Inborn errors of type 1 IFN immunity: An underlying cause of life-threatening COVID-19

Results of a recent immunology study by researchers at the University of Hong Kong (HKU), in alliance with the Coronavirus Disease 2019 (COVID-19) Human Genetic Effort (COVID HGE) international collaboration, reveal that inborn errors of type 1 interferon (IFN) immunity appear to be the underlying cause of life-threatening COVID-19, with titre and affinity enhanced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–driven induction of type 1 IFNs. 

In the study, plasma and serum samples were collected from 987 patients with life-threatening COVID-19 pneumonia and 663 patients with asymptomatic or mild SARS-CoV-2 infection during the acute phase of disease, as well as 1,227 healthy individuals prior to the COVID-19 pandemic. [Science 2020, doi: 10.1126/science.abd4585]

Life-threatening COVID-19 pneumonia was defined as pneumonia in patients with critical disease, whether pulmonary or with mechanical ventilation, septic shock, or damage to any other organ requiring intensive care unit admission. Patients with mild SARS-CoV-2 infection were those with mild, self-healing ambulatory disease with no evidence of pneumonia.

Overall, neutralizing immunoglobulin (Ig) G autoantibodies against IFN-ɷ and/or IFN-α were present in 10.2 percent (n=101) of patients. These patients were predominately male (n=95; 94.1 percent) with life-threatening COVID-19 pneumonia at the onset of critical illness, whilst 11 and 14 of 23 patients had IgM and IgA autoantibodies against IFN-ɷ and IFN-α, respectively. These autoantibodies against IFN were present prior to SARS-CoV-2 infection and were not triggered by this infection episode.

In contrast, autoantibodies were detected in only 0.33 percent (n=4) and in none of the healthy individuals and patients with asymptomatic or mild infection, respectively.

The autoantibodies were shown to neutralize the ability of corresponding type I IFNs to block SARS-CoV-2 infection in vitro and in vivo.

Results of an accompanying study using data of 659 patients (mean age, 51.8 years; female, 25.5 percent) with life-threatening COVID-19 and 534 patients with asymptomatic or mild SARS-CoV-2 infection showed that 3.5 percent of patients (n=23; age range, 17–77 years) of various ancestries with life-threatening COVID-19 had deleterious variants at the influenza susceptibility loci, including TLR and IRF, resulting in autosomal recessive (AR) or dominant deficiencies. [Science 2020, doi: 10.1126/science.abd4570]

Patients with AR IRF deficiency or AR and AD TLR3 deficiency also had impaired production of type I IFN immunity against SARS-CoV-2. In other words, 3.5 percent of patients with life-threatening COVID-19 were suggested to have inborn errors of TLR3- and IRF7-depedent type 1 immunity. Importantly, these genotypes remained silent until infection with SARS-CoV-2.

“[As a whole], the study findings highlight the crucial role of type 1 IFNs in protective immunity against SARS-CoV-2,” suggested the researchers. [Science 2020, doi: 10.1126/science.abd4585]

“Our findings have direct clinical implications. Firstly, patients with SARS-CoV-2 infection can be screened to identify those with autoantibodies at risk of developing life-threatening pneumonia. Secondly, our findings pave the way for therapeutic intervention, including plasmapheresis, monoclonal antibodies depleting plasmablasts, and inhibition of type 1 IFN-reactive B cells, [as well as administration of type 1 IFN],” concluded the researchers [Science 2020, doi: 10.1126/science.abd4570; Science 2020, doi: 10.1126/science.abd4585]