Genetic mutations hamper the immune response in severe COVID-19

The coronavirus disease (COVID-19) pandemic has spanned nine months, infecting more than 33 million people worldwide and claiming more than 997,000 lives. At the beginning of the pandemic, scientists have observed that some people were prone to severe illness, while others developed only mild to moderate symptoms. A handful of patients do not develop symptoms of the disease, known as asymptomatic carriers.

Now, a truly international team of nearly 140 researchers has set out to determine why some people develop serious illness when they are once infected with coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome, the virus that causes COVID-19 disease.

What are interferons?

Interferon (IFN) are proteins that are produced and released by host cells in response to pathogens in the body, including bacteria, viruses, parasites, or cancer cells. They act as a communication bridge between cells to induce the protective defenses of the immune system to get rid of pathogens. Once they detect foreign invaders, they alert the immune system and trigger an immune response to prevent infection.

Furthermore, interferons are a group of cytokines with antiviral properties, which have been extensively studied in the battle against COVID-19. Researchers in this study previously observed genetic mutations that hinder the production and function of interferon, making people more vulnerable to viral infections. These mutations have been seen in people with influenza, and the team hoped to find similar mutations in those with COVID-19.

COVID-19 and genetic mutations

The researchers aimed to analyze samples from 500 severe COVID-19 patients in March. In August, they had more than 1,500 patients and now they have more than 3,000. They began testing patient samples, discovering mutations in both the young and the elderly. The team found that 23 of the 659 patients had errors in the genes involved in the production of antiviral interferons.

Without these competent and active antiviral defenders, COVID-19 patients would not be able to fight off the viral infection, which could lead to serious illness.

The study

To arrive at the study’s findings, the researchers tested the specific hypothesis that toll-like receptor 3 (TLR3) errors, which play a vital role in pathogen recognition and activation of innate immunity, and type interferon I dependent on IRF7 (IFN-alpha / beta), whose response is critical immunity against viruses. These responses are the basis for life-threatening COVID-19 pneumonia.

The team considered three loci, which were previously shown to be mutated in patients with life-threatening influenza pneumonia: TLR3, interferon regulatory factor 7 (IRF7), and interferon regulatory factor 9 (IRF9). The team also considered other mutated loci in patients with other viral diseases, namely TICAM1 / TRIF, UNC93B1, TRAF3, TBK1, IRF3, and NEMO / IKBKG in the TLR3-dependent type I IFN induction pathway, and IFNAR1, IFNAR2. , STAT1, and STAT2 in the IRF7 and IRF9-dependent type I IFN amplification pathway.

The team has discovered that inborn errors or inborn errors of TLR3 and IRF3-dependent type I immunity underlie critical COVID-19. At least 23 of the 659 patients with life-threatening COVID-19 pneumonia have known (six disorders) or new (four disorders) genetic defects at eight loci implicated in TLR3 and IRF7-dependent induction and amplification of type I IFNs.

“This discovery reveals the essential role of both the TLR3 dsRNA sensor and the intrinsic immunity to IFN type I cells in the control of SARS-CoV-2 infection in the lungs, consistent with their previously documented roles in the lung immunity to influenza virus, “the researchers explained.

Interestingly, these genotypes remained silent or inactive until infection with SARS-CoV-2. In some cases of COVID-19, for example, AR IRF7 deficiency was observed in two patients, aged 49 and 50 years, and AR IFNAR1 deficiency was diagnosed in two patients aged 26 and 38, who had no history of lifetime. life-threatening infections.

A patient with IRF7 deficiency tested positive for several common viruses, including several influenza A and B viruses.

“These genetic defects, therefore, show incomplete penetrance for respiratory distress from influenza and only become clinically manifested after infection with the more virulent SARS-CoV-2,” the team added.

Based on the study’s findings, published in the journal Sciences, the team concluded that there are inborn errors or genetic defects in TLR3- and IRF7-dependent type I IFN immunity at eight loci. Therefore, the findings suggest that patients who develop life-threatening COVID-19 may have genetic defects in their immune system, making them more vulnerable to serious illness.

The team suggested that the administration of IFN type I may be a promising therapeutic candidate in some patients, at least early in the infection.