When Antibodies Go Rogue: Mutations Behind Severe COVID-19

by Alyssa Mae Santos (Hachimoji)

Recent studies from the COVID Human Genetic Effort consortium in 2020 reported that inborn errors of type I interferons in the immune system, as well as the production of auto-antibodies blocking these interferons, disrupt the antiviral defenses of the body causing people to be more susceptible to life-threatening COVID-19.

Studies have previously identified three epidemiological factors that increase the risk of severe COVID-19. This includes the elderly, especially those over 50 years old, the male population, and people with other medical conditions. However, these risk factors are not enough to explain the immense interindividual clinical variability in any given epidemiological group.  Thus, given the increasing percentage of people infected with SARS-CoV-2, it is important to understand the mechanisms behind life-threatening COVID-19. Two studies sought to examine this mechanism by focusing on the immune system of the body, specifically on type I interferons.

How Type I interferon is involved in the defense against COVID-19 disease

Interferons (IFNs) are signaling proteins produced by the cells in response to virus infection. Once triggered, interferons can inhibit viral entry, viral protein synthesis, and virus maturation. Certain genes in chromosome 9 encode for Type I IFNs, and interferon regulatory factors (IRF), a family of transcription factors, primarily regulates their production. Toll-like receptor-3 (TLR3), a protein involved in pathogen recognition, also plays a role in interferon production.

Inborn errors in type I IFN immunity

In February 2020, a group of scientists led by Qian Zhang studied inborn errors in type 1 interferon immunity, which may be involved in the increased susceptibility to the coronavirus disease. They tested 13 loci or sets of genes, including TLR3 and other types of IRFs that are involved in the production of type 1 IFN. They sequenced the genome of 659 patients from different ancestries that have severe COVID-19 pneumonia as well as 534 patients that have non-threatening symptoms. Results showed that rare mutations of TLR3- and IRF7-dependent type I IFN immunity can indeed cause severe covid-19 pneumonia. They discovered that 23 out of 659 (3.5%) patients with severe COVID-19 pneumonia either had known deficiencies or new genetic defects at 8 out of the 13 loci involved in TLR3 and IRF7 proteins which play a role in the induction and amplification of type I IFNs. 

Autoantibodies against Type I Interferons

Neutralizing antibodies are antibodies produced naturally by B-cells in the bone marrow to defend against viral invaders by binding to the virus and preventing it from entering the cells. In contrast, autoantibodies bind to an individual’s own proteins. 

Research led by Paul Bastard tested the hypothesis that neutralizing autoantibodies targeting type I IFNs may underlie severe COVID-19 as they prevent the binding of the IFNs to their receptor. Thus, they tested the autoantibodies against type I IFNs in 987 patients with life-threatening COVID-19 pneumonia, 663 patients with mild symptoms, and 1227 healthy controls before the COVID-19 pandemic. Results showed that at least 101 of 987 patients (10.2%) with severe COVID-19 pneumonia had neutralizing autoantibody various interferons of type I IFNs. These block the innate antiviral immunity provided by type I IFNs. They also found that  94% of the patients with autoantibodies were men while more than half were over 65 years old which can explain the previously identified demographics that are most at risk for COVID-19. 

How do these findings help us?

Both findings emphasize the importance of type I interferons in detecting and preventing the infection of viruses such as SARS-CoV-2. Aberrations in type I IFNS and autoantibodies leading to higher susceptibility to severe COVID-19 pneumonia are not found in people with milder cases of coronavirus. These studies provide a means to identify individuals who are most prone to severe COVID-19 infection leading to prevention by encouraging these individuals to take more precautionary methods such as vaccination. Treatments such as plasmapheresis, plasmablast depletion, and type I IFN administration can also be explored. These findings pave the way for future research to focus on understanding the mechanism behind mutations in antiviral defense-related genes and the production of neutralizing antibodies of IFN and studying the potential of using interferons to treat patients with life-threatening COVID-19.