The dual sides of interferon induction in COVID-19 treatment

Document Type : Review Article

Authors

1 Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

3 Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran

4 Cellular and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

Coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created a pandemic with immense impacts on different aspects of human life globally. Generally, type I and II interferons are essential cytokines to combat viral infections including COVID-19. However, SARS-CoV-2 adopts evasion mechanisms to overcome interferon-mediated antiviral responses and neutralizes a key human defensive strategy. The aim of this mini-review is to survey both beneficial and non-beneficial effects of interferon during COVID-19 disease course. The indication of interferon-α2b or interferon β-1a has shown benefit at the early stages of COVID-19 in some clinical trials; though, interferon administration could only help in the incubation period or before the peak viral load. The incubation period and the duration from the symptom onset till the peak viral load has been estimated 5-6 and 2-3 days, respectively. On the other hand, an increase of interferon level in the disease’s late stages leads to delayed recovery and probably increased mortality rates due to the upregulation of ACE-2 expression in human airway epithelial cells, leading to the facilitation of virus entry into the host cells. Besides, it promotes the overactivation of inflammatory responses, which often happens in the disease’s pulmonary phase causing the cytokine storm. In this stage, antiviral agents might not work, and anti-inflammatory drugs, including corticosteroids (dexamethasone or prednisolone), tocilizumab (an IL-6 inhibitor), or anakinra (a recombinant IL-1 receptor antagonist), are beneficial. Some other proposed drugs such as TNF-α inhibitors and JAK inhibitors need further investigations in future studies.

Keywords



1. Owji H, Negahdaripour M, Hajighahramani N. Immunotherapeutic approaches to curtail COVID-19. Int Immunopharmacol. 2020 Nov;88:106924. doi: 10.1016/j.intimp.2020.106924.
2. Negahdaripour M. A World of Changes: The Inheritance of COVID-19. Iran J Med Sci. 2020;45(3):155-156. doi:10.30476/ijms.2020.46530
3. Galbadage T, Peterson BM, Gunasekera RS. Does COVID-19 Spread Through Droplets Alone?. Front Public Health. 2020;8:163. Published 2020 Apr 24. doi:10.3389/fpubh.2020.00163
4. Bourouiba L, Dehandschoewercker E, Bush JW. Violent expiratory events: on coughing and sneezing. J Fluid Mech. 2014;745:537-63. doi: 10.1017/jfm.2014.88
5. Lee AJ, Ashkar AA. The Dual Nature of Type I and Type II Interferons. Front Immunol. 2018 Sep 11;9:2061. doi: 10.3389/fimmu.2018.02061.
6. Bagheri A, Moezzi SMI, Mosaddeghi P, Nadimi Parashkouhi S, Fazel Hoseini SM, Badakhshan F, et al. Interferon-inducer antivirals: Potential candidates to combat COVID-19. Int Immunopharmacol. 2021 Feb;91:107245.
doi: 10.1016/j.intimp.2020.107245.
7. Mosaddeghi P, Negahdaripour M, Dehghani Z, Farahmandnejad M, Moghadami M, Nezafat N, et al. Therapeutic Approaches for COVID-19 Based on the Interferon-mediated Immune Responses. Curr Signal Transduct Ther.(2021)16:1.
8. Kim KS, Ejima K, Ito Y, Iwanami S, Ohashi H, Koizumi Y, et al. Modelling SARS-CoV-2 Dynamics: Implications for Therapy.
medRxiv. 2020. doi: 10.1101/2020.03.23.20040493
9. Ejima K, Kim KS, Ludema C, Bento AI, Iwanami S, Fujita Y, Ohashi H, Koizumi Y, Watashi K, Aihara K, Nishiura H, Iwami S. Estimation of the incubation period of COVID-19 using viral load data. Epidemics. 2021 Mar 15;35:100454.
10. Mosaddeghi P, Shahabinezhad F, Dorvash M, Goodarzi M, Negahdaripour M. Harnessing the non-specific immunogenic effects of available vaccines to combat COVID-19. Hum Vaccin Immunother. 2020 Nov 13:1-12.
11. Sa Ribero M, Jouvenet N, Dreux M, Nisole S. Interplay between SARS-CoV-2 and the type I interferon response. PLoS Pathog. 2020;16(7):e1008737. Published 2020 Jul 29.
12. Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M, Abbasian L, Kazemzadeh H, Yekaninejad MS. A Randomized Clinical Trial of the Efficacy and Safety of Interferon β-1a in Treatment of Severe COVID-19. Antimicrob Agents Chemother.
2020 Aug 20;64(9):e01061-20.
13. Wang N, Zhan Y, Zhu L, Hou Z, Liu F, Song P, Qiu F, Wang X, Zou X, Wan D, Qian X, Wang S, Guo Y, Yu H, Cui M, Tong G, Xu Y, Zheng Z, Lu Y, Hong P. Retrospective Multicenter Cohort Study Shows Early Interferon Therapy Is Associated with Favorable Clinical Responses in COVID-19 Patients. Cell Host Microbe.
2020 Sep 9;28(3):455-464.e2.
14. Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, Perlman S. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice.
Cell Host Microbe. 2016 Feb 10;19(2):181-93
15. Kindler E, Thiel V. SARS-CoV and IFN: Too Little, Too Late. Cell Host Microbe. 2016 Feb 10;19(2):139-41
16. Jamilloux Y, Henry T, Belot A, et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev. 2020;19(7):102567. doi:10.1016/j.autrev.2020.102567
17. Hu, B, Huang, S, Yin, L. The cytokine storm and COVID‐19. J Med Virol. 2021; 93: 250– 256.
18. Negahdaripour M. The Rise and Fall in Therapeutic Candidates for COVID-19. Iran J Med Sci. 2020;45(4):231-232. doi:10.30476/ijms.2020.46689
19. Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies. Front Immunol. 2020;11:1708. Published 2020 Jul 10. doi:10.3389/fimmu.2020.01708
20. Narain S, Stefanov DG, Chau AS, et al. Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease 2019 Cytokine Storm. Chest. 2021;159(3):933-948. doi:10.1016/j.chest.2020.09.275
21. Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020 Jul;39(7):2085-2094.
22. Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M, Canetti D, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020 Jun;2(6):e325-e331.
23. Rochwerg B, Siemieniuk RA, Agoritsas T, Lamontagne F, Askie L, Lytvyn L, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020 Sep 4;370:m3379. doi: 10.1136/bmj.m3379.
Update in: BMJ. 2020 Nov 19;371:m4475. Update in: BMJ. 2021 Mar 31;372:n860. PMID: 32887691.
24. Omrani AS, Pathan SA, Thomas SA,
Harris TR, Coyle PV, Thomas CE, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19.
E Clinical Medicine. 2020;29:100645.
25. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Sevestre J, et al. Clinical and
microbiological effect of a combination of
hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis. 2020 Mar-Apr;34:101663.