Inborn errors of Immunity determine lethality of COVID-19

The COVID-19 pandemic has already claimed the life of more than a million human beings worldwide and the terrible human, social, labor, and economic consequences have not abated at all, changing our daily lives forever. The clinical manifestations range from an innocuous “cold syndrome” to the grave respiratory cases; the infection fatality rate ranges from 0.1% to 0.9% and the risk factors seem to be old  age, being male and co-morbid conditions like hypertension and diabetes.

However some patients, including younger people that do not carry the risk factors, seem to be especially susceptible to the infection, which has baffled the clinicians. Considering that some other grave respiratory diseases like Influenza pneumonia were shown to prey on some clearly defined genetic abnormalities of humans, several scientists and clinicians from many countries have established a virtual space called the COVID Human Genetic Effort to test the hypothesis that the lethality of the SARS-CoV-2 virus might be enabled by monogenic inborn errors of immunity.

In an article recently published in Science, Quian Zang, from Rockefeller University in New York City, Paul Bastard, from the Necker Hospital for Sick Children in Paris, and a long list of collaborators, genetically tested 659 patients with life-threatening COVID-19 pneumonia to find out if they showed the “rare variants of loss-of-function (LOF) at the 13 human loci known to govern TLR-3 and IRF7-dependent type I interferon (IFN) immunity to influenza virus.” First the investigators tested the hypothesis that the same genetic abnormalities that determine the increased lethality of Influenza Pneumonia might have a similar effect in grave COVID-19. They recruited 659 patients—74.55men and 25,5% women, 13.9% of whom died—from various ethnic and socio-economic backgrounds, aged between one month and 99 years; they had all been hospitalized due to life-threatening pneumonia.

They initially studied three loci—TLR3(6), IRF7 (7), and IRF9 (8)—that had been already shown to be mutated in patients with symptoms of Influenza pneumonia. They also studied 10 loci that had shown mutations in other grave viral infections. “We showed that PHA-driven T-cell blasts (PHA=-T cells) from patients with AR or AD IRF7 deficiency had low levels of IRF7 expression. We then isolated circulating plasmacytoid dendritic cells (pDCs) from a patient with IRF7 deficiency. These cells were present in normal proportions, but they did produce any detectable type I or III IFNs in response to SARS-CoV-2…” They found a relatively higher importance of the deficiency in the type I IFN production compared to type III IFN. They found the presence of neutralizing auto-antibodies against type I, but not type III IFNs in other patients with life-threatening COVID-19 pneumonia. Their studies suggest that “there might be type I IFN-related genes in other patients with life-threatening COVID-19 pneumonia. They also suggest that the administration of type I IFN may be of therapeutic benefit in selected patients, at least early in the course of SARS-CoV-2 infection.”

The tragic pandemic has spurred the creative imagination of thousands of scientists and clinicians across the world, which will bring innovative therapies to cure it. The addition of genetic based – therapies looks promising enough to foster their study.

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