- Please check and comment entries here.
Type I Interferon
Together with type III IFNs, Type I Interferons (IFNs-I) represent the first line of immune defense against viral infections. In the case of RNA viruses, after recognition of viral products by pattern recognition receptors (PRRs), such as the main cytosolic receptors RNA helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), the signal converges on the activation of the mitochondrial antiviral signaling protein (MAVS), that, in turns, activates the TANK-binding kinase 1 (TBK1), leading to the phosphorylation and activation of IFN-regulatory factors 3 and 7 (IRF3, IRF7) [6,7]. IRFs then translocate to the nucleus and induce the production of IFNs-I (IFNα, IFNβ, IFNε, IFNτ, IFNκ, IFNω, IFNδ and IFNζ).
In December 2019, an outbreak of acute respiratory syndrome of unknown etiology was reported in Wuhan, China . Soon thereafter, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the causative agent of coronavirus infectious disease 2019 (COVID-19) and, in March 2020, the World Health Organization declared the COVID-19 outbreak a global pandemic . As of 13 July 2021, the pandemic has accounted for over 210 million confirmed cases of COVID-19 worldwide, including more than 4 million deaths , together with an enormous social and economic impact throughout the world . SARS-CoV-2 infection manifests with a broad spectrum of clinical patterns, resulting in asymptomatic cases in most individuals and inducing mild to severe illness in others, with fever, cough, headache and myalgia identified as common symptoms in moderate COVID-19, whereas severe pneumonia requiring intensive care unit and mechanical ventilation occurs in critically ill patients .
Production and secretion of IFN into the surrounding tissue results in the binding of IFNs to their receptor (IFNAR) in an autocrine and paracrine manner. The interaction with IFNAR activates the receptor-associated protein tyrosine kinases Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which in turn phosphorylate signal transducer and activator of transcription 1 and 2 (STAT1 and STAT2) molecules, leading to their dimerization, nuclear translocation and binding to IRF9 to form the ISG factor 3 (ISGF3) complex. These events culminate with the transcription of hundreds of interferon stimulated genes (ISGs), that inhibit virus multiplication at distinct levels, potentiate the innate antiviral immunity and stimulate an adaptive response .
Many, if not all viruses, including the human coronaviruses SARS-CoV and MERS-CoV , have evolved distinct mechanisms to escape immune surveillance, including strategies to avoid PRRs recognition and the expression of viral proteins that impair IFN signaling at different levels . Therefore, with the experience gained during the previous Betacoronavirus outbreaks , the IFN response in SARS-CoV-2 infection was promptly investigated.
2. IFN-Based Therapy for COVID-19
|Authors||IFN Therapy||IFN Administration||Type of Study||N. Patients||Disease Stage||Outcome
(Intervention vs. Control)
|Hung, I.F.-N. et al. ||IFN-β-1b
5 days from symptoms onset
|Subcutaneous||Multicentre prospective open-label randomized phase 2 Trial||86 intervention group
41 control group
9 vs. 14.5 days
Mortality: 0% vs. 0%
Serious adverse effects: 0% vs. 2%
|Malhani, A.A. et al. ||IFN-β-1b
4 days from symptoms onset
|Subcutaneous||Observational study IFN-based vs. FPV treatment||68 treated with IFN
154 treated with FPV
|Mild–moderate–severe||Mortality: 9% vs. 12%
Need of systemic corticosteroids: 57% vs. 77%
|Davoudi-Monfared, E. et al. ||IFN-β-1a
10 days from symptoms onset
|42 intervention group
39 control group
14.8 vs. 12.2 days
Mortality: 19% vs. 43.6%
Serious adverse effects: no differences between groups
|Dastan, F. et al. ||IFN-β-1a
6.5 days from symptoms onset
|20 intervention group only||Severe||Hospitalization:
Serious adverse effects: 0%
|Ader, F. et al. ||IFN-β-1a
10 days from symptoms onset
|145 intervention group
148 control group
|Moderate–severe||Hospital discharge at day 29 significantly higher than control arm|
|Meng, Z. et al. ||Recombinant human (rh) IFN-α
Preventive Therapeutic Strategy
|2944 intervention group only||None||28-day incidence of COVID-19/new-onset clinical symptoms: 0%
Serious adverse effects: 0%
|Zhou, Q. et al. ||IFN-α2b
8 days from symptoms onset
|Inhaled||Uncontrolled, exploratory study||53 intervention group
24 control group
|Moderate||Accelerated viral clearance/reduction in systemic inflammation markers (circulating IL-6 and CRP levels)|
|Monk, P.D. et al. ||IFN-β-1a
24 h from SARS-CoV-2 positive test
|Inhaled||Randomized, double-blind, placebo-controlled,
phase 2 pilot trial
|50 intervention group
51 control group
|Moderate–severe||Greater odds of improvement in OSCI scale for intervention group
Mortality: 0% vs. 6%
Serious adverse effects: 15% vs. 28%
The entry is from 10.3390/biology10090829
- Zhou, P.; Yang, X.L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.R.; Zhu, Y.; Li, B.; Huang, C.L.; et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579, 270–273.
- WHO. WHO Director-General’s opening remarks at the media briefing on COVID-19, 11 March 2020. 2020. Available online: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020 (accessed on 13 July 2021).
- WHO. WHO Coronavirus (COVID-19) Dashboard. Available online: https://covid19.who.int/ (accessed on 25 August 2021).
- Hiscott, J.; Alexandridi, M.; Muscolini, M.; Tassone, E.; Palermo, E.; Soultsioti, M.; Zevini, A. The global impact of the coronavirus pandemic. Cytokine Growth Factor Rev. 2020, 53, 1–9.
- Brodin, P. Immune determinants of COVID-19 disease presentation and severity. Nat. Med. 2021, 27, 28–33.
- McNab, F.; Mayer-Barber, K.; Sher, A.; Wack, A.; O’Garra, A. Type I interferons in infectious disease. Nat. Rev. Immunol. 2015, 15, 87–103.
- Kindler, E.; Thiel, V.; Weber, F. Interaction of SARS and MERS Coronaviruses with the Antiviral Interferon Response. In Advances in Virus Research; Elsevier: Amsterdam, The Netherlands, 2016; Volume 96, pp. 219–243.
- Kikkert, M. Innate Immune Evasion by Human Respiratory RNA Viruses. J. Innate Immun. 2020, 12, 4–20.
- Garcia-Sastre, A. Ten Strategies of Interferon Evasion by Viruses. Cell Host Microbe 2017, 22, 176–184.
- Blanco-Melo, D.; Nilsson-Payant, B.E.; Liu, W.C.; Uhl, S.; Hoagland, D.; Moller, R.; Jordan, T.X.; Oishi, K.; Panis, M.; Sachs, D.; et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell 2020, 181, 1036–1045.e9.
- Channappanavar, R.; Fehr, A.R.; Vijay, R.; Mack, M.; Zhao, J.; Meyerholz, D.K.; Perlman, S. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe 2016, 19, 181–193.
- Clementi, N.; Ferrarese, R.; Criscuolo, E.; Diotti, R.A.; Castelli, M.; Scagnolari, C.; Burioni, R.; Antonelli, G.; Clementi, M.; Mancini, N. Interferon-β-1a Inhibition of Severe Acute Respiratory Syndrome–Coronavirus 2 In Vitro When Administered After Virus Infection. J. Infect. Dis. 2020, 222, 722–725.
- Lokugamage, K.G.; Hage, A.; de Vries, M.; Valero-Jimenez, A.M.; Schindewolf, C.; Dittmann, M.; Rajsbaum, R.; Menachery, V.D. Type I Interferon Susceptibility Distinguishes SARS-CoV-2 from SARS-CoV. J. Virol. 2020, 94, e01410-20.
- Antonelli, G.; Scagnolari, C.; Moschella, F.; Proietti, E. Twenty-five years of type I interferon-based treatment: A critical analysis of its therapeutic use. Cytokine Growth Factor Rev. 2015, 26, 121–131.
- Hung, I.F.-N.; Lung, K.-C.; Tso, E.Y.-K.; Liu, R.; Chung, T.W.-H.; Chu, M.-Y.; Ng, Y.-Y.; Lo, J.; Chan, J.; Tam, A.R.; et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: An open-label, randomised, phase 2 trial. Lancet 2020, 395, 1695–1704.
- Areej, A.M.; Mushira, A.E.; Saheb, S.-A.F.; Mona, R.A.; Roaa, T.B.-B.; Safar, A.A.; Halwani, R.; Tleyjeh, I.M. Combination of (interferon beta-1b, lopinavir/ritonavir and ribavirin) versus favipiravir in hospitalized patients with non-critical COVID-19: A cohort study. PLoS ONE 2021, 16, e0252984.
- Davoudi-Monfared, E.; Rahmani, H.; Khalili, H.; Hajiabdolbaghi, M.; Salehi, M.; Abbasian, L.; Kazemzadeh, H.; Yekaninejad, M.S. A Randomized Clinical Trial of the Efficacy and Safety of Interferon β-1a in Treatment of Severe COVID-19. Antimicrob Agents Chemother 2020, 64, e01061-20.
- Dastan, F.; Nadji, S.A.; Saffaei, A.; Marjani, M.; Moniri, A.; Jamaati, H.; Hashemian, S.M.; Baghaei, P.; Abedini, A.; Varahram, M.; et al. Subcutaneous administration of interferon beta-1a for COVID-19: A non-controlled prospective trial. Int. Immunopharmacol. 2020, 85, 106688.
- Ader, F.; Peiffer-Smadja, N.; Poissy, J.; Bouscambert-Duchamp, M.; Belhadi, D.; Diallo, A.; Delmas, C.; Saillard, J.; Dechanet, A.; Mercier, N.; et al. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19. Clin. Microbiol. Infect. 2021.
- Meng, Z.; Wang, T.; Chen, L.; Chen, X.; Li, L.; Qin, X.; Li, H.; Luo, J. The Effect of Recombinant Human Interferon Alpha Nasal Drops to Prevent COVID-19 Pneumonia for Medical Staff in an Epidemic Area. Curr. Top. Med. Chem. 2021, 21, 920–927.
- Zhou, Q.; Chen, V.; Shannon, C.P.; Wei, X.-S.; Xiang, X.; Wang, X.; Wang, Z.-H.; Tebbutt, S.J.; Kollmann, T.R.; Fish, E.N. Interferon-α2b Treatment for COVID-19. Front. Immunol. 2020, 11, 1061.
- Monk, P.D.; Marsden, R.J.; Tear, V.J.; Brookes, J.; Batten, T.N.; Mankowski, M.; Gabbay, F.J.; Davies, D.E.; Holgate, S.T.; Ho, L.-P.; et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir. Med. 2021, 9, 196–206.
- Hensley, L.E.; Fritz, E.A.; Jahrling, P.B.; Karp, C.; Huggins, J.W.; Geisbert, T.W. Interferon-β 1a and SARS Coronavirus Replication. Emerg. Infect. Dis. 2004, 10, 317–319.
- Channappanavar, R.; Fehr, A.R.; Zheng, J.; Wohlford-Lenane, C.; Abrahante, J.E.; Mack, M.; Sompallae, R.; McCray, P.B.; Meyerholz, D.K.; Perlman, S. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J. Clin. Investig. 2019, 129, 3625–3639.
- de Prost, N.; Bastard, P.; Arrestier, R.; Fourati, S.; Mahevas, M.; Burrel, S.; Dorgham, K.; Gorochov, G.; Tandjaoui-Lambiotte, Y.; Azzaoui, I.; et al. Plasma Exchange to Rescue Patients with Autoantibodies Against Type I Interferons and Life-Threatening COVID-19 Pneumonia. J. Clin. Immunol. 2021, 41, 536–544.