People, particularly men, with a mutated TLR7 gene appear to be at a much greater risk of developing severe and life-threatening COVID-19 symptoms upon infection. Why is this specific gene so important? TLR7 is part of a larger “family” of receptors responsible for activating the body’s immune system in response to a new pathogen. So, the immune systems of people with this specific gene mutation fail to recognize the coronavirus as a threat.
This discovery, made by a team of researchers at the Radboud University Medical Center, was sparked when a pair of young brothers were admitted to the medical center’s ICU. The vast majority of intensive care COVID-19 patients are either elderly or sick, so doctors immediately noticed the brothers as outliers within the ICU. Unfortunately, one of the brothers ultimately passed away from his coronavirus symptoms.
Doctors and researchers hypothesized that the two brothers, a pair of otherwise healthy, young people, must have developed severe COVID-19 symptoms due to some type of genetic predisposition.
“In such a case, you immediately wonder whether genetic factors could play a role,” explains geneticist Alexander Hoischen. “Getting sick from an infection is always an interplay 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 severely ill. But it is also possible that an inborn error of the immune system has played an important role. We investigated this possibility, together with our multidisciplinary team at Radboudumc.”
Researchers analyzed the brothers’ full spectrum of genes but focused on immune system-related genes a bit more diligently. This is important to note because many immune system genes are found on the X-chromosome.
“Women carry two X-chromosomes, while men possess a Y-chromosome apart from the X. Therefore, men have only one copy of the X-chromosomal genes. In case men have a defect in such a gene, there is no second gene that can take over that role, as in women,” says Cas van der Made, a Ph.D. student and resident at the Department of Internal Medicine.
With this in mind, it seems that men are in a far worse position in the event of a TLR7 gene mutation. The study’s authors even speculate that this could partially explain why men generally seem to be more susceptible to COVID-19. This is only a theory, though, and by no means proven.
Circling back to the research at hand, an extensive analysis of the two brothers’ immune genes showed mutations in the gene encoding for Toll-like receptor 7 (TLR7).
“A few letters were missing in the genetic code of the TLR7 gene. As a result, the code cannot be read properly and hardly any TLR7 protein is produced. TLR7 function has so far never been associated with an inborn error of immunity. But unexpectedly we now have an indication that TLR7 is essential for protection from this coronavirus. So it seems that the virus can replicate undisturbed because the immune system does not get a message that the virus has invaded. Because TLR7, which must identify the intruder and subsequently activate the defense, is hardly present. That could be the reason for the severity of the disease in these brothers,” Hoischen comments.
Unexpectedly, another pair of young (under 35 years old) brothers were admitted to the ICU.
“Then the question of the role of genetics became even more obvious.” Hoischen says. “We also investigated the genetic code of these two brothers, again via the ‘rapid-clinical exome’ method. This time we saw no deletion, no loss of letters, but a single spelling mistake of one DNA-letter of the TRL7 gene. The effect on the gene is the same, however, because these brothers also do not make sufficient functional TLR7 protein. Suddenly we had four young people with a defect in the same gene, all of whom had fallen seriously ill from the SARS-CoV-2 virus.”
Even for people with non-mutated TLR7 genes, the coronavirus is well versed at evading detection from the immune system. Researchers hypothesize that the combination of a mutated TLR7 gene and SARS-CoV-2’s innate ability to avoid immune system activation set the stage for severe, life-threatening coronavirus symptoms.
“When we mimic an infection with the coronavirus, we see that immune cells of the patients without properly functioning TLR7 hardly respond, and that minimal amounts of interferons (virus-fighting proteins) are produced. These tests make it clear that the virus appears to have free rein in people without properly functioning TLR7 because it (the virus) is not recognized by the immune system,” van der Made notes.
“Due to the serious illness of four brothers in two families, so serious that it cost one of the young men his life, we have discovered this condition,” Hoischen concludes. “It seems to be a very specific abnormality, an immunodeficiency, which is mainly related to this coronavirus. None of the four men have previously suffered from immune-related diseases. It is the first time that we can connect a clinical phenomenon so strongly with TLR7.”
The study’s authors are optimistic that treatments can be developed to help ICU COVID-19 patients with this specific gene mutation. For instance, interferons (the virus-fighting proteins triggered by TLR7) could be used as a therapy option.
The full study can be found here, published in JAMA.