The human being always wants explanations that make the vicissitudes of life more acceptable. Formerly, in pre-scientific times, to explain the vagaries of one or another disease that, like COVID-19, killed some and “forgave” others, it was common to argue that the people who were saved were pure and pious, while that those who succumbed were sinful mortals.
On the contrary, it could happen that those who were saved did so thanks to some pact with the devil, while those who succumbed obediently followed the call of destiny. In the absence of scientific knowledge, all the explanations were equally valid. Or rather, just as invalid.
Severe fraternal COVID-19
Fortunately, the knowledge accumulated over decades about the differences between human beings, both in their qualities of all kinds and in their susceptibility to diseases, has allowed us to conclude that the main factor that explains them is the genes that each of us has to inherit . COVID-19 is no exception.
We already know that this disease tends to affect older people more severely, and that it tends to be more serious in men than in women. However, it can also affect young people, and even children. In this case, it is also highly probable that the affected youngsters are siblings. Why?
This is the question asked by a team of scientists from Radboud University, in Nijmegen, the Netherlands. During the peak of the epidemic, two pairs of young siblings needed to be admitted to the hospital and put on mechanical ventilation. One of the four did not survive. The situation was surprising, and the scientists decided to study it.
One “letter” from you will be enough to make me sick
Defects in many genes lead to immunodeficiencies that prevent the correct defense against one or another type of infection. Since the patients were siblings, the main suspects were the genes they shared. Therefore, the researchers tried to find a common mutation that affected a gene involved in the defensive response of the immune system against the coronavirus. This intuition turned out to be true.
The first pair of siblings showed a mutation that had removed a few “letters” in the DNA of the gene called TLR-7. The absence of these “letters” modified the genetic information so severely that it made it impossible to generate the protein from DNA.
The second pair of siblings also had a mutation in the same gene, TLR-7. In this case, the mutation affected only one of the “letters,” but it also invalidated the information in the gene and made it impossible for the protein to form. In the latter case, only one letter in the genome of those two brothers made the difference between life and death from coronavirus infection. A death that would have occurred in the four brothers in the absence of modern medicine.
Interestingly, prior to COVID-19, no immune problems caused by defects in the TLR-7 gene had been identified.
The TLR-7 detector
What immune function does the TLR-7 gene play? It is one of the ten TLR genes that humans have. These genes produce proteins specialized in detecting molecular components of microorganisms.
When microorganisms try to invade us, TLR proteins are the first to detect them and raise the alarm. Each TLR protein detects a particular molecular component. For example, TLR-4 detects carbohydrates typical of some bacteria, and TLR-5 detects components of bacterial flagella.
The TLR-7 protein is located in vesicles inside cells, called endosomes, and is responsible for detecting foreign RNA that may have penetrated the cell . Precisely, the genome of the SARS-CoV-2 coronavirus, which causes the COVID-19 disease, is made up of RNA. In the absence of TLR-7 protein, this invasive RNA cannot be detected. It is as if the cells are deaf or blind to the presence of this type of virus.
When the TLR-7 gene is functioning normally, the TLR-7 protein is activated by detecting foreign RNA. It then triggers a series of biochemical and genetic processes that put cells in a state of defense against viruses. In this way, cells can decrease the synthesis of proteins, to prevent those of the virus that has infected them from also being synthesized, but they can also destroy proteins detected as foreign more quickly. In addition, they can secrete proteins called type 1 interferons to the outside.
These latter proteins travel from the infected cell to neighboring uninfected cells and warn them that an enemy virus is prowling around. This gets neighboring cells to change their state and prepare to make it difficult for the virus. Therefore, it can be deduced that in the absence of the TLR-7 gene, the immune system can only defend itself against coronavirus by other means that take longer to implement. Unfortunately, the time required is too much for some.
Interestingly, the TLR-7 gene is located on the X chromosome . It is one of many of the immune system that are located on that chromosome. This could explain why men are more vulnerable than women: inheriting a defective X chromosome from the carrier mother is enough to generate immune deficiency in males. Women inherit two X chromosomes, and having only one healthy one is enough to have adequate protection. This explains why the affected couples were brothers and not sisters.
Finally, it can be speculated that there are variants of the TLR-7 gene that do not disable it but nevertheless cause the protein to be produced in greater or lesser amounts in each individual. Possibly some TLR-7 variants may also be more or less effective in detecting the RNA of the coronavirus and triggering the defense processes against it. Furthermore, variants in the genes that participate in this defense mechanism could also affect its efficacy. It will be necessary to study whether, in effect, depending on which variant of the TLR-7 gene we have, it makes us more or less susceptible to the disease.
Jorge Laborda Fernández, Professor of Biochemistry and Molecular Biology, University of Castilla-La Mancha
This article was originally published on The Conversation. Read the original.
