Роль Толл-подобных рецепторов и их мутаций в патогенезе цитомегаловирусной инфекции

Толл-подобные рецепторы (TLR) представляют собой образ-распознающие рецепторы, которые экспрессируются во многих иммунных и неимунных клетках, и выполняют решающую роль в развитии воспаления и связанных с ним инфекционных заболеваний.

Цель. Обобщить знания о роли TLR и их генетических изменений в развитии цитомегаловирусной (ЦМВ) инфекции во время беременности и врожденной инфекции у новорожденных.

Материал и методы. Систематический поиск литературы, содержащей информацию о соответствующих исследованиях, проводился в системах PubMed и Google Scholar. В обзор вошел анализ 42 англоязычных и русскоязычных статей. Глубина поиска составила 19 лет за период с 2004 по 2023 годы. Поиск проводился по ключевым словам: Толл-подобные рецепторы, цитомегаловирус, полиморфизмы, внутриутробная инфекция.

Результаты. В работе представлены сведения о структуре и типах TLR, раскрыты основные молекулярные механизмы, с помощью которых рецепторы участвуют в регуляции иммунной системы и развитии воспаления при инфицировании. Продемонстрирована потенциальная роль TLR и их генетической изменчивости в патогенезе ЦМВ инфекции, как в общей популяции людей, так и у беременных. Также определено их возможное участие в развитии врожденной ЦМВ инфекции у новорожденных.

Заключение. Результаты могут быть использованы для разработки терапевтических мишеней с целью их возможного применения для иммунокоррекции воспаления, вызванного ЦМВ инфицированием.

1. Silva S., Ayoub H.H., Johnston C., Atun R., Abu-Raddad L.J. Estimated economic burden of genital herpes and HIV attributable to herpes simplex virus type 2 infections in 90 low- and middle-income countries: A modeling study // PLoS Med. 2022. Vol.19, Iss.12. Article number:1003938. https://doi.org/10.1371/journal.pmed.1003938

2. Barreiro L.B., Quintana-Murci L. Evolutionary and population (epi)genetics of immunity to infection // Hum. Genet. 2020. Vol.139, №6-7. P.723–732. https://doi.org/10.1007/s00439-020-02167-x

3. Sherwood E.R., Burelbach K.R., McBride M.A., Stothers C.L., Owen A.M., Hernandez A., Patil N.K., Williams D.L., Bohannon J.K. Innate immune memory and the host response to infection // J. Immunol. 2022. Vol.208, №4. P.785– 792. https://doi.org/10.4049/jimmunol.2101058

4. Germic N., Frangez Z., Yousefi S., Simon H.-U. Regulation of the innate immune system by autophagy: Monocytes, macrophages, dendritic cells and antigen presentation // Cell Death. Differ. 2019. Vol.26, №4. P.715–727. https://doi.org/10.1038/s41418-019-0297-6

5. Fitzgerald K.A., Kagan J.C. Toll-like receptors and the control of immunity // Cell. 2020. Vol.180, №6. P.1044– 1066. https://doi.org/10.1016/j.cell.2020.02.041

6. Fore F., Indriputri C., Mamutse J., Nugraha J. TLR10 and its unique anti-inflammatory properties and potential use as a target in therapeutics // Immune Netw. 2020. Vol.20, №3. Article number:e21. https://doi.org/10.4110/in.2020.20.e21

7. Kemball C.C., Alirezaei M., Whitton J.L. Type B coxsackieviruses and their interactions with the innate and adaptive immune systems // Future Microbiol. 2020. Vol.15, №9. P.1329–1347. https://doi.org/10.2217/fmb.10.101

8. Akira S., Takeda K. Toll-like receptor signaling // Nat. Rev. Immunol. 2004. Vol.4, №7. P.499–511. https://doi.org/10.1038/nri1391

9. Werling D., Jann O.C., Offord V., Glass E.J., Coffey T.J. Variation matters: TLR structure and species-specific pathogen recognition // Trends Immunol. 2008. Vol.30, №3. P.124–130. https://doi.org/10.1016/j.it.2008.12.001

10. Farhat K., Riekenberg S., Heine H., Debarry J., Lang R., Mages J., Buwitt-Beckmann U., Röschmann K., Jung G., Wiesmüller K.-H., Ulmer A.J. Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling // J. Leukoc. Biol. 2007. Vol.83, Iss.3. P.692–701. https://doi.org/10.1189/jlb.0807586

11. Mukherjee S., Huda S., Sinha Babu S.P. Toll‐like receptor polymorphism in host immune response to infectious diseases: A review // Scan. J. Immunol. 2019. Vol.90, №1. Article number:12771. https://doi.org/10.1111/sji.12771

12. Joosten L.A., Abdollahi-Roodsaz S., Dinarello C.A., O'Neill L., Netea M.G. Toll-like receptors and chronic inflammation in rheumatic diseases: New developments // Nat. Rev. Rheumatol. 2016. Vol.12, №6. P.344–357. https://doi.org/10.1038/nrrheum.2016.61

13. Medvedev A.E. Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer // J. Interferon Cytokine Res. 2013. Vol.33, №9. P.467–484. https://doi.org/10.1089/jir.2012.0140

14. Barreiro L.B., Ben-Ali M., Quach H., Laval G., Patin E., Pickrell J.K., Bouchier C., Tichit M., Neyrolles O., Gicquel B., Kidd J.R., Kidd K.K., Alcaïs A., Ragimbeau J., Pellegrini S., Abel L., Casanova J.-L., Quintana-Murci L. Evolutionary dynamics of human toll-like receptors and their different contributions to host defense // PLoS Gen. 2009. Vol.5, №7. Article number:1000562. https://doi.org/10.1371/journal.pgen.1000562

15. Guimarães L.O., Bajay M.M., Monteiro E.F., Wunderlich G., Santos S.E., Kirchgatter K. Genetic ancestry effects on the distribution of toll-like receptors (TLRs) gene polymorphisms in a population of the Atlantic Forest, São Paulo, Brazil // Hum. Immunol. 2018. Vol.79, №2. P.101–108. https://doi.org/10.1016/j.humimm.2017.11.007

16. Quach H., Rotival M., Pothlichet J., Loh Y.-H.E., Dannemann M., Zidane N., Laval G., Patin E., Harmant C., Lopez M., Deschamps M., Naffakh N., Duffy D., Coen A., Leroux-Roels G., Clément F., Boland A., Deleuze J.-F., Kelso J., Albert M.L., Quintana-Murci L. Genetic adaptation and Neanderthal admixture shaped the immune system of human populations // Cell. 2016. Vol.167, №3. Article number:100024. https://doi.org/10.1016/j.cell.2016.09.024

17. Deschamps M., Laval G., Fagny M., Itan Y., Abel L., Casanova J.-L., Patin E., Quintana-Murci L. Genomic signatures of selective pressures and introgression from archaic hominins at human innate immunity genes // Hum. Genet. 2016. Vol.98, №1. P.5–21. https://doi.org/10.1016/j.ajhg.2015.11.014

18. Reher D., Key F.M., Andrés A.M., Kelso J. Immune gene diversity in archaic and present-day humans // Genome Biol. Evol. 2018. Vol.11, №1. P.232–241. https://doi.org/10.1093/gbe/evy271

19. Frascaroli G., Rossini G., Maltoni V., Bartoletti M., Ortolani P., Gredmark-Russ S., Gelsomino F., Moroni A., Silenzi S., Castellani G., Sambri V., Mastroianni A., Brune W., Varani S. Genetic and functional characterization of tolllike receptor responses in immunocompetent patients with CMV mononucleosis // Front. Cell Infect. Microbiol. 2020. Vol.10. Article number:386. https://doi.org/10.3389/fcimb.2020.00386

20. El-Nabi S.H., Sayed S., Abd-Elhafez M.A., Elfiky M., Abdel Moneim A.E., El-Garawani I. Arg753Gln polymorphisms in the toll-like receptor 2 gene are associated with cytomegalovirus infection in Egyptian bone marrow recipients // Endocr. Metab. Immune Disord. Drug. Targets. 2020. Vol.20, №4. P.619–624. https://doi.org/10.2174/1871530319666191018124710

21. Sezgin E., An P., Winkler C.A. Host genetics of cytomegalovirus pathogenesis // Front. Genet. 2019. Vol.10. Article number:616. https://doi.org/10.3389/fgene.2019.00616

22. Redondo N., Rodríguez-Goncer I., Parra P., Ruiz-Merlo T., López-Medrano F., González E., Polanco N., Trujillo H., Hernández A., San Juan R., Andrés A., Aguado J.M., Fernández-Ruiz M. Influence of single-nucleotide polymorphisms in TLR3 (rs3775291) and TLR9 (rs352139) on the risk of CMV infection in kidney transplant recipients // Front. Immunol. 2022. Vol.13. Article number:929995. https://doi.org/10.3389/fimmu.2022.929995

23. Bulka C.M., Bommarito P.A., Aiello A.E., Fry R.C. Cytomegalovirus seroprevalence, recurrence, and antibody levels // Environ. Epidemiol. 2020. Vol.4, №4. Article number:1000. https://doi.org/10.1097/ee9.0000000000000100

24. Jabłońska A., Paradowska E., Studzińska M., Suski P., Nowakowska D., Wiśniewska-Ligier M., WoźniakowskaGęsicka T., Wilczyński J., Leśnikowski Z.J. Relationship between toll-like receptor 2 ARG677TRP and Arg753Gln and Toll-like receptor 4 asp299gly polymorphisms and cytomegalovirus infection // Int. J. Infect. Dis. 2014. Vol.25. P.11–15. https://doi.org/10.1016/j.ijid.2014.04.001

25. Kijpittayarit S., Eid A.J., Brown R.A., Paya C.V., Razonable R.R. Relationship between Toll-like receptor 2 polymorphism and cytomegalovirus disease after liver transplantation // Clin. Infect. Dis. 2007. Vol.44, №10. P.1315–1320. https://doi.org/10.1086/514339

26. Beima-Sofie K., Wamalwa D., Maleche-Obimbo E., Lingappa J.R., Mackelprang R., Gantt S., John-Stewart G., Casper C., Slyker J.A. Toll-like receptor 9 polymorphism is associated with increased Epstein-Barr virus and cytomegalovirus acquisition in HIV-exposed infants // AIDS. 2018. Vol.32, №2. P.267–270. https://doi.org/10.1097/QAD.0000000000001680

27. Jabłońska A., Jabłonowska E., Studzińska M., Kamerys J., Paradowska E. The TLR9 2848C/T polymorphism is associated with the CMV DNAemia among HIV/CMV co-infected patients // Cells. 2021. Vol.10, №9. Article number:2360. https://doi.org/10.3390/cells10092360

28. Ng M.T., Van't Hof R., Crockett J.C., Hope M.E., Berry S., Thomson J., McLean M.H., McColl K.E., El-Omar E.M., Hold G.L. Increase in NF-kappaB binding affinity of the variant C allele of the toll-like receptor 9 -1237T/C polymorphism is associated with helicobacter pylori-induced gastric disease // Infect. Immun. 2010. Vol.78, №3. P.1345–1352. https://doi.org/10.1128/IAI.01226-09

29. Carvalho A., Osório N.S., Saraiva M., Cunha C., Almeida A.J., Teixeira-Coelho M., Ludovico P., Pedrosa J., Pitzurra L., Aversa F., Romani L., Castro A.G., Rodrigues F. The C allele of rs5743836 polymorphism in the human TLR9 promoter links IL-6 and TLR9 up-regulation and confers increased B-cell proliferation // PLoS One. 2011. Vol.6, №11. Article number:e28256. https://doi.org/10.1371/journal.pone.0028256

30. Mhandire D.Z., Mhandire K., Magadze M., Wonkam A., Kengne A.P., Dandara C. Genetic variation in toll like receptors 2, 7, 9 and interleukin-6 is associated with cytomegalovirus infection in late pregnancy // BMC Med. Gen. 2020. Vol.21, №1. Article number:10448. https://doi.org/10.1186/s12881-020-01044-8

31. Wujcicka W., Paradowska E., Studzińska M., Wilczyński J., Nowakowska D. Toll-like receptors genes polymorphisms and the occurrence of HCMV infection among pregnant women // Virol. J. 2017. Vol.14, №1. Article number:730. https://doi.org/10.1186/s12985-017-0730-8

32. Torki S.H., Naif H.M. Gene-polymorphisms in tell like receptors (TLR-2 and TLR-9) with cytomegalovirus infection in aborted women // T.M.J. 2022. Vol.45, Iss.2. P.5815–5821.

33. Enders G., Daiminger A., Bäder U., Exler S., Enders M. Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age // J. Clin. Virol. 2011. Vol.52, №3. P.244– 246. https://doi.org/10.1016/j.jcv.2011.07.005

34. Афонин А.А., Левкович А.Ю., Левкович М.А., Кравченко Л.В. Роль экспрессии TLR2, TLR6 и полиморфизма их генов в развитии генерализованной цитомегаловирусной и герпетической инфекции у новорожденных детей // Медицинский вестник Юга России. 2015. №3. С.24–27. https://doi.org/10.21886/2219-8075-2015-3-24-27

35. Njue A., Coyne C., Margulis A.V., Wang D., Marks M.A., Russell K., Das R., Sinha A. The role of congenital cytomegalovirus infection in adverse birth outcomes: a review of the potential mechanisms // Viruses. 2020. Vol.13, №1. Article number:20. https://doi.org/10.3390/v13010020

36. Koga K., Mor G. Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy disorders // Am. J. Reprod. Immunol. 2010. Vol.63, №6. P.587–600. https://doi.org/10.1111/j.1600-0897.2010.00848.x

37. Pudney J., He X., Masheeb Z., Kindelberger D.W., Kuohung W., Ingalls R.R. Differential expression of toll-like receptors in the human placenta across early gestation // Placenta. 2016. Vol.46. P.1–10. https://doi.org/10.1016/j.placenta.2016.07.005

38. Taniguchi R., Koyano S., Suzutani T., Goishi K., Ito Y., Morioka I., Oka A., Nakamura H., Yamada H., Igarashi T., Inoue N. Polymorphisms in TLR-2 are associated with congenital cytomegalovirus (CMV) infection but not with congenital CMV disease // Int. J. Infect. Dis. 2013. Vol.17, №12. Article number:1304. https://doi.org/10.1016/j.ijid.2013.06.004

39. Fernández-Ruiz M., Corrales I., Arias M., Campistol J.M., Giménez E., Crespo J., López-Oliva M.O., Beneyto I., Martín-Moreno P.L., Llamas-Fuente F., Gutiérrez A., García-Álvarez T., Guerra-Rodríguez R., Calvo N., Fernández-Rodríguez A., Tabernero-Romo J.M., Navarro M.D., Ramos-Verde A., Aguado J.M., Navarro D. Association between individual and combined SNPs in genes related to innate immunity and incidence of CMV infection in seropositive kidney transplant recipients // Am. J. Transplant. 2015. Vol.15, №5. P.1323–1335. https://doi.org/10.1111/ajt.13107

40. Eldar-Yedidia Y., Hillel M., Cohen A., Bar-Meir M., Freier-Dror Y., Schlesinger Y. Association of toll-like receptors polymorphism and intrauterine transmission of cytomegalovirus // PLOS One. 2017. Vol.12, №12. Article number:0189921. https://doi.org/10.1371/journal.pone.0189921

41. Paradowska E., Jabłońska A., Studzińska M., Skowrońska K., Suski P., Wiśniewska-Ligier M., WoźniakowskaGęsicka T., Nowakowska D., Gaj Z., Wilczyński J., Leśnikowski ZJ. TLR9 -1486T/C and 2848C/T SNPs are associated with human cytomegalovirus infection in infants // PLoS One. 2016. Vol.11, №4. Article number:154100. https://doi.org/10.1371/journal.pone.0154100

42. Studzińska M., Jabłońska A., Wiśniewska-Ligier M., Nowakowska D., Gaj Z., Leśnikowski Z.J. Association of TLR3 L412F polymorphism with cytomegalovirus infection in children // PLoS One. 2017. Vol.12, №1. Article number:169420. https://doi.org/10.1371/journal.pone.0169420