Current observations suggest that the coronavirus SARS-CoV-2 causes severe symptoms mainly in elderly patients with chronic disease.
However, when two pairs of previously healthy young brothers from two families required mechanical ventilation at the intensive care unit in rapid succession, doctors and researchers were inclined to consider that genetic factors had a key role in compromising their immune system.
In a new study, researchers found the gene TLR7 as an essential player in the immune response against the COVID-19 virus.
This finding may help develop new treatment of COVID-19.
The research was conducted by a team at Radboud University Medical Center.
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 disease in otherwise healthy young brothers was a relatively rare occurrence, especially because the virus mainly affects the elderly.
All genes (collectively called the exome) of both brothers were sequenced, after which the team combed through the data searching for a possible shared cause.
That search quickly revealed mutations in the gene encoding for the Toll-like receptor 7, 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.
The team found 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.
Then, quite unexpectedly, the team came across another pair of brothers who have fallen seriously ill with COVID-19. Again, they are both under 35 years of age. Both of them were also in the ICU for mechanical ventilation.
The found 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.
Together, the team had four young people with a defect in the same gene, all of whom had fallen seriously ill from the SARS-CoV-2 virus.
The researchers found TLR7 triggers the production of so-called interferons, signaling proteins that are essential in the defense against virus infections.
This immune response is perhaps all the more important in the fight against the SARS-CoV-2 virus because the virus has tricks to reduce the production of interferons by immune cells.
Their future tests make it clear that the virus appears to have free rein in people without properly functioning TLR7 because [the virus is not recognized by the immune system.
This discovery not only provides scientists with more insight into the fundamental workings of the immune system, but it may also have important information for the treatment of severely ill COVID-19 patients.
One author of the study is geneticist Alexander Hoischen.
The study is published in JAMA.
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