Current observations show that the SARS-CoV-2 coronavirus causes severe symptoms, mainly in elderly patients with chronic diseases. However, when two pairs of previously healthy young brothers from two families needed rapid ventilation in the intensive care unit, doctors and researchers from Radbu University Medical Center wondered that perhaps genetic factors play a key role in their immune response to the virus. Their research identified the TLR7 gene as an important player in the immune response against SARS-CoV-2. This is a discovery with potentially serious implications for understanding and possibly treating COVID-19.

During the COVID-19 pandemic in the first half of 2020, two young brothers in Holland became seriously ill with the SARS-CoV-2 virus. They had to turn on artificial ventilation in the intensive care unit. One of them died from the effects of the infection, the other recovered. Severe illness in healthy young brothers was relatively rare, especially because the virus mainly affects the elderly. This observation piqued the curiosity of a physician from the MUMC + Department of Clinical Genetics. She contacted her colleagues in Nijmegen, who then found out why the two young brothers suffered so much.

In this case, you immediately wonder if genetic factors might play a role. Getting sick from an infection is always an interaction between the virus and the human immune system. It may be a coincidence that two brothers from the same family are so seriously ill. But it is also possible that a congenital error in the immune system played an important role. We investigated this possibility.

Geneticist Alexander Hoishen

All genes of both brothers were sequenced, after which the researchers examined the data in search of a possible common cause.

Scientists have mainly studied genes that play a role in the immune system. They knew that some of these genes are located on the X chromosome.

This search quickly identified mutations in the gene encoding Toll-like receptor 7, TLR7 for short. There are many TLR genes that belong to the receptor family that play an important role in recognizing pathogens (such as bacteria and viruses) and activating the immune system.

Several letters were missing from the genetic code of the TLR7 gene. As a result, the code cannot be read properly and the TLR7 protein is unlikely to be produced. Until now, TLR7 function has never been associated with an innate immunity error. But unexpectedly, scientists now have a sign that TLR7 is needed to protect against the new coronavirus. Thus, the virus can replicate without interference – the immune system does not receive a message that the virus has invaded. Because TLR7, which is supposed to identify the attacker and subsequently activate protection, is hardly present. This may be the reason for the severity of the disease in two brothers.

Then, out of the blue, doctors and researchers at Radboudumc ran into another pair of brothers who were seriously ill with COVID-19. Again, patients are up to 35 years old. Both were also in the intensive care unit for mechanical ventilation. Then the question of the role of genetics became even more obvious, scientists emphasize. They also examined the genetic code of the two brothers. This time they saw no errors in the TRL7 gene. However, the effect on the gene was similar – these brothers also do not produce enough functional TLR 7 protein.

Scientists have investigated the consequences of malfunctioning TLR7.

Once activated, TLR7 triggers the production of so-called interferons, signaling proteins that are needed to protect against viral infections. This immune response is perhaps even more important in the fight against the SARS-CoV-2 virus. There is evidence that the virus has the ability to reduce the production of interferons by immune cells. This gene anomaly could actually “disable” protection against COVID-19.

Scientists emphasize that this is a very specific anomaly – immunodeficiency, which is mainly associated with the new coronavirus. None of the four men had previously suffered from an immune-related illness.

The discovery not only gives scientists a deeper understanding of the basic principles of the immune system, but it could also have important implications for the treatment of critically ill COVID-19 patients.