БЦЖ, мурамилпептиды, тренированный иммунитет (часть II): низкомолекулярная альтернатива многокомпонентным бактериальным иммуностимуляторам для профилактики респираторных инфекций в условиях пандемии COVID-19
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Kalyuzhin O.V., Andronova T.M., Karaulov A.V. BCG, muramylpeptides, trained immunity (part II): a low molecular weight alternative to multicomponent bacterial immunostimulants for prevention of respiratory infections during a pandemic. Terapevticheskii Arkhiv (Ter. Arkh.). 2021; 93 (1): 108–113. DOI: 10.26442/00403660.2021.01.200554
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Ключевые слова: БЦЖ, мурамилпептиды, глюкозаминилмурамилдипептид, NOD2, тренированный иммунитет, адъювант Фрейнда, бактериальные лизаты, COVID-19, SARS-CoV-2, респираторные инфекции
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During a pandemic, nonspecific immunoprophylaxis of SARS-CoV-2 infection and other acute respiratory infections (ARI), which can worsen the course of COVID-19, is increasingly in demand in addition to specific immunization. BCG vaccine appears to be one of the candidate immunostimulants in this regard. At the same time, other microbe-derived preparations capable of inducing a state of trained immunity deserve attention. BCG and other bacterial immunostimulatory agents containing a large number of biologically active subunits have long been considered as objects of search for promising pharmacological substances. The review analyzes the linkages between BCG, mycobacterial adjuvants, bacterial lysates, trained immunity, muramylpeptides (MPs) and NOD2 receptors in light of the choice of a low molecular weight alternative to multicomponent bacterial immunostimulants for ARI prevention during the COVID-19 pandemic. The search for key molecules by which bacteria stimulate innate and adaptive immune responses proceeds in a spiral. On different loops of this spiral, MPs have repeatedly reproduced the nonspecific effects of multicomponent bacterial adjuvants, vaccines and immunostimulants. MPs and peptidoglycans containing MPs determine the adjuvant properties of the cell walls of mycobacteria and their peptide-glycolipid fraction (wax D). MPs were able to replace Mycobacterium tuberculosis in complete Freund's adjuvant. MPs determine the NOD2-dependent ability of BCG to induce trained immunity. Probably, MPs provide NOD2-mediated long-term prophylactic action of bacterial lysates. All of the above has prompted revisiting the previously obtained evidence of the efficacy of glucosaminylmuramyl dipeptide (GMDP) as a NOD2 agonist in treatment/prevention of respiratory infections. We speculate here that MPs, in particular GMDP, at rational dosing regimens will be able to reproduce many aspects of the nonspecific effects of BCG and multicomponent bacterial immunostimulants in preventing ARI during the COVID-19 pandemic and in the post-pandemic period.
Keywords: BCG, muramyl peptides, glucosaminylmuramyl dipeptide, NOD2, trained immunity, Freund's adjuvant, bacterial lysates, COVID-19, SARS-CoV-2, respiratory infections
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Available at: http://isir.ru/files/uploaded/AI_2016_N3_161-22023022017.pdf
5. Kalyuzhin O. The mechanisms of action of non-specific immunostimulants through the prism of the "trained immunity" concept. In: Sepiashvili R, eds. Allergy, Asthma & Immunophysiology: Innovative Technologies. Bologna: Filodiritto Proceedings, 2016; p. 373-8.
6. Kalyuzhin OV, Andronova TM, Karaulov AV. BCG, muramylpeptides, trained immunity (part I): linkages in the light of the COVID-19 pandemic. Terapevticheskii Arkhiv (Ter. Arkh.). 2020;92(12):100-5 (In Russ.) doi: 10.26442/00403660.2020.12.200464
7. WHO. DRAFT landscape of COVID-19 candidate vaccines – 3 November 2020. Accessed November 6, 2020. Available at: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
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9. Singh PK, Kulsum U, Rufai SB, et al. Mutations in SARS-CoV-2 Leading to Antigenic Variations in Spike Protein: A Challenge in Vaccine Development. J Lab Physicians. 2020;12(2):154-60. doi: 10.1055/s-0040-1715790
10. Selkova EP, Kalyuzhin OV. Acute respiratory viral infections and influenza. Helping the practicing doctor. Moscow: Medical News Agency, 2015 (In Russ.)
11. Chen X, Liao B, Cheng L, et al. The microbial coinfection in COVID-19. Appl Microbiol Biotechnol. 2020;104(18):7777-85. doi: 10.1007/s00253-020-10814-6
12. Ma L, Wang W, Le Grange JM, et al. Coinfection of SARS-CoV-2 and Other Respiratory Pathogens. Infect Drug Resist. 2020;13:3045-53. doi: 10.2147/IDR.S267238
13. Freund J. The mode of action of immunologic adjuvants. Bibl Tuberc. 1956;10:130-48.
14. Sabin FR, Smithburn KC, Thomas RM. Cellular reactions to wax-like materials from acid-fast bacteria: the unsaponifiable fraction from the tubercle bacillus, strain H-37. J Exp Med. 1935;62(6):751-69. doi: 10.1084/jem.62.6.751
15. Raffel S, Forney JE. The role of the wax of the tubercle bacillus in establishing delayed hypersensitivity; hypersensitivity to a simple chemical substance, picryl chloride. J Exp Med. 1948;88(4):485-502. doi: 10.1084/jem.88.4.485
16. Azuma I, Kimura H, Yamamura Y. Isolation of arabinose mycolate from Wax D fraction of human type tubercle bacillus Aoyama B strain. J Biochem. 1965;57:571-2. doi: 10.1093/oxfordjournals.jbchem.a128116
17. Kanetsuna F. Chemical analysis of mycobacterial cell walls. Biochim Biophys. Acta 1968;158:130-43.
18. White RG, Jolles P, Samour D, Lederer E. Correlation of adjuvant activity and chemical structure of Wax D fractions of mycobacteria. Immunology. 1964;7(2):158-71.
19. Azuma I, Kishimoto S, Yamamura Y, Petit JF. Adjuvanticity of mycobacterial cell walls. Jpn J Microbiol. 1971;15(2):193-97. doi: 10.1111/j.1348-0421.1971.tb00569.x
20. Lederer E. The mycobacterial cell wall. Pure Appl Chem. 1971;25(1):135-65. doi: 10.1351/pac197125010135
21. Adam A, Ciorbaru R, Petit JF, Lederer E. Isolation and properties of a macromolecular, water-soluble, immuno-adjuvant fraction from the cell wall of Mycobacterium smegmatis. Proc Natl Acad Sci USA. 1972;69(4):851-4. doi: 10.1073/pnas.69.4.851
22. Chedid L, Parant M, Parant F, et al. Biological study of a nontoxic, water-soluble immunoadjuvant from mycobacterial cell walls. Proc Natl Acad Sci USA. 1972;69(4):855-8. doi: 10.1073/pnas.69.4.855
23. Adam A, Ciorbaru R, Ellouz F, et al. Adjuvant activity of monomeric bacterial cell wall peptidoglycans. Biochem Biophys Res Commun. 1974;56(3):561-67. doi: 10.1016/0006-291x(74)90640-8. PMID: 4597063
24. Adam A, Ellouz F, Ciorbaru R, et al. Peptidoglycan adjuvants: minimal structure required for activity. Z. Immunitatsforsch. Exp Klin Immunol. 1975;149:341-48.
25. Windheim M, Lang C, Peggie M, et al. Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide. Biochem J. 2007;404(Pt. 2):179-90. doi: 10.1042/BJ20061704
26. Meshcheryakova E, Makarov E, Philpott D, et al. Evidence for correlation between the intensities of adjuvant effects and NOD2 activation by monomeric, dimeric and lipophylic derivatives of N-acetylglucosaminyl-N-acetylmuramyl peptides. Vaccine. 2007;25(23):4515-20. doi: 10.1016/j.vaccine.2007.04.006
27. Karaulov AV, Kalyuzhin OV. Sphere of muramyl dipeptide application within the major approaches to immunotherapy/prophylaxis of infectious diseases. Fiziologiya i patologiya immunnoj sistemy. Immunofarmakogenomika. 2013;17(5):3-15 (In Russ.)
28. Karaulov AV, Kalyuzhin OV. Immunotherapy for infectious diseases: challenges and prospects. Terapevticheskii Arkhiv (Ter. Arkh.). 2013;85(11):100-8 (In Russ.) Available at: https://ter-arkhiv.ru/0040-3660/article/view/31403
29. Watanabe T, Asano N, Meng G, et al. NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6. Mucosal Immunol. 2014;7(6):1312-25. doi: 10.1038/mi.2014.19
30. Cazzola M, Anapurapu S, Page CP. Polyvalent mechanical bacterial lysate for the prevention of recurrent respiratory infections: a meta-analysis. Pulm Pharmacol Ther. 2012;25(1):62-8. doi: 10.1016/j.pupt.2011.11.002
31. Del-Rio-Navarro BE, Espinosa Rosales F, Flenady V, Sienra-Monge JJL. Immunostimulants for preventing respiratory tract infection in children. Cochrane Database System Rev. 2006;2:CD004974. doi: 10.1002/14651858.CD004974.pub2
32. Yin J, Xu B, Zeng X, et al. Broncho-Vaxom in pediatric recurrent respiratory-tract infections: A systematic review and meta-analysis. Int Immunopharmacol. 2018;54:198-209. doi: 10.1016/j.intimp.2017.10.032
33. Kalyuzhin OV. OM-85 in the prevention/treatment of respiratory infections and exacerbations of chronic lung diseases: selection criteria, mechanisms and evidence. Lechaschi Vrach. 2018;3:77-82 (In Russ.) Available at:
https://www.lvrach.ru/2018/03/15436933
34. Bosisio D, Salogni L, Nowak N, et al. OM-85 shapes dendritic cell activation into a “pre-alert” phenotype. Eur Respir J. 2011;38(Suppl. 55):3872.
35. Parola C, Salogni L, Vaira X, et al. Selective activation of human dendritic cells by OM-85 through a NF-kB and MAPK dependent pathway. PLoS One. 2013;8(12):e82867. doi: 10.1371/journal.pone.0082867
36. Pinegin BV, Pashchenkov MV. Immunostimulators of muramylpeptide nature in the treatment and prevention of infectious-inflammatory processes. Immunologiya. 2019;40(3):65-71 (In Russ.) doi: 10.24411/02064952-2019-13007
37. Burkin AV, Svistushkin VM, Nikiforova GN, Dukhanin AS. Glucosaminylmuramyl dipeptide in treatment of respiratory tract diseases. Vestnik Otorinolaringolii. 2019;84(6):118-31 (In Russ.) doi: 10.17116/otorino201984061118
38. Voronina EV. GMDP (Lycopid) in reducing seasonal incidence in adults (data from a blind placebo-controlled study). Practical Medicine. 2011;3(51):2-4 (In Russ.) Available at: http://pmarchive.ru/gmdp-likopid-v-snizhenii-sezonnoj-zabolevaemosti-u-vzroslyx-dannye-slepogo-place...
39. Kiriukhin AV, Parfenova NA, Maximova TA, et al. Optimization of treatment of frequently and for a long period of time ill children: immunocorrection with likopid. Rossijskij pediatricheskij zhurnal. 2001;5:27-29 (In Russ.)
40. Maiorov RV, Chereshneva MV, Verzilin SD, Chereshnev VA. Efficiency of some immunomodulatory drugs for prevention of respiratory infections and their complications in young schoolchildren with recurrent respiratory infections. Medical Immunology (Russia). 2013;15(3):255-62 (In Russ.) doi: 10.15789/1563-0625-2013-3-255-262
41. Nesterova IV, Kovaleva SV, Kleshchenko EI, et al. Modified program of combined interferon-and immunotherapy in associated respiratory and herpetic viral infections in immunocompromised children. Effektivnaya Farmakoterapiya. 2013;27:26-32 (In Russ.)
42. Soleimanian S, Yaghobi R. Harnessing Memory NK Cell to Protect Against COVID-19. Front Pharmacol. 2020;11:1309. doi: 10.3389/fphar.2020.01309
1 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
2 АО «Пептек», Москва, Россия
________________________________________________
O.V. Kalyuzhin1, T.M. Andronova2, A.V. Karaulov1
1 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;
2 Peptek, Moscow, Russia