Two studies recently published by Brazilian scientists help to understand genetic factors that protect some people from infection or even from developing the severe form of Covid-19.
One of the studies was carried out with a group of elderly people over 90 years old who are resistant to Sars-CoV-2 and the other describes the case of identical twins with a different outcome for the so-called long Covid.
Since 2020, researchers from several countries, including Brazil, have sought to identify genes that provide protection against the new coronavirus, both preventing infection and favoring a mild disease, in the hope that this knowledge will allow the development of new vaccines and treatments against this disease. and others caused by viruses.
“If we really prove that some genes promote resistance to Sars-CoV-2, this may also be true for other types of viruses. From this, further work may seek to understand the mechanisms behind this resistance and develop drugs to increase the protection of people against viral infections”, says Professor Mayana Zatz, from the Biosciences Institute of the University of São Paulo (IB-USP) to Agência Fapesp.
Zatz is the coordinator of the Center for Studies on the Human Genome and Stem Cells (CEGH-CEL), a Center for Research, Innovation and Diffusion (Cepid) at Fapesp, and the lead author of two articles published in journals of the Frontiers group.
In one of the studies, scientists were looking for possible genes for resistance to Sars-CoV-2 and wanted to understand mechanisms involved in the extremes – cases of elderly people who are resilient to the disease, even though they may have comorbidities, as opposed to younger people without comorbidities who had very different forms. serious, some lethal.
For this, they worked with a cohort of 87 individuals called “super-elderly”, that is, over 90 years old who recovered from Covid-19 with mild symptoms or who remained asymptomatic after testing positive for the new coronavirus. The mean age was 94 years, and a woman was 114 years old at the time of the study and was considered the oldest person in Brazil to recover from the disease.
The data were compared with those of 55 people under 60 years of age who contracted the severe form or died, in addition to a base of the general elderly population in the city of São Paulo, obtained through a gene bank (read more here).
The researchers analyzed the region of chromosome 6, known as the Major Histocompatibility Complex (MHC). This area has dozens of genes that control the immune system in different ways, but it depends on special equipment and tools for analysis. There was also the sequencing of the exome (fraction of the genome that encodes the genes).
The SARS-CoV-2 infection was confirmed by the RT-PCR test, with samples collected in early 2020 – before local Covid-19 vaccination programs.
They obtained three important results in their work, two of which were only possible by using samples from a mixed population, as is the case in Brazil.
The first was that the group with mild Covid had an increased frequency of some variants of the MUC22 gene, twice that of patients with severe cases and even more frequent in the resilient super elderly. This gene is part of the mucin family and is one of those linked to the production of mucus, responsible for the lubrication and protection of the airways. On the other hand, the excessive production of this mucus has already been linked to inflammatory lung diseases found in severe cases of Covid-19.
According to the study, these mutations (missense-like variants, which change amino acids in the protein) of MUC22 may be reducing hyperactive immune responses against Sars-CoV-2 and, with that, playing an important protective role in the airways against the virus. . That is, one hypothesis is that individuals with better control of mucin production may be more resistant.
“It is possible that this variant, classified as missense, interferes not only in the production of mucus, but in its composition, since there is an exchange of amino acids in the protein. It will now be necessary to conduct new studies to understand how it acts during infection or in people healthy”, explains Erick Castelli, a researcher at the Faculty of Medicine of the Universidade Estadual Paulista (Unesp), in Botucatu, and first author of the article together with Mateus Vidigal, a postdoctoral fellow at CEGHCEL.
The work was published in Frontiers in Immunology and received support from Fapesp through Cepid, the National Institute of Science and Technology (INCT) on Aging and Genetic Diseases and four other projects (19/19998-8, 20/09702-1 , 13/17084-2 and 17/19223-0).
In addition, a point found to be investigated is the binding of MUC22 variants with the increased expression of miR-6891 microRNA. In genetic databases, it has already been shown that this microRNA associates with the virus genome and manages to break it. Therefore, the greater production of these molecules could somehow reduce the reproduction of the virus inside the cell, which would be related to mild Covid.
accumulated knowledge
The other two research findings are linked to more frequent gene variants in African and South American individuals, one being the *01:02 allele of the HLA-DOB gene. Through computer analysis, the scientists realized that HLA-DOB can interfere with the transit of some antigens (pieces of the virus) to the cell surface.
The immune system identifies these antigens and creates a response if they are “foreign” to the body. The researchers detected that the transit could be modified in these proteins from inside the cell to the surface, aggravating the infection. When comparing mild and severe cases of Covid-19, the frequency of this gene was three times higher in the second group.
“This is the second time that this variant of HLA-DOB appears in our studies. We have already found it in the survey with couples, where it was associated with cases of Covid-19 infection compared to uninfected. Now, it appears in serious records We were only able to locate it because of the miscegenation of our sample, with components of African and South American ancestry. As most studies are carried out in Europe, they are unlikely to be found there”, adds Castelli.
The researcher refers to another work published in 2021, with the participation of the three scientists, which took the first steps to understand why some people are naturally resistant to infection with the new coronavirus and others are not. At the time, genetic material was analyzed from 86 couples in which only one of the spouses was infected with Sars-CoV-2, although both were exposed without protection.
The results suggested that certain genetic variants found more frequently in resistant partners would be associated with more efficient activation of defense cells known as natural killers (or NK for “natural killers”). When NKs are activated correctly, they are able to recognize and destroy infected cells, preventing the disease from taking hold in the body (read more here).
With an important role in the collection of samples, Vidigal highlights the relevance of the cohort used.
“We work with extremes, not only in relation to cases —mild, severe and who died — but also in terms of age, with the super-elderly. We continue to monitor these patients and are developing new projects with centenarians”, adds Vidigal.
Finally, the third result is linked to the HLA-A gene, one of the main factors responsible for creating a kind of “showcase” on the cell surface, showing defense cells which proteins are inside that cell. A variant of this gene appeared twice as often in individuals who had the severe form of the disease.
Post-Covid
In the other study, the scientists reported a case of identical (monozygotic) twins, 32 years old at the time, who simultaneously had severe Covid-19 requiring hospitalization and oxygen use, despite their age and previous good health.
Coincidentally, the two were hospitalized and intubated on the same day, but one of the brothers spent eight more days in the hospital and only he had long-term Covid, that is, he continued with symptoms, mainly fatigue, even after seven months of infection.
After evaluating the profile of immune cells and specific responses to Sars-CoV-2, in addition to complete exome sequencing (the part of the genome responsible for encoding proteins), the scientists pointed out that the different clinical evolution between them reinforces the role of the immune response and genetics in the development of the disease.
According to the work, published in Frontiers in Medicine, although identical twins share the same genetic mutations that may be associated with an increased risk of developing the severe form, the clinical course was different. In relation to the post-Covid syndrome, it corroborated an association between the length of hospital stay and the occurrence of long-term symptoms.
“Cases of seven pairs of adult identical twins who died from the disease within days of each other had already been recorded in Brazil, which draws attention to the genetic component of Covid-19. at the same time and it was only to find out about each other in the hospital, we were interested in describing the case. The fact that they were infected simultaneously and developed a severe form of the disease reinforces the hypothesis of a genetic factor”, says Vidigal, first author of the work. , which also received support from Fapesp.
According to the researcher, among the systemic parameters linked to post-Covid fatigue that appeared altered are ferritin (a protein produced by the liver involved in iron metabolism) and creatine kinase (a muscle protein).
“In research like these, teamwork is extremely important, involving genomics, immunology, the clinical part and others. When you want to answer complex questions, it is important to know how to design the experiment and identify the patients who can best help answer the question. And this is not easy”, summarizes Zatz.
Such is this difficulty that an international team of researchers launched in October last year in the journal Nature a kind of global hunt for people genetically resistant to infection by Sars-CoV-2.
The article “MUC22, HLA-A, and HLA-DOB variants and Covid-19 in resilient super-agers from Brazil” (“MUC22, HLA-A and HLA-DOB variants and Covid-19 in resilient super-agers from Brazil” ) can be read here.
The study “Follow-up of young adult monozygotic twins after simultaneous critical coronavirus disease 2019: A case report” is accessible here.
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