, when someone has just been determined by a drug test to be infected. They will allow us to determine which people are at high risk of developing a severe form of the disease. In addition, they will allow us to offer these people at higher risk special treatment from the onset of infection, “summarizes the researcher.

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