The interferon system: Modern view on structural and functional organization and clinical application

Currently, the high incidence of respiratory tract infections (influenza A, B, other acute respiratory viral infections, COVID-19) contributes to the optimization of therapeutic protocols and deepening knowledge about the pathogenetic significance of interferons (IFN) in various nosologies. This article presents a literature review. A search for publications was conducted using information resources and databases of Russian and international electronic libraries covering the past 40 years. After eliminating duplicates, 39 articles were selected, including current research on the IFN system as a key component of innate and adaptive immunity. A detailed classification (types I, II, and III) is given, as well as a description of their genetic organization, receptor specificity, and molecular mechanisms of induction through pattern-recognizing receptors. The ways of signal transduction and the mechanisms of formation of the antiviral status of the cell are considered in detail. Special attention is paid to the immunomodulatory function of interferons in viral infections of the respiratory tract, as well as strategies for viral evasion. Based on the analysis of clinical data, the effectiveness of the use of intranasal forms of recombinant IFN-α2b, in particular, the drug (nasal spray), for the prevention and treatment of influenza and acute respiratory viral infections, has been substantiated. The interferon system is a key component of innate and adaptive immunity, providing the body’s universal first line of defense against viral invasions. A thorough understanding of the molecular mechanisms of action of these cytokines has allowed us to substantiate the high efficacy of topical forms of recombinant IFN-α2b in clinical practice.

1. Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci. 1957;147(927):258–267. https://doi.org/10.1098/rspb.1957.0048.

2. Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM, Foster GR, Stark GR. Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov. 2007;6(12):975–990. https://doi.org/10.1038/nrd2422.

3. Sadler AJ, Williams BR. Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008;8(7):559–568. https://doi.org/10.1038/nri2314.

4. Billiau A, Matthys P. Interferon-γ: a historical perspective. Cytokine Growth Factor Rev. 2009;20(2):97–113. https://doi.org/10.1016/j.cytogfr.2009.02.004.

5. Feng E, Balint E, Poznanski SM, Ashkar AA, Loeb M. Aging and Interferons: Impacts on Inflammation and Viral Disease Outcomes. Cells. 2021;10(3):708. https://doi.org/10.3390/cells10030708.

6. Osidak LA, Obraztsova EV, Golovacheva EG, Afanasyeva OI, Sukhovetskaya VF, Drinevsky VP et al. Viferon in treatment of influenza and other ari of viral and viral-bаcterial еtiology in children. Children Infections. 2012;11(1):44–50. (In Russ.) Available at: https://elibrary.ru/oxnfzj.

7. Lokshina EE, Zaitseva OV, Mazankova LN, Chebotareva TA, Korovina NA, Kurbanova HI et al. Modern possibilities of using interferons in the complex therapy of acute respiratory infections in children. Lechaschi Vrach. 2011;(8):116–119. (In Russ.) Available at: https://www.lvrach.ru/2011/08/4525722.

8. Shcheplyagina LA, Kruglova IV. Age-related features of immunity in children. RMJ. 2009;(23):1564. (In Russ.) Available at: https://www.rmj.ru/articles/pediatriya/Vozrastnye_osobennosti_immuniteta_u_detey.

9. Karaulov АV, Rubalskly ЕО, Afanas’ev SS, Alieshkin VA, Chichkova MA, Afanas’ev MS. The soluble isoforms of IFN-I receptor and anti-interferon antibodies as effect regulators of exogenous and endogenous interferon. Immunologiya. 2007;28(4):240–243. (In Russ.) Available at: https://elibrary.ru/iatzdt.

10. Chuntharapai A, Gibbs V, Lu J, Ow A, Marsters S, Ashkenazi A et al. Determination of residues involved in ligand binding and signal transmission in the human IFN-alpha receptor 2. J Immunol. 1999;163(2):766–773. Available at: https://pubmed.ncbi.nlm.nih.gov/10395669/.

11. Ершов ФИ, Киселев ОИ. Интерфероны и их индукторы. М.: ГЭОТАР-Медиа; 2005. 368 с.

12. Cao L, Zhang L, Zhang X, Liu J, Jia MA, Zhang J et al. Types of Interferons and Their Expression in Plant Systems. J Interferon Cytokine Res. 2022;42(2):62–71. https://doi.org/10.1089/jir.2021.0148.

13. de Jong TD, Vosslamber S, Mantel E, de Ridder S, Wesseling JG, van der Pouw Kraan TC et al. Physiological evidence for diversification of IFNα- and IFNβ-mediated response programs in different autoimmune diseases. Arthritis Res Ther. 2016;18:49. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC4756531/.

14. Decker T, Müller M, Stockinger S. The yin and yang of type I interferon activity in bacterial infection. Nat Rev Immunol. 2005;5(9):675–687. https://doi.org/10.1038/nri1684.

15. Negishi H, Taniguchi T, Yanai H. The Interferon (IFN) Class of Cytokines and the IFN Regulatory Factor (IRF) Transcription Factor Family. Cold Spring Harb Perspect Biol. 2018;10(11):a028423. https://doi.org/10.1101/cshperspect.a028423.

16. Walter MR. The Role of Structure in the Biology of Interferon Signaling. Front Immunol. 2020;11:606489. https://doi.org/10.3389/fimmu.2020.606489.

17. Alspach E, Lussier DM, Schreiber RD. Interferon γ and Its Important Roles in Promoting and Inhibiting Spontaneous and Therapeutic Cancer Immunity. Cold Spring Harb Perspect Biol. 2019;11(3):a028480. https://doi.org/10.1101/cshperspect.a028480.

18. Lazear HM, Schoggins JW, Diamond MS. Shared and Distinct Functions of Type I and Type III Interferons. Immunity. 2019;50(4):907–923. https://doi.org/10.1016/j.immuni.2019.03.025.

19. Stanifer ML, Pervolaraki K, Boulant S. Differential Regulation of Type I and Type III Interferon Signaling. Int J Mol Sci. 2019;20(6):1445. https://doi.org/10.3390/ijms20061445.

20. Gad HH, Dellgren C, Hamming OJ, Vends S, Paludan SR, Hartmann R. Interferon-λ is functionally an interferon but structurally related to the interleukin-10 family. J Biol Chem. 2009;284(31):20869–20875. https://doi.org/10.1074/jbc.M109.002923.

21. Kotenko SV, Rivera A, Parker D, Durbin JE. Type III IFNs: Beyond antiviral protection. Semin Immunol. 2019;43:101303. https://doi.org/10.1016/j.smim.2019.101303.

22. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45(2):164–171. https://doi.org/10.1038/ng.2521.

23. Wang H, Hu H, Zhang K. Overview of interferon: characteris tics, signaling and anti-cancer effect. Arch Biotechnol Biomed. 2017;1(1):001–016. https://doi.org/10.29328/journal.hjb.1001001.

24. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14(1):36–49. https://doi.org/10.1038/nri3581.

25. Kienes I, Weidl T, Mirza N, Chamaillard M, Kufer TA. Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation. Int J Mol Sci. 2021;22(3):1301. https://doi.org/10.3390/ijms22031301.

26. Zhao J, Qin C, Liu Y, Rao Y, Feng P. Herpes Simplex Virus and Pattern Recognition Receptors: An Arms Race. Front Immunol. 2021;11:613799. https://doi.org/10.3389/fimmu.2020.613799.

27. Danastas K, Miranda-Saksena M, Cunningham AL. Herpes Simplex Virus Type 1 Interactions with the Interferon System. Int J Mol Sci. 2020;21(14):5150. https://doi.org/10.3390/ijms21145150.

28. Schenten D, Medzhitov R. The control of adaptive immune responses by the innate immune system. Adv Immunol. 2011;109:87–124. https://doi.org/10.1016/B978-0-12-387664-5.00003-0.

29. Abe T, Barber GN. Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-κB activation through TBK1. J Virol. 2014;88(10):5328–5341. https://doi.org/10.1128/JVI.00037-14.

30. Boxx GM, Cheng G. The Roles of Type I Interferon in Bacterial Infection. Cell Host Microbe. 2016;19(6):760–769. https://doi.org/10.1016/j.chom.2016.05.016.

31. Mesev EV, LeDesma RA, Ploss A. Decoding type I and III interferon signalling during viral infection. Nat Microbiol. 2019;4(6):914–924. https://doi.org/10.1038/s41564-019-0421-x.

32. Yin Y, Favoreel HW. Herpesviruses and the Type III Interferon System. Virol Sin. 2021;36(4):577–587. https://doi.org/10.1007/s12250-020-00330-2.

33. Tsarev SV, Khaitov MR. The role of respiratory viruses in bronchial asthma. RMJ. 2009;(2):136–139. (In Russ.) Available at: https://www.rmj.ru/articles/bolezni_dykhatelnykh_putey/Roly_respiratornyh_virusov_pri_bronhialynoy_astme.

34. Zakharova IN, Cheburkin AV, Malinovskaya VV, Torshkhoeva LB, Kurbanova KhI, Parshina OV, Guseva TS. The significance of the interferon system for formation of the immune response in children with acute respiratory viral infections. Clinical Practice in Pediatrics. 2009;4(5):38–45. (In Russ.) Available at: https://www.phdynasty.ru/katalog/zhurnaly/voprosy-prakticheskoy-pediatrii/2009/tom-4-nomer-5/10403.

35. Fritsch SD, Weichhart T. Effects of Interferons and Viruses on Metabolism. Front Immunol. 2016;7:630. https://doi.org/10.3389/fimmu.2016.00630.

36. Fensterl V, Sen GC. Interferons and viral infections. Biofactors. 2009;35(1):14–20. https://doi.org/10.1002/biof.6.

37. Hayden FG, Albrecht JK, Kaiser DL, Gwaltney JM Jr. Prevention of natural colds by contact prophylaxis with intranasal alpha 2-interferon. N Engl J Med. 1986;314(2):71–75. https://doi.org/10.1056/NEJM198601093140202.

38. Gao L, Yu S, Chen Q, Duan Z, Zhou J, Mao C et al. A randomized controlled trial of low-dose recombinant human interferons alpha-2b nasal spray to prevent acute viral respiratory infections in military recruits. Vaccine. 2010;28(28):4445–4451. https://doi.org/10.1016/j.vaccine.2010.03.062.

39. Yu DX, Chen Q, Zhang LL, Liu Y, Yu ZA, Li ZF et al. A field trial of recombinant human interferon alpha-2b for nasal spray to prevent SARS and other respiratory viral infections. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2005;19(3):216–219. (In Chinese) Available at: https://pubmed.ncbi. nlm.nih.gov/16261200/.

40. Chebotareva TA, Mazankova LN, Ulyanova II, Meshkova EN, Koltsov VD. Rational therapeutic tactics for ARVIs and influenza in children. Clinical Practice in Pediatrics. 2008;3(1):56–59. (In Russ.) Available at: https://elibrary.ru/ijuoun.