DOI 10.53511/PHARMKAZ.2023.47.95.009
Г.Н.Нурланова1, А.Н. Искакова1, А.Б. Байғулиева1, Ә.Р. Астраханов1, А.А. Аманжанова1, Г.Д. Жумагалиева2
1 Западно-Казахстанский медицинский университет имени Марата Оспанова, г. Актобе, Казахстан
2 Медицинский университет Астана, г. Астана, Казахстан
РОЛЬ ПОЛИМОРФИЗМА TLR3
В РАЗВИТИИ ХРОНИЧЕСКИХ ВИРУСНЫХ ГЕПАТИТОВ В И Сc
Резюме: Вирусные гепатиты остаются одной из самых актуальных проблем мирового здравоохранения, занимая 7-е место среди причин летальности от всех заболеваний. На современном этапе вирусные инфекционные гепатиты (B, C, D) представляют серьезную медицинскую и социальную проблему в связи с широким распространением во всем мире (около 7% от общей численности населения в мире являются хроническими носителями ВГВ (ХВГВ), тогда как заражение вирусом гепатита С (ХВГС) – у 3% населения мира (185млн. человек). По новым данным Всемирной организации здравоохранения (ВОЗ), предположительно 325 миллионов человек в мире живут с хронической инфекцией, вызванной вирусом гепатита B (HBV) или вирусом гепатита C (HCV). В РК
по данным Национального регистра, на 1 января 2018 года больных вирусными гепатитами В, С
зарегистрировано 47 563 человека: с С – 27 035, В – 20 528 случаев. На взаимодействия вирус — макроорганизм влияют различные генетические, иммунологические и вирусные факторы хозяина.
Проблема вирусных гепатитов, по-прежнему, продолжает оставаться актуальной, и является одной из центральных для здравоохранения, в странах всего мира. Вирусные гепатиты относятся
к социально значимым инфекциям, получившим широкое распространение в настоящее время. Несмотря на снижение уровня официально регистрируемой заболеваемости вирусными гепатитами,
их повсеместное распространение, поражение трудоспособных слоев населения, развитие хронических форм, цирроза и первичного рака печени после некоторых этиологических форм, наибольший экономический ущерб в структуре всей инфекционной патологии обусловливают социальноэкономическую значимость и научный интерес к данной проблеме.
Ключевые слова: Хронический вирусный гепатит, гепатит В, гепатит С, TLR3 рецепторы, полморфизм TLR3.
СПИСОК ЛИТЕРАТУРЫ
1 Zheng Z, Sze CW, Keng CT, et al. Hepatitis C virus mediated chronic inflammation and tumorigenesis in the humanised immune system and liver mouse
model. PLoS ONE. 2017;12(9):e0184127.
2 Saxena, R., Chawla, Y.K., Verma, I., Kaur, J., 2014. Association of interleukin-10 with hepatitis B virus (HBV) mediated disease progression in Indian
population. Indian J. Med. Res. 139, 737–745.
3 Seki E., Brenner D.A. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008; 48 (1): 322–35.
4 Mencin A., Kluwe J., Schwabe R.F. Toll-like receptors as targets in chronic liver diseases. Gut. 2009; 58 (5): 704–20.
5 Wang N., Liang Y., Devaraj S., Wang J., Lemon S.M., Li K. Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in
hepatoma cells. J. Virol. 2009; 83 (19): 9824–34.
6 Xiao X., Zhao P., Rodriguez-Pinto D., Qi D., Henegariu O., Alexopoulou L. et al. Inflammatory regulation by TLR3 in acute hepatitis. J. Immunol. 2009; 183
(6): 3712–9.
7 Mashael R. Al-Anazi,SabineMatou-Nasri et al., “Association of Toll-Like Receptor 3 Single-Nucleotide Polymorphisms and Hepatitis C Virus Infection ” Hindawi
Journal of Immunology Research Volume 2017, Article ID 1590653,11 pages https://doi.org/10.1155/2017/1590653
8 M.-M.Yuan,Y.-Y.Xu,L.Chen,X.-Y.Li,J.Qin,andY. Shen, “TLR3 expression correlates with apoptosis, proliferation and angiogenesis in hepatocellular carcinoma
and predicts prognosis,”BMC Cancer,vol.15,no.1,article245,2015.
9 Y. — Y. Xu , L . Ch e n , I . — M. Z h o u , Y. — Y. Wu , a n d Y. — Y. Z h u , “Inhibitory effect of dsRNA TLR3 agonist in a rat hepatocellular carcinoma
model,”Molecular Medicine Reports,vol.8,no.4,pp. 1037–1042, 2013.
10 Z. Guo, L. Chen, Y. Zhu et al., “Double-stranded RNA-induced TLR3 activation inhibits angiogenesis and triggers apoptosis of human hepatocellular
carcinoma cells,”OncologyReports,vol. 27,no.2,pp.396–402,2012.
11 Секлер Д.Э., Худайберганова Д.М., Латыпов Р.Р., Усманова Г.З., Рахманов М.И., МусабаевЭ.И“полиморфизм генаIL28B и прогноз эффективности
противовирусной терапии при вирусном гепатитеС в Узбекистане” Эпидемиология и инфекционные болезни, т. 19, № 6, стр. 37-42, 2014
12 Михайлов М.И., Шахгильдян И.В., Онищенко Г.Г., Энтеральные вирусные гепатиты (эпидемиология, диагностика, профилактика). − М: ГОУ ВУМЦ
МЗ, 2003. − 349 с.
13 Global hepatitis report, 2017: World Health Organization. (Электронный ресурс). URL: http://www.who.int/hepatitis/publications/global-hepatitis-report2017/
en (дата обращения: 15.04.2017).
14 Гепатит С. Информационные бюллетени № 164 и № 204. ВОЗ, 2013 [GepatitС. Informatsionnyyebyulleteni № 164 i № 204. VOZ, 2013 (in Russian)].
(Электронныйресурс). URL: http://www.who.int/mediacentre/factsheets/fs164/ru/;http://www.euro. who.int/__data/assets/pdf_fi le/0005/195332/Viral-Hepatitispres-Rus.pdf (датаобращения: 15.04.2017).
15 Хазанов А.И., Плющин С.В., Васильев А.П. и др. Алкогольные и вирусные циррозы печени у стационарных больных (1996–2005 гг.):
распространенность и исходы // Рос.журн. гастроэнтерол., гепатол., колопроктол. 2007. Т. 17. № 2. С. 19–27 .
16 El-Serag H.B. Epidemiology of viral hepatitis and hepatocellular carcinoma // Gastroenterology. 2012. Vol. 14(2). P. 1264–1273.
17 Nersesov A, KaibullayevaZh, Raissova A, Dzhumabaeva AE. et al. The Liver Week 2014, Jeju, Korea, Abstract book; P. 176
18 Lopatkina T.N., Kudlinskiy I.S. The role of gene polymorphisms of interleukin 28B in assessing the effectiveness of antiviral therapy for chronic hepatitis C
// KlinicheskayaGepatoogia. – 2011. – Vol. 2. – P.28-38. (in Russian)
19 Lange C.M., Zeuzem S. IL28B single nucleotide polymorphism in the treatment of hepatitis C // Journal of hepatology. – 2011. – Vol. 55. №3 – P.692-701.
20 E. J.Mifsud, A. C. L. Tan, andD. C. Jackson, “TLR agonists as modulators of the innate immune response and their potential as agents against infectious
disease,” Frontiers in Immunology, vol. 5, article 79, 2014
21 Janeway CA., Jr Как иммунная система защищает хозяина от инфекции. Инфекция микробов. 2001; 3 : 1167–71.
22 Рок Ф.Л., Хардиман Г., Тиманс Ю.С., Кастелейн Р.А., Базан Ю.Ф. Семейство человеческих рецепторов, структурно связанных с Drosophila Toll.
Proc Natl AcadSci USA. 1998; 95 : 588–93.
23 K. Huik, R. Avi, M. Pauskar et al., “Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users,”
Infection, Genetics and Evolution, vol. 20, pp. 78–82, 2013.
24 Миеттинен М., Саренева Т., Юлкунен И., Матикайнен С. ИФН активируют экспрессию генов toll-подобных рецепторов при вирусных инфекциях.
Гены Иммун. 2001; 2 : 349–55.
25 Vercammen, E., Staal, J. &Beyaert, R. Sensing of Viral Infection and Activation of Innate Immunity by Toll-Like Receptor 3. ClinicalMicrobiologyReviews21,
13–25 (2008).
26 Dhiman, N. et al. Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine:
Preliminary results. Vaccine 26, 1731–1736 (2008).
27 Tanabe M, Kurita-Taniguchi M, Takeuchi K, Takeda M, Ayata M, Oyura H, Matsumoto M, Seya T, 2003. Mechanism of up-regulation of human Toll-like
receptor receptor 3 secondaryto infection of measles virus-attenuated strains. BiochemBiophys Res Commun 311: 39–48.
28 Табета К., Георгель П., Янссен Е., Ду Х, Хобе К., Крозат К. и др. Toll-подобные рецепторы 9 и 3 как важнейшие компоненты врожденной иммунной
защиты от цитомегаловирусной инфекции мыши. ProcNatlAcadSciUSA. 2004; 101 : 3516–21.
29 Кук Г.С., Хилл А.В. Генетика предрасположенности к инфекционным заболеваниям человека. NatRevGenet. 2001; 2 : 967–77.
30 Akira S, Uematsu S, Takeuchi O, 2006. Pathogen recognition and innate immunity. Cell 124: 783–801.
31 T. Kawai and S. Akira, “The role of pattern-recognition receptors in innate immunity: update on toll-like receptors,” Nature Immunology, vol. 11, no. 5, pp.
373–384, 2010.
32 M. Matsumoto, K. Funami, H. Oshiumi, and T. Seya, “Tolllike receptor 3: a link between toll-like receptor, interferon and viruses,” Microbiology and
Immunology, vol. 48, no. 3, pp. 147–154, 2004.
33 M.-M. Yuan, Y.-Y. Xu, L. Chen, X.-Y. Li, J. Qin, and Y. Shen, “TLR3 expression correlates with apoptosis, proliferation and angiogenesis in hepatocellular
carcinoma and predicts prognosis,” BMC Cancer, vol. 15, no. 1, article 245, 2015.
34 Y.-Y. Xu, L. Chen, I.-M. Zhou, Y.-Y.Wu, and Y.-Y. Zhu, “Inhibitory effect of dsRNA TLR3 agonist in a rat hepatocellular carcinomamodel,”MolecularMedici
ne Reports, vol. 8, no. 4, pp. 1037–1042, 2013.
35 Z. Guo, L. Chen, Y. Zhu et al., “Double-stranded RNA-induced TLR3 activation inhibits angiogenesis and triggers apoptosis of human hepatocellular
carcinoma cells,” Oncology Reports, vol. 27, no. 2, pp. 396–402, 2012.
36 Y.-T. Lin, A. Verma, and C. P.Hodgkinson, “Toll-like receptors and human disease: lessons from single nucleotide polymorphisms,” Current Genomics, vol.
13, no. 8, pp. 633–645, 2012.
37 M. Sironi, M. Biasin, R. Cagliani et al., “A common polymorphism in TLR3 confers natural resistance to HIV-1 infection,” Journal of Immunology, vol. 188,
no. 2, pp. 818–823, 2012.
38 K. Huik, R. Avi, M. Pauskar et al., “Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users,”
Infection, Genetics and Evolution, vol. 20, pp. 78–82, 2013.
A. Al-Qahtani, M. Al-Ahdal, A. Abdo et al., “Toll-like receptor 3 polymorphism and its association with hepatitis B virus infection in SaudiArabian
patients,” Journal ofMedical Virology, vol. 84, no. 9, pp. 1353–1359, 2012.
39 E. Askar, R. Bregadze, J. Mertens et al., “TLR3 gene polymorphisms and liver disease manifestations in chronic hepatitis C,” Journal of Medical Virology,
vol. 81, no. 7, pp. 1204–1211, 2009.
A. V. Barkhash, M. I. Voevoda, and A. G. Romaschenko, “Association of single nucleotide polymorphism rs3775291 in the coding region of the TLR3
gene with predisposition to tickborne encephalitis in a Russian population,” Antiviral Research, vol. 99, no. 2, pp. 136–138, 2013.
40 Svensson, P. TunbЁack, I. NordstrЁom, L. Padyukov, and K. Eriksson, “Polymorphisms in Toll-like receptor 3 confer natural resistance to human herpes
simplex virus type 2 infection,” Journal of General Virology, vol. 93, no. 8, pp. 1717–1724, 2012.
41 Nahum, H. Dadi, A. Bates, and C. M. Roifman, “The L412F variant of Toll-like receptor 3 (TLR3) is associated with cutaneous candidiasis, increased
susceptibility to cytomegalovirus, and autoimmunity,” Journal of Allergy and Clinical Immunology, vol. 127, no. 2, pp. 528–531, 2011.
42 T. S. Assmann, L. De Almeida Brondani, A. C. Bauer, L. H. Canani, and D. Crispim, “Polymorphisms in the TLR3 gene are associated with risk for type 1
diabetes mellitus,” European Journal of Endocrinology, vol. 170, no. 4, pp. 519–527, 2014.
43 K. H. Kim, B. K. Jang, W. J. Chung et al., “Peginterferon alpha and ribavirin combination therapy in patients with hepatitis C virus-related liver cirrhosis,”
The Korean Journal of Hepatology, vol. 17, no. 3, pp. 220–225, 2011.
44 N.Wang, Y. Liang, S. Devaraj, J.Wang, S.M. Lemon, and K. Li, “Toll-like receptor 3mediates establishment of an antiviral state against hepatitis C virus in
hepatoma cells,” Journal of Virology, vol. 83, no. 19, pp. 9824–9834, 2009.
45 R.Firdaus,A.Biswas, K. Saha et al., “ModulationofTLR3, 7 and 8 expressions in HCV genotype 3 infected individuals: potential correlations of pathogenesis
and spontaneous clearance,” BioMed Research International, vol. 2014, Article ID 491064, 7 pages, 2014.
46 F. Qian, C. R. Bolen, C. Jing et al., “Impaired toll-like receptor 3-mediated immune responses from macrophages of patients chronically infectedwith hepatitis
C virus,” Clinical and VaccineImmunology, vol. 20, no. 2, pp. 146–155, 2013.
47 K. S. Sґa,O. D. Pires-Neto, B. B. Santana et al., “Toll-like receptor 3 gene polymorphisms are not associated with the risk of hepatitis B and hepatitis C virus
infection,” Revista da SociedadeBrasileiradeMedicina Tropical, vol. 48, no. 2, pp. 136–142, 2015.
48 S. Medhi,M. Deka, P. Deka et al., “Promoter region polymorphism & expression profile of toll like receptor-3 (TLR-3) gene in chronic hepatitis C virus (HCV)
patients from India,” Indian Journal of Medical Research, vol. 134, no. 8, pp. 200–207, 2011.
49 P. Geng, L. Song, H. An, J. Huang, S. Li, and X. Zeng, “Tolllike receptor 3 is associated with the risk of HCV infection and HBV-Related Diseases,” Medicine,
vol. 95, no. 21, p. e2302, 2016.
50 Q. He, C. S. Graham, E. D. Mangoni, andM. J. Koziel, “Differential expression of toll-like receptor mRNA in treatment nonresponders and sustained virologic
responders at baseline in patients with chronic hepatitis C,” Liver International, vol. 26, no. 9, pp. 1100–1110, 2006.
51 K. Sato, T. Ishikawa, A. Okumura et al., “Expression of Tolllike receptors in chronic hepatitis C virus infection,” Journal of Gastroenterology and Hepatology,
vol. 22, no. 10, pp. 1627–1632, 2007.
52 K. I. Mohammed, L. A. Adel, F. A. Ali-Eldin, and S. Eladawy, “Expression of Toll like receptors 3 & 7 in peripheral blood from patients with chronic hepatitis
C virus infection and their correlation with interferon-alpha,”The Egyptian Journal of Immunology, vol. 20, no. 1, pp. 13–22, 2013.
53 Q. Yang, S. Fu, and J. Wang, “Hepatitis C virus infection decreases the expression of Toll-like receptors 3 and 7 via upregulation of miR-758,” Archives of
Virology, vol. 159, no. 11, pp. 2997–3003, 2014.
54 M. Taura, A. Eguma, M. A. Suico et al., “p53 regulates tolllike receptor 3 expression and function in human epithelial cell lines,” Molecular and Cellular
Biology, vol. 28, no. 21, pp. 6557– 6567, 2008.
55 S. Yin and B. Gao, “Toll-like receptor 3 in liver diseases,” Gastroenterology Research and Practice, vol. 2010, Article ID 750904, 6 pages, 2010.
56 X.Huang,H. Li, J.Wang et al., “GeneticpolymorphismsinTolllike receptor 3 gene are associated with the risk of hepatitis B virus-related liver diseases in a
Chinese population,” Gene, vol. 569, no. 2, pp. 218–224, 2015.
57 L. Sun, J. Dai, W. Hu, and J. Wang, “Expression of toll-like receptors in hepatic cirrhosis and hepatocellular carcinoma,” Genetics and Molecular Research,
vol. 15, no. 2, 2016.
58 Y. Takii, M. Nakamura, M. Ito et al., “Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis,” Laboratory Investigation,
vol. 85, no. 7, pp. 908–920, 2005.
59 T. R. Gardner, Q. Chen, Y. Jin, and M. N. Ajuebor, “Toll-like receptor 3 ligand dampens liver inflammation by stimulating V-14 invariant natural killer T cells
to negatively regulate -T cells,” The American Journal of Pathology, vol. 176, no. 4, pp. 779–1789, 2010.
60 R. Zampino, A. Marrone, L. Restivo et al., “Chronic HCV infection and inflammation: clinical impact on hepatic and extra-hepaticmanifestations,”World
Journal of Hepatology, vol. 5, no. 10, pp. 528–540, 2013.
61 J. Wang, J. Xu, W. Zhang, H. Wei, and Z. Tian, “TLR3 ligandinduced accumulation of activated splenic natural killer cells into liver,” Cellular & Molecular
Immunology, vol. 2, no. 6, pp. 449–453, 2005.
62 Helbig KJ, Beard MR. The interferon signaling pathway genes as biomarkers of hepatitis C virus disease progression and response to treatment. Biomark
Med. 2012;6:141–150.
63 Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5:558–567.
64 Sanclemente G, Moreno A, Navasa M, et al. Genetic variants of innate immune receptors and infections after liver transplantation. World J Gastroenterol.
2014;20:11116–11130.
65 Skevaki C, Pararas M, Kostelidou K, et al. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious diseases. ClinExpImmunol.
2015;180:165–177.
66 Medhi S, Deka M, Deka P, et al. Promoter region polymorphism & expression profile of toll like receptor-3 (TLR-3) gene in chronic hepatitis C virus (HCV)
patients from India. Indian J Med Res. 2011;134:200–207.
67 Lin YT, Verma A, Hodgkinson CP. Toll-like receptors and human disease: lessons from single nucleotide polymorphisms. Curr Genomics. 2012;13:633–645.
68 Al-Qahtani A, Al-Ahdal M, Abdo A, et al. Toll-like receptor 3 polymorphism and its association with hepatitis B virus infection in Saudi Arabian patients. J
Med Virol. 2012;84:1353–1359.
69 He D, Tao S, Guo S, et al. Interaction of TLR-IFN and HLA polymorphisms on susceptibility of chronic HBV infection in Southwest Han Chinese. Liver Int.
2015;35:1941–1949.
70 Huang X, Li H, Wang J, et al. Genetic polymorphisms in Toll-like receptor 3 gene are associated with the risk of hepatitis B virus-related liver diseases in a
Chinese population. Gene. 2015;569: 218–224.
71 Lee SO, Brown RA, Razonable RR. Association between a functional polymorphism in Toll-like receptor 3 and chronic hepatitis C in liver transplant
recipients. Transpl Infect Dis.2013;15:111–119.
72 Li G, Zheng Z. Toll-like receptor 3 genetic variants and susceptibility to hepatocellular carcinoma and HBV-related hepatocellular carcinoma. Tumour Biol.
2013;34:1589–1594.
73 Qian F, Bolen CR, Jing C, et al. Impaired toll-like receptor 3-mediated immune responses from macrophages of patients chronically infected with hepatitis
C virus. Clin Vaccine Immunol.2013;20:146–155.
74 Rong Y, Song H, You S, et al. Association of Toll-like receptor 3 polymorphisms with chronic hepatitis B and hepatitis B-related acute-on-chronic liver failure.
Inflammation. 2013;36:413–418.
75 de Sa´ KS, Pires-Neto Ode S, Santana BB, et al. Toll-like receptor 3 gene polymorphisms are not associated with the risk of hepatitis B and hepatitis C virus
infection. Rev Soc Bras Med Trop.2015;48:136–142.
