They are 'dodgers' of SARS-CoV-2, 'super resistant', 'surfers' of all the pandemic waves that have not been infected despite maintaining continuous exposures, living with infected people or doing jobs in which contagion was almost inevitable. This 'shield' contrasts with the situation of people who, despite not presenting greater predisposing factors -age or associated morbidities, for example-, not only became infected but, in some cases, presented the most serious forms of the infection and even died.
Individual immunity was one of the first causes considered in this kind of 'viral autoimmunity'. But, personal genetic traits were not lost sight of, whose peculiarities would act as protectors against SARS-CoV-2, giving the organism a range of 'hyperimmunity'. In fact, the potential power of genes in the development and severity of Covid-19 and its influence on immune responses has been in the spotlight since the first months of the pandemic.
In a paper published in Nature Immunology, the French immunologist and pediatrician Jean-Laurent Casanova, director of the Laboratory that he shares between the Rockefeller University of New York, and the Necker Children's Hospital, in Paris, pointed out that “the genetic landscape of an individual in particular and of a population in general would play a fundamental role in shaping the dynamics of Covid-19.”
What's more, this renowned world expert told Diario Médico that the multisystem inflammatory syndrome of Covid-19 (MIS-C), which seriously affects some children, also has a genetic explanation.. “There is a genetic cause and, at least in some children, MIS-C appears due to congenital errors,” Casanova advanced.
From severe to asymptomatic
The questions and the steps that were taken around the genetic causes of the severity of Covid-19 began to move, almost simultaneously, to the other side of the coin: people who have never been infected with this viral disease, opening up the mystery once again: can genetics also clarify why there are people who continually avoid SARS-CoV-2?
According to the findings of a new study published in the latest Nature, the answer seems to be yes and the key would be to be a carrier of a specific genetic variant, the HLA-B*15:01 mutation.
The work, which offers one of the first evidences of the genetic basis for asymptomatic SARS-CoV-2, shows that carriers of this variant can become infected but do not get sick.
The secret is in the human leukocyte antigen (HLA). One of the HLA-encoding genes appears to help virus-clearing T-cells identify SARS-CoV-2 and launch a 'blitzkrieg attack'. Thus, the T cells of people who carry this variant can identify the new coronavirus, even if they have never encountered it before, thanks to its resemblance to the seasonal cold viruses they already know.
Pointing to new targets for future Covid-19 drug and vaccine development, this exciting discovery is the result of a US-Australia collaborative led by Danillo Augusto of the University of North Carolina at Charlotte; Jill Hollenbach, from the University of California, San Francisco; and Stephanie Gras, from La Trobe University, in Australia.
The common denominator
Hollenbach, a professor of neurology, epidemiology and biostatistics at the Neill Institute for Neurosciences at the University of California, San Francisco, and her team collected data from the beginning of the pandemic on 29,947 unvaccinated people who were tested using a mobile app designed specifically to track symptoms of Covid-19, including 1,428 who tested positive for the virus between February 2020 and the end of April 2021, before vaccines were available.
Of these, 136 people remained asymptomatic for at least two weeks before and after testing positive.. Only one of the HLA variants, HLA-B*15:01, had a strong association with asymptomatic Covid-19 infection, a fact that was reproduced in two independent cohorts.
“Risk factors for this pathology, such as age, being obese, and having chronic diseases such as diabetes, did not appear to influence those who remained asymptomatic,” says Hollenbach, the study's lead author, whose team focused on the concept of T-cell memory through which the immune system remembers previous infections.
According to Augusto, it has been observed that T cells from people who carried HLA-B15, but who had never been exposed to the SARS-CoV-2 virus, still responded to a part of the new coronavirus called the NQK-Q8 peptide.. “Exposure to some seasonal coronaviruses, which have a very similar peptide called NQK-A8, allowed the T cells of these people to quickly recognize SARS-CoV-2 and mount a faster and more effective immune response.”
The HLA-B*15:01 mutation is quite common, as it is carried by about 10% of the population studied.. It doesn't prevent the virus from infecting cells, but it does prevent infected people from developing any symptoms, which would also include a runny nose or even a barely noticeable sore throat.
In the new study, UC researchers found that 20% of participants who remained asymptomatic after infection had at least one copy of the HLA-B*15:01 variant, compared with 9% of those who reported symptoms.. Carriers of two copies of this variant were eight times less likely to present pathological symptoms.
For Gras, Professor and Head of the Laboratory at La Trobe University in Australia, this first finding opens the door to greater and new possibilities promoting immune protection against SARS-CoV-2 that could “be used in the future development of vaccines or drugs”.
The challenge of revealing more answers
Confirming that genetics is directly involved in the different pathological responses to the coronavirus has been one of the challenges for global consortia of scientists.
The first data offered by the French immunologist and pediatrician Jean-Laurent Casanova, on the severity of Covid-19 and genetic involvement, as well as that of other first investigations, led to the development, in March 2020, promoted by geneticists and immunologists, of the international COVIDHGE (COVID Human Genetic Effort) Consortium, led by Casanova.
His first project was to specify how genetics could help to understand extreme cases of severity: young people without comorbidities who died or who, in the best of cases, required assistance in Intensive Care Units (ICU) with ventilation needs. On this occasion, several studies in Science confirmed that up to 5% of cases were due to mutations in interferon genes and that around 10% were associated with the presence of autoantibodies against interferon, the line of defense. knocked out or by genetic mutations or by blocks by the antibodies themselves.
These enlightening results were a new starting point for the researchers that make up this international consortium.. Can genes also explain why there are people 'super resistant' to SARS-CoV-2?
Again, the experts did not lose sight of the influence of genes. “Actually, they are 'sides of the same coin': applying genomic medicine to understand side A; young people, with no previous pathology and who have severe illness, and side B; those who are overexposed to the virus – they sleep for a week with their partners who have tested positive, do not use the protection of the mask or any preventive measure – and do not become infected. Could the key be in your genes?. This is the response that is going to be analyzed,” the geneticist Aurora Pujol explained to DM.
This specialist, ICREA professor, group leader at the Bellvitge Biomedical Research Institute (Idibell) in Barcelona, and coordinator in Spain of the international COVIDHGE Consortium (COVID Human Genetic Effort) for the subproject for the study of superimmunity against Covid-19, whose first arguments are already known after the work recently published in the latest Nature.
This subprogram on hyperimmunity also includes the presence of Jesús Troya, from the Internal Medicine Service of the Infanta Leonor Hospital, in Madrid, and Carlos Rodríguez-Gallego, from the University Hospital of Gran Canaria Dr.. negrin.
adaptive benefit
Jesús Troya -expert who verified the presence of neutralizing autoantibodies to interferon in patients with severe Covid-19 pneumonia in a study carried out at his hospital and published in the Journal Clinical of Immunology-, pointed out that as occurs with all pathogens, a certain percentage of the population is refractory to the development of the infection. “Usually, the phenomenon is conditioned by genetic mutations that express genes of various kinds.”
What, initially, genetics results in an abnormal transformation in a person, can become an adaptive benefit in individual cases, considers Troya, who gives another clear example: “If the pandemic had been Ebola, it would have decimated the world population, but some subgroup would have survived. It's what we call a 'genetic lottery' for a certain type of infection or other disease.”