Brazilian researchers evaluated seniors over the age of 90 and the case of identical twins; The expectation is that the findings will contribute to the search for new treatments and vaccines
AGENCIA FAPESP – Two recently published studies by Brazilian scientists help understand the genetic factors that protect some people from infections or even the development of the severe form of the disease. COVID-19. One of the studies was conducted with a group of elderly over 90 years resistant to SARS-CoV-2 and the other describes the case of identical twins with different outcomes for the so-called long covid.
Since 2020, researchers from several countries, including Brazil, have been trying to identify genes that provide protection against the novel coronavirus, both by preventing infection and by promoting mild disease, in the hope that this knowledge will enable the development of new vaccines and treatments against this and other diseases caused by viruses.
“If we really show that some genes promote resistance to SARS-CoV-2, this could also apply to other types of viruses. From this, further work could seek to understand the mechanisms behind this resistance and develop drugs to increase protection. of people against viral infections, “the professor tells Agência FAPESP Maya Zatz of the Institute of Biosciences of the University of São Paulo (IB-USP).
Mayana Zatz is coordinator of the Center for the Study of the Human Genome and Stem Cells (CEGH-CEL), a Center for Research, Innovation and Diffusion (CEPID) of FAPESP and lead author of two articles published in journals of the Frontiers group.
In one of the studies, scientists were looking for possible SARS-CoV-2 resistance genes and wanted to understand the mechanisms involved in extremes – cases of elderly people who are resilient to the disease, even though they may have comorbidities, as opposed to young people without comorbidities. which had very different forms, severe, some lethal.
For this they worked with a cohort of 87 individuals called “super-elderly”, or over 90 who have recovered from covid-19 with mild symptoms or who remained asymptomatic after testing positive for the new coronavirus. The median age was 94, and a woman was 114 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 who contracted the severe form or died, as well as a base of the general elderly population in the city of São Paulo, obtained through a gene bank (read more on : https://agenzia.FAPESP.br/38069/).
chromosome 6
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 exome sequencing (fraction of the genome that codes for genes). SARS-CoV-2 infection was confirmed by RT-PCR testing, with samples collected in early 2020 – prior to local covid-19 vaccination programs.
They achieved three important results in their work, two of which were only possible using samples from a mixed population, as in the case of Brazil.
The first was that the mild covid group 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 related to the production of mucus, responsible for lubricating and protecting the airways. On the other hand, 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 modify amino acids in the protein) of MUC22 could reduce overactive immune responses against SARS-CoV-2 and, thereby, play 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 works during infection or in healthy people “, explains Erick Castelli, researcher at the Faculty of Medicine of the Universidade Estadual Paulista (Unesp), in Botucatu, and first author of the article together with Mateus Vidigal, postdoctoral fellow at CEGH-CEL.
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).
Furthermore, one point that needs to be investigated is the binding of MUC22 variants with increased expression of the miR-6891 microRNA. It has already been shown in genetic databases that this microRNA binds to the genome of the virus and manages to break it down. Therefore, the increased production of these molecules could somehow reduce the reproduction of the virus within the cell, which would be related to the mild covid.
accumulated knowledge
The other two research findings are linked to genetic variants more frequent in African and South American individuals, one of which is the * 01: 02 allele of the HLA-DOB gene. Through computer analysis, scientists realized that HLA-DOB can interfere with the transit of certain antigens (pieces of the virus) on the cell surface.
The immune system identifies these antigens and creates a response if they are “foreign” to the body. The researchers found that the transit of these proteins could be changed 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 this variant of HLA-DOB has appeared in our studies. We already found it in the couple survey, where it was associated with cases of covid-19 versus uninfected. Now it appears in serious records. We were only able to locate it because of the crossing of our sample’s breeds with components of African and South American descent. Since most of the studies are conducted in Europe, it is unlikely that they will 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, the genetic material of 86 couples in which only one of the spouses was infected with SARS-CoV-2 was analyzed, although both had been exposed unprotected.
The results suggested that some genetic variants found more frequently in resistant partners would be associated with more efficient activation of defense cells known as natural killer (or NK for natural killer). 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 on: agency.FAPESP.br/35752/).
With an important role in sample collection, Vidigal emphasizes the relevance of the cohort used. “We work with extremes, not only in relation to cases – mild, severe and deceased – but also in terms of age, with the super seniors. 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 sort of “showcase” on the cell surface, which shows the 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 twins (monozygotic), 32 years old at the time, who simultaneously suffered from severe covid-19 which required hospitalization and the use of oxygen, despite his age and previous good health conditions.
Coincidentally the two were hospitalized and intubated on the same day, but one of the brothers spent another eight days in the hospital and only he had long-standing covid, meaning he continued with symptoms, mainly fatigue, even after seven months of infection. .
After evaluating the immune cell profile and specific responses to SARS-COV-2, as well as complete exome sequencing (the part of the genome responsible for protein coding), the scientists pointed out that the different clinical evolution between the two strengthens the role of the immune and genetic response in the development of the disease.
According to the work, published in Borders 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 post-covid syndrome, it corroborated an association between the length of hospital stay and the onset of long-term symptoms.
“The 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 was just to find out for each other in the hospital, we were interested in describing the case. The fact that they were infected at the same time and developed a severe form of the disease strengthens the hypothesis of a genetic factor, “says Vidigal, first author of the Opera. , 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 this, teamwork is extremely important, involving genomics, immunology, the clinical part and more. When you want to answer complex questions, it is important to know how to design the experiment and identify the patients who can to help answer the question in the best possible way. And it’s not easy “, summarizes Mayana Zatz.
Such is this difficulty that an international team of researchers launched in October last year in the journal nature a sort of global hunt for people genetically resistant to SARS-CoV-2 infection.
.