Mutations in genes in interferon signaling and autoantibodies targeting interferon explain ~14% of severe COVID-19 cases. Image shows DNA, interferon, and antibodies. [Credit: Nancy R. Gough, BioSerendipity, LLC]

Gene Mutations and Autoantibodies in Severe COVID-19

Genetic variations and autoantibodies that compromise interferon signaling explain ~14% of severe COVID-19 cases.

As researchers evaluate patients that develop severe COVID-19, the disease caused by the coronavirus SARS-CoV2, they are discovering answers to why some people become so critically ill and others do not. A pair of papers in Science by international teams of scientists led by Jean-Laurent Casanova reports reasons for why ~14% of severe cases of COVID-19 occur. Importantly, this information is clinically useful and will help screen at-risk individuals, prioritize vaccination, and treat patients. Additionally, these findings support a key theory regarding why COVID-19 shows so much variability: Interferon signaling varies within the population.

Genetic Variation that Compromises Interferon Signaling

In the first study, researchers proposed that genetic variations in the population may underlie susceptibility to severe COVID-19 and established the COVID Human Genetic Effort to identify such genetic mutations. They studied 659 patients hospitalized with severe, life-threatening COVID-19 and 534 people with mild or asymptomatic disease.

Because interferon signaling is a key antiviral response, 13 genes encoding proteins involved in this immune pathway were targeted for analysis. Using such a targeted approach enabled rapid identification of potentially important variations within the patient populations, rather than having to search for the “needle in the haystack” by evaluating the entire genomes of all of the patients. However, this means that there are likely other mutations in other genes involved in antiviral responses that can impact COVID-19 severity. These await future discovery.

Of the 13 genes sequenced, 8 had disease-causing mutations: TLR3, UNC93B1, TICAM1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2. These genes encode proteins that function in two parts of the interferon response. They function in either the infected cells that are sensing the infection and producing interferons or in the cells that respond to the interferons.

Mutations in genes encoding multiple proteins involved in interferon production and response contribute to severe COVID-19. For simplicity, not all proteins are shown. Except for IRF9, the labeled proteins are the ones that have been identified with mutations associated with COVID-19 severity. Credit: Nancy R. Gough, BioSerendipity using BioRender.com.

TLR3, TBK1, IRF3, IRF7, UNC93B1, and TICAM1 are important for detecting viruses in infected cells and stimulating the expression of interferon genes. These join the previously discovered mutation in TLR7 that also caused severe COVID-19. TLR3 and TLR7 are receptors that detect viral nucleic acids in cells. UNC93B1 is important for delivering these receptors to the correct part of the cell to engage the viral genetic material. TBK1 and TICAM1 are part of the signaling network activated by the receptors. IRF3 and IRF7 are transcription factors that bind DNA to turn on genes encoding interferons. Thus, the mutations span multiple parts of the viral response such that infected cells with any of the mutated genes cannot properly turn on interferons.

IFNAR1 and INFAR2 are proteins that form the receptor for type 1 interferons, which are produced by the genes stimulated by TLR3 and TLR7 activation. So, cells with either of these mutated genes cannot properly respond to the presence of the interferons. In response to interferons, cells turn on hundreds of genes called interferon-stimulated genes. These interfere with viral infection in multiple ways and feedback on this antiviral immune response.

For patients with mutations in genes involved in interferon production, treatment with interferons should be beneficial. In patients with mutations in the interferon receptor genes, interferons will not help because the cells cannot properly respond to the interferons. These patients may require alternative treatments, such as virus-neutralizing antibodies.

Compromised Interferon Signaling Due to Autoantibodies

In the second paper, the researchers hypothesized the aberrant interferon response may occur because some people have antibodies that inactivate interferons. These antibodies are called “autoantibodies” because they recognize “self” proteins instead of foreign ones. Some forms of autoimmune disease, including autoimmune polyendocrinopathy syndrome type I (APS-I) and systemic lupus erythematosus (SLE), have autoantibodies against type I interferons.

Their analysis showed that ~14% (135 out of 987) of patients with severe, life-threatening COVID-19 had autoantibodies against at least one member of the type I interferon family, which includes 13 interferon-α (IFN-α) proteins, IFN-β, IFN-κ, IFN-ε, and IFN-ω. The patient's own immune system was preventing them from fighting the virus by blocking the body’s critical antiviral proteins.

As an initial screen, the blood plasma or serum from the patients was tested for autoantibodies against IFN-α2 and IFN-ω. Some patients had antibodies against only one or the other and some had antibodies against both. Of the 135 patients, 101 had autoantibodies that completely blocked signaling by IFN-α2 or IFN-ω or both. Thus, 10% of the patients with severe COVID-19 had “neutralizing” autoantibodies, meaning that the antibodies bind to the interferon molecule and blocked their function. (This is not to be confused with neutralizing antibodies that target the virus. Those kinds of neutralizing antibodies are beneficial.)

Further testing showed that all 22 of the patients evaluated who had autoantibodies against IFN-α2 also had autoantibodies the entire IFN-α family of 13 members. Thus, these patients would not benefit from therapy based on any IFN-α family member.

Of the 4 types of antibody tested, IgG was the most abundant in most of the patients with the autoantibodies. Depleting IgG from the serum or plasma samples restored interferon signaling. Thus, these patients could benefit from plasmapheresis, a procedure used to treat autoimmune diseases that removes antibodies from the blood.

Of practical importance, any recovered COVID-19 patient with these interferon-targeted autoantibodies should not donate plasma for convalescent plasma therapy to treat other COVID-19 patients. Additionally, donated plasma should be tested for the presence of these antibodies. Fortunately, interferon-targeted autoantibodies occur with a very low frequency in the healthy population (0.33% in this study, representing 4 of 1,227 people), so there should be a limited risk of these in the donated blood supply.

One of the intriguing findings from this study was that 95 of 101 patients with interferon-neutralizing autoantibodies were male. This suggests that the production of these autoantibodies is linked to the X chromosome. Men have one X chromosome and one Y chromosome, whereas women have two X chromosomes. Supporting this theory, one of the women who had severe COVID-19 and interferon-neutralizing autoantibodies had a disorder associated with having a single functional X chromosome.

Identifying the At-Risk for Vaccine Prioritization

Together with the previous study finding TLR7, these two studies provide key information for understanding who is at risk for developing severe COVID-19 and for developing effective and personalized therapeutic strategies. Testing for interferon-targeted autoantibodies can be done with a simple blood test to identify these people at high risk for severe COVID-19 within the population and to avoid collecting their plasma for treating COVID-19 patients.

Genetic testing can identify those with interferon receptor mutations who will not benefit from interferon therapy. Genetic testing for mutations in other genes in the interferon pathway can identify these at-risk individuals.

Knowledge of the at-risk population and understanding variability in the individual immune response will enable not only vaccine prioritization but effective inclusion of such individuals in vaccine trials. It is possible that with the multiple types of vaccines undergoing testing, different formulations may be more effective in some than others. Understanding the immune variability in the population could aid in matching the most effective vaccine or therapy to individuals, thus personalizing prevention and treatment.

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