Genes play a key role in virus resistance

Genes play a key role in virus resistance
Genes play a key role in virus resistance

French immunologist Jean-Laurent Casanova has begun research on the role of genetic variation in coronavirus susceptibility. Why can the virus be fatal for some, but at the same time not cause any symptoms in others?

The Covid-19 epidemic has killed more than 128,000 people around the world, but its impact is manifested in completely different ways depending on the person: the pathogen can be fatal for some, but at the same time it does not cause any symptoms in others. Genetic predisposition plays a key role in resistance to infectious disease. It is in this area that the pediatrician and immunologist Jean-Laurent Casanova, who, together with Laurent Abel, heads the laboratory of human genetics of infectious diseases in Paris and New York, conducts research. On March 23, Professor Casanova joined the scientific council on Covid-19.

Le Monde: As for people who are not at risk of Covid-19, why do some remain unharmed, while others show severe symptoms or even death?

Jean-Laurent Casanova: For about 20 years, we have been adhering to the hypothesis that all infectious diseases are associated with a genetic factor. The theory of the existence of a genetic basis for infectious diseases was confirmed by studies of classical genetics from 1905 to 1945. The question of the molecular structure of such a predisposition remained open. Since 1985 and especially 1996, we and other teams have identified many genetic changes that may explain a predisposition to serious infections, including herpes encephalitis and severe forms of tuberculosis and influenza.

In the case of infection with SARS-CoV-2, there are rare cases of severe forms, including fatal ones, in children, adolescents and relatively young adults. That is, we are not talking about two main risk factors here: adulthood and chronic diseases. These unexplained cases indicate the existence of genetic factors that influence the response to the virus.

What is your research?

- The hypothesis is that relatively young patients may have a genetic predisposition that does not manifest itself in any way until the first contact with the virus, but then leads to a severe form of the disease until the patient enters intensive care. According to this hypothesis, at the moment of contact with an infection, your phenotype appears, the vulnerability existing in your genes to it. Therefore, our goal is to identify genome variations that can explain the occurrence of severe forms.

Over the past 25 years, several teams of scientists have identified genetic variations that lead to selective vulnerability to certain infectious diseases in children, adolescents and young adults. In the past, we talked not about genetic variation, but about mutations, that is, about small differences in the genome that determine the uniqueness of each person.

More specifically, a blood test is performed to extract DNA and analyze the genome. The genomes of patients are examined both individually and collectively to find genetic variations that may be common in several patients. The research is led by the international consortium Covid Human Genetic Effort.

How many patients did you attract?

- We recruit patients under 50 years of age without chronic diseases who have been admitted to intensive care. This research started in China and then continued in Iran and southern Europe. Now it is being conducted all over the world. Some patients died in intensive care, others survived. Most of them are men. To date, we have recruited about 20 patients in New York and about 40 in Paris. First of all, we are looking for related forms: brothers and sisters, parents and children, cousins … We hope to attract at least 500 people, preferably about 2,000, which would allow us to more easily identify the variations existing in patients.

In principle, our research can be carried out on the basis of one patient, one genome. This may be enough to understand the genetic basis of a serious illness. However, if you find a gene A mutation in only one person from the 15th arrondissement of Paris, it will be difficult to prove that she is guilty of something. If such a mutation is revealed in three more patients from Columbia, Australia and California, it will be easier to determine its responsibility.

Many experts believe that the virus can enter human cells through the ACE2 receptor, which manifests itself differently in people under 50. Do you agree with this hypothesis?

- It does not seem to me a priority. First of all, we conduct a complete analysis of the genome, we test genetic, not immunological hypotheses, at least at first.

We are not currently testing receptors, although this does not mean that physiological, pathological, immunological and virological data do not play a role. All this will be considered in the second phase after the genetic analysis and in addition to it.

In younger adults, the development of a severe form occurs with a delay. There is talk of a "second wave" and an acute reaction of the immune system, which can lead to fatal shock. What do you think of it?

- I think genetic analysis can shed light on this question. Unlike an immunoassay, infection does not affect its results. The observed immunological response during infection or illness can be a cause or a consequence of a viral infection. It is impossible to say something definite. Genetic analysis will help establish the causes.

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