Reactome | IFNAR2:JAK1:STAT2 binds type 1 interferon analogs

IFNAR2:JAK1:STAT2 binds type 1 interferon analogs

Stable Identifier

R-HSA-9696179

Type

Reaction [binding]

Species

Homo sapiens

Compartment

extracellular region, plasma membrane

ReviewStatus

5/5

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IFNAR2:JAK1:STAT2 binds type 1 interferon analogs

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Natural ligands of the IFNAR1/2 receptor include interferon beta (IFNB), interferon alpha (IFNA) and interferon kappa (IFNK, also called IFN-epsilon), with binding affinity to the receptor decreasing in that order. However, weaker binding still triggers the signal, but differs in the pathways that are activated. Specifically, the antiviral response is always triggered but an additional antiproliferative program appears to require stronger binding like that from IFNB (Schreiber, 2020). Recombinant interferon alpha and beta, and their pegylated versions (peginterferon-alfa and peginterferon-beta) are widely applied in cancer, multiple sclerosis and viral infections.

The type I interferon beta (IFNB) is a key modulator of the immune defence against viruses. SARS-CoV-2, the coronavirus that causes Covid-19, appears to suppress production of types I and III IFNs as part of its strategy to evade immune detection and destruction (Hadjadj et al. 2020, Blanco-Melo et al. 2020). Administering recombinant human IFNB1 is suggested to reactivate the anti-viral immune response against SARS-CoV-2 (Davoudi-Monfared et al. 2020). In a small trial, direct lung delivery via a nebuliser showed Covid-19 patients were more than twice as likely to recover from the disease as those on placebo (Monk et al, 2021). In another small trial, time to clinical improvement in the group receiving IFNB1b was significantly shorter than the control group (Rahmani et al, 2020).

The recombinant human interferons IFNB1a and INFB1b are approved drugs for the treatment of multiple sclerosis (Schwid & Panitch 2007, Comi et al. 2001, Freedman 2014), so safety has been established. At the moment 23 trials with IFNB1A for the treatment of COVID-19 are underway, 7 of them using inhaled application.

IFNA is used in antiviral therapy, mostly for treating hepatitis B and hepatitis C, often in combination with other antiviral drugs. In one small uncontrolled COVID-19 trial, nebulized IFN-α2b had positive effects on virus load and blood markers (Zhou et al, 2020).

In addition to recombinant and pegylated IFN with an amino acid sequence nearly identical to wild-type, there have been attempts to optimize binding properties by scrambling the wild-type sequence and picking versions out of the mix that show an improvement. One such product, novaferon was approved in China as cancer treatment, and in a randomized, open-label, parallel-group trial it showed antiviral effects in COVID-19 patients (Zheng et al, 2020). Further trials are underway (NCT04669015, NCT04708158).

Literature References

PubMed ID	Title	Journal	Year
33193462	Corrigendum: Interferon-α2b Treatment for COVID-19 Wei, XS, Shannon, CP, Kollmann, TR, Xiang, X, Zhou, Q, Tebbutt, SJ, Wang, X, Wang, ZH, Chen, V, Fish, EN	Front Immunol	2020
33396578	Interferon-α2b Treatment for COVID-19 Is Associated with Improvements in Lung Abnormalities Zarin, P, MacArthur, MR, He, X, Xiang, X, Zhou, Q, Wang, ZH, Hanna, BS, Wei, X, Fish, EN	Viruses	2020
11377645	Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study Barkhof, F, Comi, G, Hommes, OR, Sørensen, PS, Early Treatment of Multiple Sclerosis Study Group, -, Edan, G, Martinelli, V, Rovaris, M, Durelli, L, Fernandez, O, Filippi, M, Seeldrayers, P, Hartung, H	Lancet	2001
32758689	SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: A randomized, open-label, parallel-group trial Xie, Y, Niu, P, Zheng, F, Zuo, Q, Xu, Y, Ye, F, Huang, Y, Zhou, Z, Xiao, X, Tan, X, Ma, J, Xie, J, Li, Y, Gong, G, Cai, C, Wang, W, Huang, B, Tan, W, Peng, F, Zhou, Y, Tang, W, Zhou, Z, Jiang, Y, Zhou, N	Int J Infect Dis	2020
32661006	Efficacy and safety of interferon β-1a in treatment of severe COVID-19: A randomized clinical trial Kazemzadeh, H, Hajiabdolbaghi, M, Abbasian, L, Khalili, H, Yekaninejad, MS, Salehi, M, Rahmani, H, Davoudi-Monfared, E	Antimicrob. Agents Chemother.	2020
18035202	Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis Schwid, SR, Panitch, HS	Clin Ther	2007
32862111	Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial Fazeli, MR, Khalili, H, Yekaninejad, MS, Rahmani, H, Hajizadeh, N, Ghazaeian, M, Jalalabadi, NZ, Nourian, A, Davoudi-Monfared, E	Int Immunopharmacol	2020
33189161	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 Djukanovic, R, Mankowski, M, Wilkinson, TMA, Gabbay, FJ, Brookes, J, Monk, PD, Davies, DE, Holgate, ST, Tear, VJ, Ho, LP, Batten, TN, Clark, T, Marsden, RJ	Lancet Respir Med	2021
25371710	Evidence for the efficacy of interferon beta-1b in delaying the onset of clinically definite multiple sclerosis in individuals with clinically isolated syndrome Freedman, MS	Ther Adv Neurol Disord	2014
32574262	Interferon-α2b Treatment for COVID-19 Wei, XS, Shannon, CP, Kollmann, TR, Xiang, X, Zhou, Q, Tebbutt, SJ, Wang, X, Wang, ZH, Chen, V, Fish, EN	Front Immunol	2020
33117408	The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19 Schreiber, G	Front Immunol	2020