The researcher explained why some people have severe COVID-19 disease

However, there are very serious and unfortunately sometimes fatal cases among young people who have not had any health problems before. It is these cases that have led researchers to suspect that different human responses to the SARS-CoV-2 virus may also be due to genetic differences, the media reported.

“One of the first studies of its kind was conducted in the spring of 2020, when at least two pairs of young siblings from different families became ill with the very serious form of COVID-19 in the Netherlands,” says Dr. Miglė Tomkuvienė. – One of these patients died. The researchers looked at their genomes (or, more precisely, tests, just those parts of the genome that code for proteins) and found that all of these young men had a lost and mutated function, the TLR7 gene. “

According to the researcher, the TLR7 gene encodes a protein receptor that is essential for the functioning of innate and acquired immunity. This receptor recognizes single-stranded viral RNA and initiates an immune response based on the interferon signaling pathway. The researchers showed that due to mutations in TLR7, the activation of interferons in these patients was impaired. The situation is complicated by the fact that TLR7 is on the X chromosome, so men only have one copy of this gene and if it has a defect, the immune response can no longer function properly.

Do women get sick more easily?

Women have two X chromosomes and, at the same time, a high probability that at least one allele of the gene encodes an activity protein. Therefore, COVID-19 disease would be easier in women, even with an inactive TLR7 gene. A classic example of an X-linked disease is hemophilia, in which there is a blood clotting problem. And in the case of the TLR7 mutation, the body’s defense system, which responds to viruses, is affected. However, such TLR7 mutations, while obviously important, are very rare and cannot be used to explain all the variations in COVID-19 morbidity associated with human genetics. Subsequent studies involving hundreds and thousands of patients have identified a variety of other genetic changes in the interferon signaling pathway and have even suggested appropriate treatments.

“Basically, the genetic factors associated with COVID-19 morbidity can be divided into two groups: some result in different susceptibility to the virus, that is, different access to the virus in cells, other differences in severity of the disease. disease due to different immune responses, “says Dr. M. Tomkuvienė.

ACE2 (angiotensin converting enzyme 2) is embedded in the cell membranes of various organs, including the lungs. The usual function of ACE2 is to regulate blood pressure while maintaining a balance of relevant hormones. However, in COVID-19 disease, ACE2 is the primary pathway for the SARS-CoV-2 virus to enter the cell: the viral spike protein S interacts with ACE2 like a key to the lock, allowing the virus enters the cell, where it eventually spreads. Italian researchers have identified several variants of the ACE2 gene and its encoded protein sequence that may have led to changes in protein structure and stability and weaker interactions with the SARS-CoV-2 spike protein, as well as an entry reduced virus in the cell.

The researcher explains, however, that the differences in ACE2 were more important when linked to the main function of this enzyme: they led to differences in the state of the pulmonary and cardiovascular systems, which also affected the course of the COVID-19 disease . Interestingly, the ACE2 gene is also present on the X chromosome and this may contribute to the explanation of why COVID-19 (hormones are also very important for gender morbidity differences, but this is another topic). Invasion of the virus requires another enzyme, TMPRSS2, which cleaves proteins that protrude from the surface of the adherent virus before the virus enters the cell. Changes in the gene for this enzyme can also lead to decreased susceptibility to the virus. However, studies show that the sequences of these two genes are quite stable in the population and are therefore not the main reason why COVID-19 is expressed so differently.

The point is in the genes

It is the variability in the genes of the immune system that is the main cause of the differences in the course of COVID-19. These are the aforementioned disorders of the interferon signaling pathway that lead to its inactivity. In contrast, overexpression of the TYK2 immune signal gene causes excessive inflammation. On the human chromosome, designated no. 6 is a region with up to 100 different genes involved in the immune response. The HLA genes it contains are responsible for the production of specific antibodies. In silico modeling has shown that antibodies to SARS-CoV-2 are more easily formed in some HLA genetic variants, and even partially formed antibodies that have been previously exposed to other human coronaviruses are suitable. In the case of another HLA variant, the opposite is true. HLA genes are highly variable, with many variants prevalent in the human population. This suggests that when faced with different pathogens, different HLA variants provide an advantage, and those that have two different HLA alleles are probably the most resistant to various infections. Consequently, differences in immune system genes can lead to different responses to vaccines.

“In short, we are all a little different genetically. This is completely natural. COVID-19, in particular, highlights the genetic differences in our immune systems. By knowing exactly which genetic changes lead to a more serious condition in a particular patient, scientists and doctors could make a more specific choice of appropriate treatment. This is called personalized medicine. Although not widely used yet, it holds a promising future not only for the treatment of COVID-19, but also for the treatment of many other diseases, ”says Dr. M. Tomkuvienė.

Erratum

In order to promote a culture of open data and responsible research and advertising, the authors provide a link to material errors, corrections, or changes of opinion or interpretation found in this text. Public link to the GoogleDoc Errata document for this post: https://bit.ly/3nbXKoP. There you will also find a list of used scientific sources.