Abstract
Introduction. Immunomodulatory complexes based on yeast RNA and ascorbic acid are regarded as a natural multitarget platform capable of affecting innate immune receptors, interferon signaling and cellular redox balance. However, variability of the interferon response to such compositions and the reasons for differences between experimental models, batches and potential patient groups remain insufficiently understood.
Objective. To systematize current concepts of the interferon signature as a tool for assessing and stratifying response to yeast RNA and ascorbic acid complexes, to identify key molecular markers of efficacy and to propose a conceptual framework for their application.
Material and methods. An analytical review of Russian and international publications devoted to innate immunity, receptors recognizing exogenous RNA, interferon response, interferon-stimulated genes, redox regulation, immunomodulatory effects of ascorbic acid and critical quality attributes of RNA-containing compositions was performed.
Basic provisions. The interferon signature may be considered an integrated molecular profile reflecting interactions between the characteristics of the complex, the baseline state of target cells and parameters of innate immune response. The most promising components of this signature include TLR3, TLR7, TLR8, DDX58, IFIH1, MAVS, IRF3, IRF7, IFN-α/β, ISG15, MX1, OAS1, IFIT1 and CXCL10. Cellular redox status represents an important modifying contour.
Conclusion. The interferon signature is the most promising tool for the molecular stratification of the effectiveness of immunomodulatory complexes of yeast RNA and ascorbic acid. Its use makes it possible to move from a general description of immunotropic activity to a predictive assessment of response and to the development of personalized application schemes. The most promising area of further research is the integration of quality control of RNA compositions with a panel of laboratory markers that characterize the readiness of cells for an interferon response and its early implementation
Keywords
Authors and affiliations
https://elibrary.ru/sqwqws T.V. Potupchik(1), V.V. Ermolaev(2), S.V. Generalov(3), Yu.S. Alikin(4), L.S. Evert(5), T.S. Fedotova(6), K.N. Grishina(6), D.S. Vladimirova(7)
1Federal State Budgetary Educational Institution of Higher Education “Krasnoyarsk State Medical University named after Professor
V.F. Voyno-Yasenetsky” of the Ministry of Health of the Russian Federation, Partizana Zheleznyaka St., 1, Krasnoyarsk, 660022,
Russian Federation; 2State Research Center of Virology and Biotechnology “Vector” of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, Koltsovo, Novosibirsk Region, 630559, Russian Federation; 3Federal State Scientific Institution “Russian Anti-Plague Research Institute “Microbe” of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, Universitetskaya St., 46, Saratov, 410005, Russian Federation; 4LLC “NPO Evolution of Nature”, Voskhod St., 20/1 premises 1.2, Novosibirsk, 630102, Russian Federation; 5Federal State Budgetary Educational Institution of Higher Education “Khakass State University
named after N.F. Katanov” of the Ministry of Science and Higher Education, 20/1 premises 1.2, Abakan, 20/1 premises 1.2, 655017,
Russian Federation; 6The Russian National Research Medical University named after N.I. Pirogov, Ostrovityanova St., 1, Moscow, 117513, Russian Federation; 7Saint-Petersburg State Pediatric Medical University, Litovskaya St., 2, Saint-Petersburg, 194100, Russia
References
Потупчик Т.В., Аликин Ю.С., Генералов С.В., Ермолаев В.В., Плужникова А.В., Ферзилаева Н.Р., Козаренко М.А. Молекулярные паттерны РНК-патогенов и иммунный ответ на экзогенные РНК: механизмы распознавания и терапевтический потенциал. Молекулярная медицина. 2026; 24 (1): 31–8. DOI: 10.29296/24999490-2026-01-04. [Potupchik T.V., Alikin Yu.S., Generalov S.V., Ermolaev V.V., Pluzhnikova A.V., Ferzilaeva N.R., Kozarenko M.A. Molecular patterns of RNA pathogens and immune response to exogenous RNA: recognition mechanisms and therapeutic potential. Molekulyarnaya meditsina. 2026; 24 (1): 31–8. DOI: 10.29296/24999490-2026-01-04 (in Russian)].
2. Потупчик Т.В., Аликин Ю.С., Генералов С.В., Эверт Л.С., Тымчук В.И., Халакоева Д.А., Абдуллаева С.Р. и др. Синергизм аскорбиновой кислоты и РНК-индукторов интерферона в активации противовирусного иммунитета: молекулярные механизмы и терапевтические перспективы. Молекулярная медицина. 2025; 23 (6): 76–83. DOI: 10.29296/24999490-2025-06-10. [Potupchik T.V., Alikin Yu.S., Generalov S.V., Evert L.S., Tymchuk V.I., Khalakoeva D.A., Abdullaeva S.R. et al. Synergism of ascorbic acid and RNA interferon inducers in activation of antiviral immunity: molecular mechanisms and therapeutic prospects. Molekulyarnaya meditsina. 2025; 23 (6): 76–83. DOI: 10.29296/24999490-2025-06-10 (in Russian)].
3. Потупчик Т.В., Кучеренко А.М., Генералов С.В., Аликин Ю.С., Спицын А.А., Ермолаев В.В., Эверт Л.С. и др. Фармацевтические аспекты разработки комплексов одноцепочечной дрожжевой РНК с аскорбиновой кислотой. Часть 1. Физико-химические характеристики и критические атрибуты качества. Вопросы биологической, медицинской и фармацевтической химии. 2026; 29 (4): 3–13. DOI: 10.29296/25877313-2026-04-01. [Potupchik T.V., Kucherenko A.M., Generalov S.V., Alikin Yu.S., Spitsyn A.A., Ermolaev V.V., Evert L.S. et al. Pharmaceutical aspects of development of complexes of single-stranded yeast RNA with ascorbic acid. Part 1. Physicochemical characteristics and critical quality attributes. Problems of biological, medical and pharmaceutical chemistry. 2026; 29 (4): 3–13. DOI: 10.29296/25877313-2026-04-01 (in Russian)].
4. Потупчик Т.В., Аликин Ю.С., Генералов С.В., Ермолаев В.В., Кудлай Д.А., Ксанаева Д.А., Банарь Л.С. и др. Дрожжевые РНК как источник иммуномодулирующих нуклеотидов: от биохимии до клинического применения. Молекулярная медицина. 2026; 24 (2): 65–74. DOI: 10.29296/24999490-2026-02-09. [Potupchik T.V., Alikin Yu.S., Generalov S.V., Ermolaev V.V., Kudlay D.A., Ksanaeva D.A., Banar L.S. et al. Yeast RNAs as a source of immunomodulatory nucleotides: from biochemistry to clinical application. Molekulyarnaya meditsina. 2026; 24 (2): 65–74. DOI: 10.29296/24999490-2026-02-09 (in Russian)].
5. Потупчик Т.В., Эверт Л.С., Аликин Ю.С., Генералов С.В., Уварова Д.Д., Белоусова Е.Д., Шавалова Д.С. и др. РНК-терапия в России: от советских разработок до современных препаратов. Вопросы биологической, медицинской и фармацевтической химии. 2025; 28 (11): 30–41. DOI: 10.29296/25877313-2025-11-00. [Potupchik T.V., Evert L.S., Alikin Yu.S., Generalov S.V., Uvarova D.D., Belousova E.D., Shavalova D.S. et al. RNA therapy in Russia: from Soviet developments to modern drugs. Problems of biological, medical and pharmaceutical chemistry. 2025; 28 (11): 30–41. DOI: 10.29296/25877313-2025-11-00 (in Russian)].
6. Schlee M., Hartmann G. Discriminating self from non-self in nucleic acid sensing. Nat Rev Immunol. 2016; 16 (9): 566–80. DOI: 10.1038/nri.2016.78.
7. Rehwinkel J., Gack M.U. RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol. 2020; 20 (9): 537–51. DOI: 10.1038/s41577-020-0288-3.
8. Heil F., Hemmi H., Hochrein H., Ampenberger F., Kirschning C., Akira S. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004; 303 (5663): 1526–9. DOI: 10.1126/science.1093620.
9. Kato H., Takeuchi O., Sato S., Yoneyama M., Yamamoto M., Matsui K., Uematsu S. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006; 441 (7089): 101–5. DOI: 10.1038/nature04734.
10. Carr A.C., Maggini S. Vitamin C and immune function. Nutrients. 2017; 9 (11): 1211. DOI: 10.3390/nu9111211.
11. Ang A., Pullar J.M., Currie M.J., Vissers M.C.M. Vitamin C and immune cell function in inflammation and cancer. Biochem Soc Trans. 2018; 46 (5): 1147–59. DOI: 10.1042/BST20180169.
12. Manning J., Mitchell B., Appadurai D.A., Shakya A., Pierce L.J., Wang H., Nganga V. et al. Vitamin C promotes maturation of T-cells. Antioxid Redox Signal. 2013; 19 (17): 2054–67. DOI: 10.1089/ars.2012.4988.
13. Blaschke K., Ebata K.T., Karimi M.M., Zepeda-Martinez J.A., Goyal P., Mahapatra S., Tam A. et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature. 2013; 500 (7461): 222–6. DOI: 10.1038/nature12362.
14. Schneider W.M., Chevillotte M.D., Rice C.M. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol. 2014; 32: 513–45. DOI: 10.1146/annurev-immunol-032713-120231.
15. Ivashkiv L.B., Donlin L.T. Regulation of type I interferon responses. Nat Rev Immunol. 2014; 14 (1): 36–49. DOI: 10.1038/nri3581.
16. Sampson D.L., Fox B.A., Yager T.D., Bhide S., Cermelli S., McHugh L.C. et al. A four-gene pan-African blood signature predicts progression to tuberculosis. Am. J. Respir Crit Care Med. 2021; 203 (8): 1044–56. DOI: 10.1164/rccm.202007-2913OC.
17. Генералов С.В., Перевозников Д.А., Абрамова Е.Г., Никифоров А.К., Спицын А.А., Потупчик Т.В., Шендерович Е.М. Противовирусная активность препарата на основе комплекса одноцепочечной высокополимерной РНК в отношении вируса бешенства in vitro. Вопросы биологической, медицинской и фармацевтической химии. 2025; 28 (8): 38–44. DOI: 10.29296/25877313-2025-08-05. [Generalov S.V., Perevoznikov D.A., Abramova E.G., Nikiforov A.K., Spitsyn A.A., Potupchik T.V., Shenderovich E.M. Antiviral activity of a drug based on a complex of single-stranded high-polymer RNA against rabies virus in vitro. Problems of biological, medical and pharmaceutical chemistry. 2025; 28 (8): 38–44. DOI: 10.29296/25877313-2025-08-05 (in Russian)].
18. Потупчик Т.В., Генералов С.В., Акаева А.В., Шаблинская К.С. Новые стратегии постэкспозиционной профилактики бешенства: роль иммуномодулирующих и таргетных молекулярных технологий в персонализированной медицине. Молекулярная медицина. 2025; 23 (5): 49–57. DOI: 10.29296/24999490-2025-05-06. [Potupchik T.V., Generalov S.V., Akaeva A.V., Shablinskaya K.S. Novel strategies for post-exposure prophylaxis of rabies: the role of immunomodulatory and targeted molecular technologies in personalized medicine. Molekulyarnaya meditsina. 2025; 23 (5): 49–57. DOI: 10.29296/24999490-2025-05-06 (in Russian)].
19. Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity. Nat Immunol. 2010; 11 (5): 373–84. DOI: 10.1038/ni.1863.
20. Alexopoulou L., Holt A.C., Medzhitov R., Flavell R.A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001; 413 (6857): 732–8. DOI: 10.1038/35099560.
21. Ren Z., Ding T., Zuo Z., Xu Z., Deng J., Wei Z. Regulation of MAVS expression and signaling function in the antiviral innate immune response. Front Immunol. 2020; 11: 1030. DOI: 10.3389/fimmu.2020.01030.
22. Шрайнер Е.В., Быстрова В.И., Покушалов Е.А., Романова А.Д., Маркин Д.С., Кудлай Д.А. Глутатион: ключевая молекула редокс-гомеостаза и возможности ее нутриентной и метаболической регуляции (обзор литературы). Молекулярная медицина. 2025; 23 (5): 79–88. DOI: 10.29296/24999490-2025-05-09. [Shrayner E.V., Bystrova V.I., Pokushalov E.A., Romanova A.D., Markin D.S., Kudlay D.A. Glutathione: a key molecule of redox homeostasis and its potential for nutritional and metabolic regulation (review of the literature). Molekulyarnaya meditsina. 2025; 23 (5): 79–88. DOI: 10.29296/24999490-2025-05-09 (in Russian)].
23. West A.P., Shadel G.S., Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol. 2011; 11 (6): 389–402. DOI: 10.1038/nri2975.
24. Mills E.L., Kelly B., O’Neill L.A.J. Mitochondria are the powerhouses of immunity. Nat Immunol. 2017; 18 (5): 488–98. DOI: 10.1038/ni.3704.
25. Minich D.M., Brown B.I. A review of dietary phytonutrients for glutathione support. Nutrients. 2019; 11 (9): 2073. DOI: 10.3390/nu11092073.
26. Баратова И.В., Бодунова Н.А., Деева Т.А., Бордин Д.С., Чеботарева М.В., Цапкова Л.А. Влияние генетических полиморфизмов генов Toll-подобных рецепторов на взаимодействие с Helicobacter pylori. Молекулярная медицина. 2025; 23 (5): 89–96. DOI: 10.29296/24999490-2025-05-10. [Baratova I.V., Bodunova N.A., Deeva T.A., Bordin D.S., Chebotareva M.V., Tsapkova L.A. Influence of genetic polymorphisms of Toll-like receptor genes on interaction with Helicobacter pylori. Molekulyarnaya meditsina. 2025; 23 (5): 89–96. DOI: 10.29296/24999490-2025-05-10 (in Russian)].
27. Kayesh M.E.H., Kohara M., Tsukiyama-Kohara K. TLR agonists as vaccine adjuvants in the prevention of viral infections: an overview. Front Microbiol. 2023; 14: 1249718. DOI: 10.3389/fmicb.2023.1249718.
28. Pardi N., Hogan M.J., Porter F.W., Weissman D. mRNA vaccines – a new era in vaccinology. Nat Rev Drug Discov. 2018; 17 (4): 261–79. DOI: 10.1038/nrd.2017.243.
29. Bateneva N.A., Gamaley S.G., Danilenko E.D., Lebedev R.L. Stimulating effect of double-stranded yeast RNA on the activity of interferon system genes. Medical Immunology (Russia). 2021; 22 (6): 1155–62. DOI: 10.15789/1563-0625-SEO-2082.
30. Luan X., Wang Y., Yue R., Zhou W. Innate immune responses to RNA: sensing and signaling. Front Immunol. 2024; 15: 1287940. DOI: 10.3389/fimmu.2024.1287940.