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Mutations in Type I Interferon Immunity Genes Underlie Severe COVID-19

NEW YORK – A new study from an international group of researchers has found that a portion of patients with life-threatening COVID-19 pneumonia carry mutations affecting the type I interferon (IFN) pathway, explaining the severity of their symptoms.

In a paper published on Thursday in Science, researchers led by Howard Hughes Medical Institute investigator and Rockefeller University professor Jean-Laurent Casanova described their findings from sequencing the exomes or genomes of 659 patients with life-threatening COVID-19 pneumonia and 534 individuals with asymptomatic or benign infection. In the severely affected patients, they discovered an enrichment of rare loss-of-function variants in 13 loci known to govern type I IFN immunity.

"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 medications and interventions," Casanova said in a statement. "COVID-19 may now be the best understood acute infectious disease in terms of having a molecular and genetic explanation for nearly 15 percent of critical cases across diverse ancestries."

The study participants included people from Asia, Europe, Latin America, and the Middle East. The findings are the first results from the COVID Human Genetic Effort, an international project co-led by Casanova and National Institute of Allergy and Infectious Diseases researcher Helen Su, with participation from 50 sequencing hubs and hundreds of hospitals around the world. The initiative, which kicked off in March, aims to identify genetic pathways involved in COVID-19 in patients that get severely ill, and could lead to new preventative and therapeutic strategies.

For their study, the investigators first tested the hypothesis that inborn errors of TLR3- and IRF7-dependent type I IFN immunity may underlie life-threatening COVID-19 pneumonia, as they do life-threatening influenza pneumonia. They found four unrelated patients with biallelic variants of IRF7 or IFNAR1, and 113 patients carrying monoallelic variants at 12 different loci, including TLR3 and IRF7. Nine of the variants were predicted to be loss-of-function (pLOF), whereas in the 534 controls with asymptomatic or mild SARS-CoV-2 infection, the investigators found only one heterozygous pLOF variation.

They then tested 113 of these variants experimentally in ad hoc overexpression systems and found that 24 variants in eight genes were deleterious. Twenty-three patients carried these 24 variants, resulting in four autosomal recessive (AR) deficiencies and 19 autosomal dominant (AD) deficiencies.

The researchers then went on to diagnose AR IRF7 deficiency in two individuals aged 49 and 50, and AR IFNAR1 deficiency in two individuals aged 26 and 38 years, all with no prior history of life-threatening infections. One patient with IRF7 deficiency who was tested was seropositive for several common viruses, including various influenza A and B viruses. This suggested that these genetic defects display incomplete penetrance for influenza respiratory distress, and only manifested clinically upon infection with SARS-CoV-2, which is more virulent.

In a related study published in Science on Thursday, the consortium looked at inter-individual clinical variability in the course of SARS-CoV-2 infection, finding that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-antibodies against IFN-ω, the 13 types of IFN-α, or both, at the onset of critical disease. A few patients also had auto-antibodies against the other three type I IFNs, hampering their ability to block SARS-CoV-2 infection in vitro. The researchers did not find these auto-antibodies in 663 individuals with asymptomatic or mild SARS-CoV-2 infection, and found them in only four of 1,227 healthy individuals.

They concluded that B cell-related inborn errors of type I IFN immunity underly life-threatening COVID-19 pneumonia in at least 2.6 percent of women and 12.5 percent of men.

"All of these findings strongly indicate that these auto-antibodies are actually the underlying reason some people get very sick, and not the consequence of the infection," Casanova said in a statement, adding, that "these two papers provide the first explanation for why COVID-19 can be so severe in some people, while most others infected by the same virus are okay."

The findings have direct clinical implications, the researchers said. SARS-CoV-2-infected patients should be screened to identify individuals with auto-antibodies at risk of developing life-threatening pneumonia, and those recovering from life-threatening COVID-19 should be excluded from donating convalescent plasma for ongoing clinical trials.

The results also pave the way for therapeutic interventions, they added, including plasmapheresis, monoclonal antibody-depleting plasmablasts, and the specific inhibition of type I IFN-reactive B cells. Further, early treatment with IFN-α in these patients is unlikely to be beneficial, but treatment with injected or nebulized IFN-β may have beneficial effects.

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