Covid-19: discovered hidden immune weakness in gravely ill patients

More than 10% of healthy patients who develop life-threatening COVID-19 have dysfunctional antibodies that attack the immune system instead of the virus, making it less effective in fighting the infection. Another 3.5% of patients are carriers of a predisposing genetic mutation.

In both cases, the problem is a reduced functionality of type I interferon, which is neutralized by autoantibodies in the first group of patients while it is impaired due to the genetic mutation in the second group.

It’s the combined result of two studies conducted by COVID Human Genetic Effort (CovidHGE), an international consortium involving more than 150 institutes and universities worldwide, including Ospedale San Raffaele and Vita-Salute San Raffaele University. The studies have been published in two separate articles in the prestigious journal Science.

“These findings provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening Covid-19. And at least in theory, such interferon problems could be treated with existing medical interventions” says Jean-Laurent Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University, who coordinated the research in collaboration with Luigi Notarangelo and Helen Su, both from the National Institute of Allergy and Infectious Diseases in Bethesda.

“The approach adopted by the consortium will enables us to understand the molecular and genetic mechanisms that explain the most serious forms of Covid-19 and to suggest targeted therapeutic solutions for specific groups of patients. This is only the first result, but it is already very promising” says Alessandro Aiuti, deputy director of the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and full professor of Pediatrics at the Vita-Salute San Raffaele University, member of the steering committee of the consortium.


Auto-antibodies at the origin of severe forms of Covid-19

SARS-CoV-2 infection manifests itself with enormous variability: the virus can cause a disease with mild symptoms or it can kill in a few days. Why? Why are men more affected than women by the severe forms of Covid-19? And what are the mechanisms behind the sharp increase in mortality rate among older patients?

Examining the biological tissues of 987 patients with life-threatening Covid-19 pneumonia, scientists found that more than 10% of these patients had autoantibodies against interferon I, which is a key component of the immune response to viruses. These autoantibodies are relatively rare in the overall population: out of 1227 randomly selected healthy individuals, only 4 tested positive.

In most patients, positivity to these autoantibodies has been detected in blood samples collected at the moment of hospitalization. But, when possible, researchers were able to confirm the presence of the antibodies also in older blood samples. The hypothesis is that the antibodies are already present when the patients became infected and are a predisposing factor for severe Covid-19.

"We believe that the auto-antibodies for type I interferon can explain a significant part of life-threatening Covid-19 cases and the distribution of these severe forms in the overall population, i.e. affecting more men and older people. Not surprisingly, 95% of the patients with auto-antibodies were men and more than 50% were over 65 years of age” explains Lorenzo Piemonti, director of the Diabetes Research Institute at IRCCS San Raffaele Hospital and associate professor at the Vita- Salute San Raffaele University, among the authors of the paper.


New therapeutic strategies for severe forms of Covid-19

The result obtained is consistent with what we already knew: interferons are one of the fundamental tools of innate immunity, that part of the immune response that starts working first during an infection, while adaptive immunity takes time to build a more specific response. There are also other examples of infectious diseases facilitated by the presence of auto-antibodies that inhibit the action of the immune system.

To further validate the discovery, there are also the results of the second study published in Science by the CovidHGE consortium: scientists found that 3.5% of patients with severe forms of Covid-19 are carriers of genetic mutations that prevent the production or proper use of type I interferon.

“Taken together, the two studies strongly suggest that restoring the correct levels of interferon I in the early stages of the infection could be effective against the more severe forms of Covid-19, at least in a selected group of patients” says Fabio Ciceri, scientific director of IRCCS San Raffaele Hospital and full professor of Hematology at the Vita-Salute San Raffaele University.