Based on this knowledge, it will be possible to not only create completely new diagnostic tests, but also identify patients most at risk of severe course and design innovative treatment methods.

In the study, the preprint of which has just been published, researchers looked at four large groups of patients: two from America, one from Spain and one from Poland (Szczecin) - over 700 people in total.

All this to answer the question: How to identify patients who will have a severe COVID-19, will require intubation and intensive care. What distinguishes them from people whose infection is mild or non-symptomatic? 'We know, of course, that the risk of a severe course of COVID-19 increases with certain comorbidities, such as diabetes or obesity, and in people at an advanced age', says the project leader, Dr. Tomasz K. Wojdacz, head of the Independent Clinical Epigenetics Laboratory of the Pomeranian Medical University in Szczecin and a professor at Aarhus University in Denmark. 'But despite this, we also see young, healthy people dying from COVID-19, while some people from risk groups have a very mild course. So there has to be more to it'.

SARS-CoV-2 CHANGES OUR GENES

Last year, the group led by Professor Manel Esteller from the Josep Carreras Leukaemia Research Institute in Barcelona published the results of the study that showed epigenetic changes in the blood of COVID-19 patients, based on which patients could be segregated according to the severity of the disease. However, this study did not say anything about the genesis of these changes. 'It showed that the infected have changes that correlated with the disease, but whether they had occurred as a result of the direct action of the virus, or had been present before - this issue was not dealt with at all in that study', says Dr. Wojdacz.

'We therefore decided to determine whether epigenetic changes appeared only as a result of infection, or perhaps they had been in the genes before the infection and only correlated with the severe course of the disease, and whether they occurred in patients with similar clinical symptoms caused by other viruses. In other words, we wanted to check if the SARS-CoV-2 virus itself induced epigenetic changes', he explains.

In addition to Dr. Wojdacz, several eminent Polish scientists were involved in the study, including Professor Miłosz Parczewski from Szczecin - a specialist in the field of infectious diseases, Professor Bogusław Machaliński - the rector of the Pomeranian Medical University, and Professor Dominik Strapagiel from the University of Lodz. As for the foreign institutions involved in the project, these were the Josep Carreras Leukaemia Research Institute and the University Hospital of Bellvitge in Spain.

'I was quite sceptical about the results of this study at first, because it usually takes a long time for epigenetic changes to occur in genes under the influence of contact with the factor causing them', says Dr. Wojdacz. 'And here we are dealing with a situation where patients had their first contact with the virus only a week, maybe 10 days earlier'.

It turned out that such a quick reaction was possible. Dr. Wojdacz explains that it is most likely because the blood - which the study concerned - is a specific tissue. Most blood cells divide very often; they live relatively shortly. Skin cells, for example live for several dozen days, liver cells for several hundred days, and bone cells for up to 10 years. Meanwhile, most of the cells of the immune system circulating in our bloodstream are short lived.

Why did the study focus on blood cells? 'Because the first front in the fight against SARS-CoV-2 is at the level of blood cells, and more precisely the cells of the immune system. What happens next, for example in the lungs, are the effects of the disease, which appear when the immune system cannot handle the virus. That is why we wanted to see if anything and what happens in blood cells', the scientist says.

He and his team compared epigenetic profiles of blood cells from over 700 patients from different regions of the world, including those hospitalised, outpatients, and completely non-symptomatic ones, who had positive PCR test results. 'And then we checked if these profiles correlated in any way with the severity of the disease', he says. 'It turned out that they did'.

'We identified specific genes affected by these changes and, most importantly, we examined whether and how these changes affected gene expression. Remember that not every epigenetic change results in a change in gene expression. We know a lot of cases where this is not the case. But from the point of view of the development of the disease, the most important changes are those that also result in a change in gene expression, because the products of gene expression, i.e. proteins, are directly involved in the development of the disease', adds Dr. Wojdacz.

To sum up, in order to prove the link between epigenetic changes and the development or course of the disease, it is necessary to prove that they affect gene expression. 'And we did it', the scientist emphasizes.

WHO SHOULD BE AFRAID OF COVID?

There were not many such changes. 'Only a few of the most important ones. They concerned genes that are involved in the body's response to SARS-CoV-2 infection, specific genes from interferon pathways', explains the study co-author.

'Importantly, these specific epigenetic changes occur in all patients who have come into contact with the virus. Literally everyone! Not just patients, simply all people, because they are also present in those with a non-symptomatic infection, who are hardly patients'. he emphasises. 'So it's safe to say that they are excellent COVID-19 biomarkers'.

According to the expert, it has been established indisputably that the virus alters epigenetics in everyone who comes into contact with it. So why some people have a severe infection, while others have a mild or even non-symptomatic one? How are these people different from each other?

'It turns out that the difference is that although epigenetic changes are always present in SARS-CoV-2 infection, they only occasionally cause changes in gene expression. In other words: everyone has them, but only in some people they actually change the activity of certain genes. In others, the expression of these genes does not change at all. And it is the latter that more often end up in intensive care units, require intubation, etc.', explains Tomasz Wojdacz.

'We do not yet know the reason why it sometimes happen and sometimes not. But we know for sure that this is exactly what is happening here. And that a patient who triggers a response at the gene expression level will have a milder course of COVID-19', he says. 'We have thus proven that epigenetic changes can modulate a rapid immune response. It's a very important discovery that one virus can change the epigenetic mechanisms that determine how our tissues function'.

THE MYSTERIOUS LONG TAIL

Along with the results, the question arose whether the epigenetic changes caused by SARS-CoV-2 would regress immediately after passing COVID-19, or would they persist in the body for a longer time, perhaps permanently? This is the topic of another project planned by Dr. Wojdacz.

'It is especially interesting in the context of long covid, which we see in patients more and more often. We don't know yet if there is any connection between these things, but it seems possible. We want to check if the changes we are talking about do not persist longer in people with long covid. Perhaps epigenetics has something to do with long-lasting post-covid complications, because so far we have no reason to believe that people with long covid are genetically different from those with a mild course of infection', he explains.

THE STUDY THAT OPENS MANY DOORS

A very interesting discovery, to which this study led, was that the epigenetic changes caused by SARS-CoV-2 in blood cell genes were specific to this particular virus. The scientists checked whether infections with other viruses (coronaviruses and rhinoviruses) causing the same symptoms as SARS-CoV-2 could cause such changes, and found that they could not.

'We compared our covid patients with people who had identical clinical symptoms caused by other pathogens, such as the influenza virus. None of them had such epigenetic changes as people with COVID-19', says Dr. Wojdacz.

'This means that not only have we shown that SARS-CoV-2 induces these changes, but also that they are specific for this particular virus. And since they are specific, it means that they can be not only great biomarkers for identifying infected people, but also a potential target for the development of new treatment methods', he emphasizes.

What methods could those be? Dr. Wojdacz explains that it is enough to activate the genes affected by epigenetic changes in those people, in whom they did not activate themselves. Medicine has ways to do this. 'Most importantly, we already know which genes in COVID-19 patients need to be activated to prevent a severe course. Potentially, it could be done preventively in anyone who is infected', he explains.

'In conclusion: We have established that epigenetics indeed participates in the pathology of SARS-CoV-2 infection; that the changes caused by the virus are an excellent material for a new type of diagnostic test and a test that allows to segregate patients into those who have a severe or mild course of the disease; that the correlation we have discovered between epigenetics and immune response gene expression is a target for completely new treatments. We have opened the door for diagnosis, identification of risk groups and for treatment. It is an excellent starting point for further research for cell biologists, immunologists and clinicians. And since this type of research requires the cooperation of many research groups, we would like to invite scientists from all over the country to collaborate in our next projects', concludes Dr. Wojdacz.

PAP - Science in Poland, Katarzyna Czechowicz

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