REPLY
We read with great interest the comments by Dorgham et al. (1) with regard to our recently published article (2). Also, we appreciate sharing the results of their valuable work reporting a correlation between interferon beta (IFN-β) serum levels and COVID-19 mortality, which was summarized in their letter. It helps us to understand the role of IFNs in the pathogenesis and treatment of COVID-19.
Type I IFNs are a part of the innate immune system. Although they are used for the treatment of some autoimmune diseases, like multiple sclerosis, some patients with other immune-mediated diseases, like systemic lupus erythematous, have high levels of IFNs related to activation of the disease (3). Also, IFNs are prescribed for viral hepatitis owing to their antiviral activities (4).
During the emergence of the COVID-19 pandemic, the role of IFNs in the prevention and treatment of this disease was proposed. Some promising results in two other epidemics of coronavirus, i.e., SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome), have been reported (5). As with other family members, SARS-CoV-2 possesses some mechanisms (like the proteins ORF6 and ORF8) that can inhibit the production of type I IFNs (6).
It was proposed that administration of IFNs to COVID-19 patients with increased serum IFN-β levels might have detrimental effects. However, the role of type I IFNs in COVID-19 pathogenesis has been proposed to be reduced. Most patients with severe COVID-19 displayed impaired IFN activity that also correlated with lower viral clearance (7). The culprit proteins (like nuclear shuttle protein [NSP]-type and open reading frame [ORF]-type proteins) of the virus can antagonize the production of IFNs, so SARS-CoV-2 may evade the innate immune system (8). Some findings have been reported (9, 10). In the Dorgham et al. study (1), COVID-19 patients with increased serum IFN-β levels experienced significantly higher mortality. Only 11 out of 112 patients were categorized in this subpopulation. Also, it should be considered that IFNs are components of the cytokine storm phase. Patients in this stage have high serum levels of IFNs and probably high mortality (11).
We agree with Dorgham et al. that early administration of IFNs for the treatment of COVID-19 should be taken into account. It is suggested not only because of the probable deterioration of the patient’s condition and because IFN may promote cytokine release in the later stages of the disease but also because of the diminished antiviral effect of IFN in late phases of the disease (12, 13). After about 8 to 12 days, the immune system will encounter the cytokine storm, and the use of IFNs at this stage did not show beneficial effects (14). In addition, sampling for measurement of serum levels of IFN-β in this study was done during days 0 to 25 of hospital admission; therefore, patients were probably in different stages of the disease.
Finally, in agreement with Dorgham et al., we acknowledge the concept of personalized IFN-β therapy with a consideration of the pathogenesis of COVID-19 and the stage of the disease. Unfortunately, many aspects of the pathogenesis of COVID-19 have not been clarified yet. Future studies are needed to determine which intervention at which stage of the disease might help certain patients.
ACKNOWLEDGMENT
The authors’ statement of financial interests and conflicts of interest are the same as those in the original article.
Footnotes
This is a response to a letter by Dorgham et al. (https://doi.org/10.1128/AAC.00065-21).
REFERENCES
- 1.Dorgham K, Neumann AU, Decavele M, Luyt C-E, Yssel H, Gorochov G. 2021. Considering personalized interferon beta therapy for COVID-19. Antimicrob Agents Chemother 65:e00065-21. doi: 10.1128/AAC.00065-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M, Abbasian L, Kazemzadeh H, Yekaninejad MS. 2020. A randomized clinical trial of the efficacy and safety of interferon beta-1a in treatment of severe COVID-19. Antimicrob Agents Chemother 64:e01061-20. doi: 10.1128/AAC.01061-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Crow MK, Ronnblom L. 2019. Type I interferons in host defence and inflammatory diseases. Lupus Sci Med 6:e000336. doi: 10.1136/lupus-2019-000336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Qiu K, Liu B, Li S-Y, Li H, Chen Z-W, Luo A-R, Peng M-L, Ren H, Hu P. 2018. Systematic review with meta‐analysis: combination treatment of regimens based on pegylated interferon for chronic hepatitis B focusing on hepatitis B surface antigen clearance. Aliment Pharmacol Ther 47:1340–1348. doi: 10.1111/apt.14629. [DOI] [PubMed] [Google Scholar]
- 5.Strayer DR, Dickey R, Carter WA. 2014. Sensitivity of SARS/MERS CoV to interferons and other drugs based on achievable serum concentrations in humans. Infect Disord Drug Targets 14:37–43. doi: 10.2174/1871526514666140713152858. [DOI] [PubMed] [Google Scholar]
- 6.Li JY, Liao CH, Wang Q, Tan YJ, Luo R, Qiu Y, Ge XY. 2020. The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway. Virus Res 286:198074. doi: 10.1016/j.virusres.2020.198074. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, Péré H, Charbit B, Bondet V, Chenevier-Gobeaux C, Breillat P, Carlier N, Gauzit R, Morbieu C, Pène F, Marin N, Roche N, Szwebel TA, Merkling SH, Treluyer JM, Veyer D, Mouthon L, Blanc C, Tharaux PL, Rozenberg F, Fischer A, Duffy D, Rieux-Laucat F, Kernéis S, Terrier B. 2020. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 369:718–724. doi: 10.1126/science.abc6027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Lei X, Dong X, Ma R, Wang W, Xiao X, Tian Z, Wang C, Wang Y, Li L, Ren L, Guo F, Zhao Z, Zhou Z, Xiang Z, Wang J. 2020. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat Commun 11:3810. doi: 10.1038/s41467-020-17665-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Schreiber G. 2020. The role of type I interferons in the pathogenesis and treatment of COVID-19. Front Immunol 11:595739. doi: 10.3389/fimmu.2020.595739. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Zheng Y, Zhuang M-W, Han L, Zhang J, Nan M-L, Zhan P, Kang D, Liu X, Gao C, Wang P-H. 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) protein inhibits type I and III interferon production by targeting RIG-I/MDA-5 signaling. Signal Transduct Target Ther 5:299. doi: 10.1038/s41392-020-00438-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Nile SH, Nile A, Qiu J, Li L, Jia X, Kai G. 2020. COVID-19: pathogenesis, cytokine storm and therapeutic potential of interferons. Cytokine Growth Factor Rev 53:66–70. doi: 10.1016/j.cytogfr.2020.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Park A, Iwasaki A. 2020. Type I and type III interferons—induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe 27:870–878. doi: 10.1016/j.chom.2020.05.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Channappanavar R, Fehr AR, Zheng J, Wohlford-Lenane C, Abrahante JE, Mack M, Sompallae R, McCray PB, Meyerholz DK, Perlman S. 2019. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest 129:3625–3639. doi: 10.1172/JCI126363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Jamilloux Y, Henry T, Belot A, Viel S, Fauter M, El Jammal T, Walzer T, François B, Sève P. 2020. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev 19:102567. doi: 10.1016/j.autrev.2020.102567. [DOI] [PMC free article] [PubMed] [Google Scholar]