Covid-19: asymptomatic forms explained by genetics?

Would we finally be able to explain why some people do not fall ill with Covid-19 after being infected? Researchers from the University of California, San Francisco and La Trobe University, Australia, have spotted a genetic variant that would prevent people from developing characteristic symptoms of the disease, such as a runny nose or sore throat. This discovery, published in the journal Nature, is the first evidence that there is a genetic basis for asymptomatic forms of Covid-19.

Nicknamed “super dodgers”, some of the 20% of people infected with Sars-CoV-2, but showing no symptoms of Covid-19, could in fact hold a rare genetic asset. . According to the researchers, they are more than twice as likely to carry a specific genetic variation that makes it easier to clear the virus. This variation, known as "HLA-B*15:01", is carried by one of the genes responsible for the production of human leukocyte antigen (HLA), a protein that plays a key role in the recognition of pathogens by the immune system.

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The researchers suspected the role of HLA because its genetic variations in the population determine the efficiency with which the defense system of individuals fights infectious diseases, including Covid-19 but also HIV for example. "Until now, we had not specifically looked at the role of the HLA in asymptomatic forms because studies were first interested in severe forms", explains Laurent Abel, director of the human genetics laboratory for infectious diseases at the Inserm. The problem is that since no individual carries the same HLA genetic variations, or HLA variants, locating the differences remains tedious. However, for organ recipients and donors, the identification of these HLA variants is systematic because this makes it possible to predict the compatibility of the graft. This is why the researchers were interested in 30,000 Americans registered on the list of marrow donors and for whom they therefore already had access to HLA variants.

During the first year of the pandemic, these 30,000 people were regularly tested when there was no vaccine yet. The researchers were thus able to identify 1,428 people positive for Covid-19 between February 2020 and the end of April 2021. Among them, 136 remained asymptomatic. By comparing the HLA variants of people with and without developing symptoms, the team found that 20% of asymptomatic individuals carried at least one copy of the HLA-B*15:01 variant, compared to 9% of people with had symptoms. Carriers of both copies of the variant were eight times less likely to develop symptoms.

To understand how this genetic variation allows super dodgers not to get sick, the researchers looked at how their immune system reacts to the virus responsible for Covid-19. Assuming a probable link with the action of memory T lymphocytes, immune cells capable of remembering previous infections to better fight them, they were able to demonstrate their hypothesis: “The T lymphocytes of super dodgers carrying the HLA-B*15 variation :01 and having never been exposed to the SARS-CoV-2 virus, seem to be able to quickly recognize the virus due to its similarity to other species of previous coronaviruses, such as HCoV-HKU1”, explains Prof. Seiamak Bahram, Director of the Molecular Immuno Rheumatology Unit at Inserm and Head of the Immunology Department of Strasbourg University Hospitals.

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This early recognition in super dodgers would trigger a faster and more effective defense against the virus. Proof finally that we are not all equal in the face of infections. “It's a bit as if these individuals had benefited from a natural vaccination, observes Laurent Abel. What seems surprising, however, is that these “naturally vaccinated” people should also have less serious forms. However, this has not yet been verified.

The authors also point out that they are also not certain of the implication of this discovery for the development of vaccines or treatments. “It's a relative protective effect. Current vaccines against Covid-19 protect much more”, underlines Professor Abel. “The results remain very interesting for better understanding the individual response to an infection, notes for his part Seiamak Bahram. But we suspect that even after verification on other cohorts, the asymptomatic forms of Covid-19 are probably based on a very wide variety of factors which are not limited to HLA variations.