Washington [US], November 22 (ANI): Two recent papers by Brazilian researchers have added to the scientific understanding of the genetic factors that protect people from SARS-CoV-2 infection or prevent progression to severe COVID-19. The first describes the findings of a study involving a group of resilient older people aged 90 or more, while the second examines a case of severe COVID-19 in identical twins, only one of whom had long-term symptoms of the disease.
"If we can really prove that some genes promote resistance to SARS-CoV-2, the same may also be true for other viruses. More research can then be based on these findings to try to understand the mechanisms underlying this resilience and develop medications that enhance protection against viral infections," Mayana Zatz, and lead author of the articles published in "Frontiers in" journals, told Agencia FAPESP.
In one of the studies, the scientists set out to identify genes conferring resistance to SARS-CoV-2 and understand the mechanisms involved in two extremes: elderly people who were resilient to the disease even when they had co-morbidities; and younger people without co-morbidities who developed very severe COVID-19, even dying in some cases.
They compared the data for these patients with data for 55 patients under the age of 60 who recovered or died from severe COVID-19, and with a database containing whole-genome sequences for elderly inhabitants of Sao Paulo city (read more at: agencia.fapesp.br/38194).
They also analyzed the exome (the sequence of all exons), reflecting the protein-coding portion of the genomes concerned.
They arrived at three very important results, two of which were made possible only by the use of samples from a population that is highly mixed in terms of ethnicity and ancestry.
These mutations in MUC22 are technically termed "missense" variants, DNA changes that result in different amino acids being encoded at particular positions in the resulting proteins. According to the article, they may weaken the hyperactive immune responses to SARS-CoV-2 and play an important role in protecting the airways against the virus. One of the hypotheses entertained by the authors is therefore that the resilient subjects may have optimal control of mucin production.
The paper is published in Frontiers in Immunology. The study was supported by FAPESP via HUG-CELL, the National Science and Technology Institute on Aging and Genetic Disorders, and four other projects (19/19998-8, 20/09702-1, 13/17084-2 and 17/19223-0).
Another point to be investigated is the link between variants of MUC22 and increased expression of a microRNA called miR-6891. Research involving genetic databases has shown that this microRNA is associated with the viral genome. The authors hypothesize that higher expression of miR-6891-5p associated with all MUC22 protective variants may somehow reduce viral reproduction in cells and contribute to less severe symptoms during SARS-CoV-2 infection.
Accumulated knowledge
"This is the second time this HLA-DOB variant has been detected in our research. We found it in our study of married couples, where it was associated with COVID-19 cases as compared with non-infected subjects," Castelli said. "This time we found it in severe cases. We were able to locate it only because of the admixed composition of our samples, with African and South American ancestral components. Most research in this field is done in Europe, and they're unlikely to find it there."
The results suggested that certain genetic variants found more frequently in the resilient subjects were associated with more efficient activation of defense cells known as natural killers (NKs). When NKs are correctly activated, they are able to recognize and destroy infected cells, preventing the disease from developing in the organism (read more at: agencia.fapesp.br/35839).
The third important result had to do with HLA-A, one of the genes responsible for creating a "window" on the cell surface to show defense cells which proteins are inside the cell. A variant of this gene appeared twice as many times in severe COVID-19 patients.
In the other study, the scientists analyzed a case of monozygotic (identical) twins, then aged 32, who simultaneously presented severe COVID-19. They were hospitalized and given oxygen support despite their age and prior good health. Coincidentally, they were admitted directly to intensive care and intubated on the same day. However, one of the brothers spent a week longer in hospital and only this twin had long COVID, continuing to suffer from fatigue and other symptoms even seven months after being infected.
In an article on the study published in Frontiers in Medicine, they note that the brothers' clinical progression was different despite the fact that they shared the same genetic mutations potentially associated with an increased risk of developing severe COVID-19, and that the post-COVID syndrome observed in one of them pointed to an association between hospital stay and the occurrence of long-COVID symptoms.
The altered systemic parameters associated with post-COVID fatigue included ferritin (a protein produced by the liver and involved in the body's iron metabolism) and creatine-kinase (an enzyme found in the heart, brain and skeletal muscle).
The difficulty is so great that last October an international team of researchers published in Nature a call for people who are genetically resistant to SARS-CoV-2.
(ANI)