Genetic mutations predispose individuals to severe COVID-19.

Current observations suggest that the SARS-CoV-2 coronavirus causes severe symptoms primarily in elderly patients with chronic disease. However, when two pairs of previously healthy young siblings from two families required mechanical ventilation in the intensive care unit in rapid succession, doctors and researchers at Radboud University Medical Center were inclined to consider genetic factors to play a key role. in compromising your immune system. Their research identified the TLR7 gene as an essential player in the immune response against SARS-CoV-2. A finding with potentially important consequences for the understanding and possibly the treatment of COVID-19.

During the wave of COVID-19 patients that flooded Dutch hospitals in the first half of 2020, two young brothers became seriously ill with the SARS-CoV-2 virus and had to be mechanically ventilated in the ICU. One of them died from the consequences of the infection, the other recovered. The severe course of the disease in otherwise healthy young siblings was a relatively rare occurrence, especially since the virus primarily affects the elderly. This observation sparked the curiosity of an attentive physician in the MUMC + clinical genetics department. She contacted her colleagues in Nijmegen, who then investigated why these two young brothers were so severely affected.

Genetic factors

“In such a case, you immediately wonder if genetic factors could play a role,” says geneticist Alexander Hoischen. “Getting sick from an infection is always an interaction between, in this case, the virus and the human immune system. It may be a mere coincidence that two brothers from the same family become so seriously ill. But it is also possible that an innate The immune system has played an important role. We investigated this possibility, together with our multidisciplinary team at Radboudumc. “

An X chromosome

All of the genes (collectively called the exome) of both siblings were sequenced, after which the researchers analyzed the data for a possible shared cause. Cas van der Made, Ph.D. student and resident of the Internal Medicine department: “We mainly observe the genes that play a role in the immune system. We know that several of these genes are found on the X chromosome, and with two pairs of siblings they affect the genes on the X chromosome” were more suspicious. Women carry two X chromosomes, while men have one Y chromosome apart from X. Therefore, men only have a copy of the X chromosome genes. In case men have a defect in that gene, there is no second gene that can take on that role, as in women. “

Gene identification

That search quickly revealed mutations in the gene encoding the 7 Toll-like receptor, TLR7 for short. There are multiple TLR genes, which belong to a family of receptors with an important role in the recognition of pathogens (such as bacteria and viruses) and the activation of the immune system. Hoischen: “Some letters were missing from the genetic code of the TLR7 gene. As a result, the code cannot be read correctly and almost no TLR7 protein is produced. Until now, the TLR7 function has never been associated with an innate immunity error. But unexpectedly we now have an indication that TLR7 is essential for protection against this coronavirus. Therefore, it appears that the virus can replicate without discomfort because the immune system does not receive a message that the virus has invaded. Due to TLR7, which it must identify the intruder and later activate the defense, as soon as it is present. That could be the reason for the severity of the disease in these brothers. “

Additional confirmation

Then, unexpectedly, Radboudumc doctors and investigators encounter another pair of siblings who have become seriously ill with COVID-19. Again, both are under the age of 35. Both were also in the ICU for mechanical ventilation. “Then the question of the role of genetics became even more obvious.” Hoischen says. “We also investigated the genetic code of these two siblings, again through the ‘rapid clinical exome’ method. This time we saw no deletion, letter loss, but a single spelling mistake for a DNA letter of the TRL7 gene.” However, the effect on the gene is the same because these siblings also do not produce enough functional TLR7 protein. Suddenly, we had four young people with a defect in the same gene, all of whom had become seriously ill with the SARS-CoV-2 virus. “

Essential role in defense

Van der Made and colleagues have investigated the consequences of TLR7 receptor malfunction. “Once activated, TLR7 triggers the production of so-called interferons, signaling proteins that are essential in defending against virus infections,” says van der Made. “This immune response is perhaps even more important in the fight against the SARS-CoV-2 virus, because we know from the literature that the virus has tricks to reduce the production of interferons by immune cells. When we mimic an infection with the coronavirus, We see that the immune cells of adequately functioning patients without TLR7 hardly respond, and that minimal amounts of interferons are produced. These tests make it clear that the virus appears to be unleashed in people without functioning TLR7 because [the virus] is not recognized by the immune system. “

Consequences

“Because of the serious illness of four siblings in two families, so severe that it cost one of the youths their lives, we have discovered this condition,” says Hoischen. “It appears to be a very specific abnormality, an immunodeficiency, that is primarily related to this coronavirus. None of the four men has had immune-related diseases. It is the first time that we can connect a clinical phenomenon so strongly to TLR7.”

“This discovery not only provides us with more information about the fundamental functioning of the immune system, but it may also have important consequences for the treatment of seriously ill patients with COVID-19,” says Frank van de Veerdonk, immunologist and infectologist. “The substance interferon can be administered as therapy. It is currently being investigated whether the administration of interferon in COVID-19 can really help.”