How genetic mutations in healthy young men made them susceptible to severe Covid-19

• New research shows how genetic mutations may predispose individuals to severe Covid-19
• Scientists based in the Netherlands investigated the genes of four patients who ended up on mechanical ventilation
• The four patients, two pairs of brothers, were young and generally healthy 

When two pairs of generally healthy young brothers with no immune-related disease required mechanical ventilation in the intensive care unit (ICU), doctors and researchers at Radboud University Medical Center in the Netherlands considered whether genetic factors may have played a role in compromising their immunity.

Although the new coronavirus, SARS-CoV-2, can affect people of all ages, studies have highlighted two groups of people that are at a higher risk of getting severe Covid-19: older people, and those with underlying medical conditions.

In the case of the first pair of brothers, one of them died due to infection, while the other recovered. 

Curiosity about patients' genes

This rare occurrence triggered the curiosity of a physician from the MUMC+ (Maastricht University Medical Centre+) department of clinical genetics. She alerted her colleagues in Nijmegen who then followed up with an investigation.

"In such a case, you immediately wonder whether genetic factors could play a role," said 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 became so severely ill. But it is also possible that an inborn error of the immune system played an important role. We investigated this possibility, together with our multidisciplinary team at Radboudumc."

The team found that the gene TLR7 (toll-like receptor 7) played a key role in the brothers’ immune response to the virus – a finding that potentially has huge consequences for understanding and treating Covid-19.

Their research paper is published in The Journal of the American Medical Association (JAMA).

Genes and the immune system

All genes (collectively known as the "exome") of both brothers were sequenced. The team then followed this with a search for a possible link between their genes and Covid-19. 

"We mainly looked at genes that play a role in the immune system,” said Cas van der Made, a PhD student and resident at the Department of Internal Medicine, adding:

“We know that several of these genes are located on the X-chromosome, and with two brother pairs affected X-chromosomal genes were the most suspicious. 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."

The role of TLR7

TLR7 is a protein of the immune system that is encoded by the TLR7 gene. There are multiple TLR-genes which belong to a family of receptors, and these play a significant role in the recognition of pathogens (such as bacteria and viruses) and the activation of the immune system.

In this case, the researchers found mutations in the gene encoding for TLR7. Hoischen explained: "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.”

Hoischen  also explained that TLR7 function has thus far never been associated with an “inborn error of immunity”, and that scientists now have an indication that TLR7 is actually essential for protection against the new coronavirus.

“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 defence, is hardly present. That could be the reason for the severity of the disease in these brothers," said Hoischen.

Second pair of brothers infected

When the researchers came across another pair of brothers who suffered severe Covid-19 and were both put on mechanical ventilation in the ICU, the researchers wanted to dig deeper, so they proceeded to investigate the genetic code of these two brothers as well.

They found that these two men 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," said Hoischen.

Van der Made explained that their results show that SARS-CoV-2 “appears to have free rein in people” who do not have properly functioning TLR7, because the virus is not recognised by their immune system.

‘Very specific abnormality’

According to Frank van de Veerdonk, immunologist and infectologist, and co-author of the study, the condition “seems to be a very specific abnormality, an immunodeficiency, which is mainly related to this coronavirus”, and added that this is the first time scientists have been able to connect a clinical phenomenon so strongly with TLR7.

Apart from providing new insight into the intricacies behind the operation of the immune system, the team’s findings may also have critical consequences for the treatment of patients with severe Covid-19. Van de Veerdonk said that the substance "interferon" is currently being investigated for treating patients with this condition.