Genetic Mutation Found to Cause Severe COVID-19 Symptoms in Individuals

Researchers have identified the gene TLR7 as an essential player in the immune response against SARS-CoV-2, suggesting that genetic factors play a key role in compromising the immune system of COVID-19 patients.

The finding with potentially major consequences for understanding and possibly treatment of COVID-19 was made by researchers at the Radboud University Medical Center (Nijmegen, The Netherlands), based on their observation of two pairs of previously healthy young brothers from two families which required mechanical ventilation at the intensive care unit (ICU) in rapid succession. 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, while 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. This observation triggered an investigation into why these two young brothers were so severely affected.

All genes (collectively called the exome) of both brothers were sequenced, after which the investigators combed through the data searching for a possible shared cause. Their search quickly revealed mutations in the gene encoding for the Toll-like receptor 7, TLR7 for short. A few letters were missing in the genetic code of the TLR7 gene, as a result of which, the code could not be read properly and hardly any TLR7 protein was produced. The researchers then came across another pair of brothers who had fallen seriously ill with COVID-19, both of whom were also under 35 years of age and admitted in the ICU for mechanical ventilation. An investigation of the genetic code of the two brothers revealed a single spelling mistake of one DNA-letter of the TRL7 gene that led to insufficient production of functional TLR7 protein.

“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,” said geneticist Alexander Hoischen. “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.”

“Once activated, TLR7 triggers the production of so-called interferons, signaling proteins that are essential in the defense against virus infections," said Van der Made who has investigated the consequences of improper functioning of the TLR7 receptor. “This immune response is perhaps all the 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 immune cells of the patients without properly functioning TLR7 hardly respond, and that minimal amounts of interferons 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.”

"This discovery not only provides us with more insight into the fundamental workings of the immune system, but it may also have important consequences for the treatment of severely ill COVID-19 patients," said Frank van de Veerdonk, immunologist and infectiologist. "The substance interferon can be given as a therapy. It is currently being investigated whether administering interferon in COVID-19 can indeed help."

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Radboud University Medical Center