March 28, 2022


Types 1 and 3 interferon (IFN) expression and activity have been shown to play a significant role in determining the disease severity of SARS-CoV-2 infection. It is becoming clear that the timing of IFN expression is critical in the efficacy of the early response to viral infection on reducing disease severity. Indeed, a recent study has shown the pattern of a transient early peak of type 1 IFN expression in unvaccinated virus-naïve infected individuals who did not experience severe Covid-19. Its peak precedes the detection of the virus and the appearance of antibodies by a week or more. This is accompanied by a rapid expansion of SARS-CoV2 specific CD8+ T cells, suggesting that induction of CD8+ cells is also important in protection. However, high levels of IFN expression after this early time period can lead to deleterious effects on the disease outcome.

The importance of the type 1 IFN response against SARS-CoV2 is reflected on the deployment of anti-interferon defenses by the virus. This consists of the numerous viral proteins that are devoted to inhibiting key proteins in IFN signaling pathways. These include non-structural proteins 1, 3, 5-10 and 12-16, the matrix and nucleocapsid structural proteins, and ORFs 3a, 6, 7a, 7b and 9b. A detailed description of these comprehensive interactions can be found at here.


An early report has shown that pre-existent neutralizing autoantibodies against type 1 and -3 IFN are highly correlated with the incidence of severe Covid-19 . Strikingly, these autoantibodies were detectable in 10% of more than 950 patients with severe disease but were absent in those patients with asymptomatic or mild infections. The incidence of these autoantibodies in normal healthy people sampled prior to the pandemic was 0.03%. Interestingly, in the severe disease cohort, men constituted 94% of those with IFN autoantibodies, perhaps suggesting a possible reason for the greater susceptibility of men to severe Covid-19. A more recent study has found a similar correlations of IFN autoantibodies with severe vs milder Covid-19 . Moreover, analysis of single cell transcriptomics showed that the presence of these autoantibodies correlated with a lack of expression of INF-stimulated genes and elevated expression of LAIR1, a receptor that inhibits immune activation and is not expressed in healthy controls. Further, IFN autoantibody levels increased with age, thus suggesting that age is the strongest correlate of risk. Among IFN autoantibodies, infection fatality rates correlated most closely with those against IFN-α2 and/or IFN-ω. This is explainable in part by the ability of IFN-α2 autoantibodies to neutralize all types of IFN.


Inborn errors of immunity (especially involving genes important for IFN responses) represent further risk factors for severe Covid-19. An earlier report has described two unrelated pairs of brothers in the Netherlands who, although young and healthy, nevertheless progressed to severe Covid-19 (one died). Each pair of brothers had variants of the X-linked TLR7 gene, the product of which recognizes single stranded RNA in endosomes and responds by stimulating IFN expression through a series of signaling intermediates. These variants appear to cause a loss of TLR7 function, as evidence by decreased mRNA expression of genes involved in IFN production (IRF7, IFNB1, and ISG15) upon TLR7 stimulation. Another study has shown a significant enrichment of any of 13 autosomal-dominant or -recessive genes involved in IFN induction and activation in patients with severe Covid-19 compared with those with mild disease or who were asymptomatic. Another report confirmed the association of severe disease with variants of IFNAR2, a type 1 IFN receptor.

Moreover, a recent study has shown that children have elevated constitutive expression of IFN-related pattern receptors in upper airway epithelial cells, resulting in an accelerated IFN response relative to older people, perhaps helping explain their relative resistance to Covid-19. Clearly, there are other genetic markers unrelated to IFN that can lead to severe outcomes of Covid-19. However, it appears that defects in the timing and magnitude of type 1 IFN responses, either inborn or due to higher IFN autoantibody levels, are a major risk factor for severe Covid-19 development.


Numerous immunomodulating agents are currently being studied in clinical trials for the treatment of COVID-19, including interferon therapies (9); those have a potential to contribute to the treatment of COVID-19 patients. However, timing, type of interferon, and route of administration need to be further determined. Advanced knowledge on immunopathology of SARS-CoV-2 and a combinational approach using interferon and conventional antiviral drugs might also facilitate the development of innovative therapeutics for COVID-19.


  1. Chandran, A., et al., Rapid synchronous type 1 IFN and virus-specific T cell responses characterize first wave non-severe SARS-CoV-2 infections. Cell Reports Medicine, 2022. 3(3).
  2. Bastard, P., et al., Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science, 2020
  3.  van der Wijst, M.G.P., et al., Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19. Sci Transl Med, 2021. 13(612): p. eabh2624.
  4. Manry, J., et al., The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies. Res Sq, 2022.
  5. van der Made, C.I., et al., Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA, 2020. 324(7): p. 663-673.
  6. Zhang, Q., et al., Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science, 2020.
  7. Horowitz, J.E., et al., Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease. Nat Genet, 2022.
  8. Loske, J., et al., Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat Biotechnol, 2021.
  9. Calabrese LH, Lenfant T, Calabrese C. Interferon therapy for COVID-19 and emerging infections: Prospects and concerns. Cleve Clin J Med. 2020 Dec 3. doi: 10.3949/ccjm.87a.ccc066. Epub ahead of print. PMID: 33219050.

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