Inborn Errors of Type I IFN Immunity in Patients With Life-Threatening COVID-19

Abstract

One of the harrowing aspects of the coronavirus disease 2019 (COVID-19) pandemic has been that many otherwise healthy individuals experienced severe disease after being infected with severe acute respiratory syndrome coronavirus 2. Although clear risk factors for severe disease have been identified, including advanced age and a host of chronic illnesses, there have been many without any identifiable risks who have died or been severely affected. One hypothesis is that severe coronavirus disease (COVID) in otherwise healthy people represents a specific deficit in immune defense and or immune response. This could be interpreted as a severe COVID representing a primary immunodeficiency or, because now these diseases are also known, an inborn error of immunity (IEI). The IEI term is increasingly preferred as opposed to primary immunodeficiency because not all genetic aberrancies of immunity result in a “deficiency.” To evaluate this hypothesis several international collaboratives of clinical investigators were formed and contributed to a recent report offering some initial findings.In this study, the researchers included 659 individuals with severe COVID-19 pneumonia and 534 individuals with asymptomatic or mild infection.Genomic DNA was extracted from whole blood and whole exome or genome sequencing was performed.Most notably, IEI-affecting type-I interferon (IFN) were identified in 3.5% of the severe COVID-19 cohort. The type-I IFN system, including both IFN-α and IFN-β, is part of the response arm of innate viral sensing. When produced, these proteins have the ability to induce many antiviral functions, including restraining cellular proliferation, inducing cellular antiviral programs and proteins, and activating natural killer cell cytotoxicity. Loss of function (LOF) variants in a number of genes in this pathway have been previously associated with severe influenza. LOF variants were identified in an autosomal dominant or autosomal recessive pattern of inheritance in 23 individuals with severe disease (none of whom had been previously hospitalized for viral infection). The genes identified were TLR3, UNC93B1, TICAM1, TBK1, IRF3, IRF7, and IFNAR1/2. Although informatics can be used to identify damaging variants, in this study, all variants were evaluated in experimental in vitro systems to define the detrimental impact of variant identified on the type-I IFN system. Thus, each LOF variant found in a patient was proven to be damaging through what is known as functional genomics, revealing an irrefutable association between the variant and biological relevance.The initial hypothesis of the investigators regarding severe COVID-19 potentially representing the expression of an IEI, especially with regards to Type-I IFN in otherwise healthy individuals, was substantiated. Thus, through the exploration of individuals with severe COVID-19, the importance of type-I IFN in human defense against severe acute respiratory syndrome coronavirus 2 has been confirmed and underscored.In this work, the authors raise several important possibilities (specifically, if type-I IFN gene pathway screens should be performed in patients with severe COVID-19 and if these individuals should be treated with type-I IFN). Importantly type-I IFN is a US Food and Drug Administration–approved treatment of other conditions and, therefore, is available in therapeutically applicable formats for additional study applications. Furthermore, it is likely that the investigative team has discovered other variants of interest in their analyses. Specifically, ones that have not yet been associated with disease and may represent novel IEI, which will have been uncovered by severe COVID-19. These novel IEI will likely require further and more extensive work in functional genomics but should be anticipated.