Abstract
ROLE OF Β-DEFENSINS IN IMMUNE RESPONSE IN TUBERCULOSIS PATIENTS
Shevchenko O., Pohorielova O.
Expanding of tuberculosis drug-resistance makes host-directed treatment an important part of tuberculosis treatment. Host-directed treatment is aimed at stimulating the production of antimicrobial peptides by the patient's immune cells. The use of β-defensins is very interesting in this field because of their pronounced bactericidal and bacteriostatic effects, as well as the ability to stimulate the chemotaxis of immune cells. The article presents a review on the immunological properties of the defensin family and the possibility of their use in practice. To complete the review 114 articles from “PubMed” resource were analyzed to perform the study. 34 of them were chosen to review immunomodulatory and antimicrobial action of β-defensins.
The own research results on Human-beta-defensine-1 use as tuberculosis severity marker are also added to the research. To obtain our own research results, 100 TB patients and 20 healthy persons were included in the study. Human-beta-defensin-1 level in serum was investigated in all the patients at the treatment onset and in healthy persons. Mann-Whitney U test (for comparison of 2 independent groups) and Spearman's rank correlation coefficient were used for statistical data processing. It was found that Human-beta-defensin-1 level was significantly higher in TB patients than in healthy persons. A correlation of medium strength (r=+0.53, p<0.05) between Human-beta-defensin-1 and tuberculosis lesion volume was revealed. The data obtained allows to use human β-defensin-1 as a diagnostic marker of tuberculosis.
Key words: tuberculosis, β-defensins, immunity, prognostic marker
Резюме.
РОЛЬ Β-ДЕФЕНЗИНІВ В ІМУННІЙ ВІДПОВІДІ У ХВОРИХ НА ТУБЕРКУЛЬОЗ
Шевченко О.С., Погорєлова О.О.
Розширення лікарської стійкості туберкульозу робить лікування, спрямоване на активацію власних резервів організму-хазяїна, важливою частиною терапії. Таке лікування спрямоване на стимулювання продукції антимікробних пептидів імунними клітинами пацієнта. Використання β-дефензинів в даній області є перспективним через їх виражену бактерицидну і бактеріостатичну дію, а також здатність стимулювати хемотаксис імунних клітин. У статті представлений огляд імунологічних властивостей сімейства дефензинів і можливостей їх використання на практиці. Для створення огляду було проаналізовано 114 статей з ресурсу «PubMed». З них 34 були обрані для вивчення імуномодулюючої і антимікробної дії β-дефензинів.
Результати власного дослідження можливостей використання β-дефензину-1 також були включені в роботу. Для отримання власних результатів у дослідження було включено 100 хворих на туберкульоз і 20 здорових людей. Рівень β-дефензіну-1 в сироватці крові був досліджений у всіх пацієнтів на початку лікування і у здорових людей. U-критерій Манна-Уїтні (для порівняння 2 незалежних груп) і коефіцієнт кореляції застосовувалися для статистичної обробки даних. Було виявлено, що рівень β-дефензину-1 був значно вищим у хворих на туберкульоз, ніж у здорових людей. Виявлено кореляцію середньої сили (r = + 0,53, р <0,05) між рівнем β-дефензину-1 і об’ємом туберкульозного ураження. Отримані дані дозволяють використовувати β-дефензин-1 в якості діагностичного маркеру перебігу туберкульозу.
Ключові слова: туберкульоз, β-дефензини, імунітет, прогностичний маркер
Резюме.
РОЛЬ Β-ДЕФЕНЗИНОВ В ИММУННОМ ОТВЕТЕ У БОЛЬНЫХ ТУБЕРКУЛЕЗОМ
Шевченко О.С., Погорелова О.А.
Расширение лекарственной устойчивости туберкулеза делает лечение, направленное на активацию резервов организма-хозяина, важной частью терапии. Такое лечение направлено на стимулирование производства антимикробных пептидов иммунными клетками пациента. Использование β-дефензинов в данной области является перспективным из-за их выраженного бактерицидного и бактериостатического действия, а также способности стимулировать хемотаксис иммунных клеток. В статье представлен обзор иммунологических свойств семейства дефензинов и возможности их использования на практике. Для создания обзора было проанализировано 114 статей из ресурса «PubMed». 34 из них были выбраны для изучения иммуномодулирующего и антимикробного действия β-дефензинов.
Собственные результаты исследования возможностей использования β-дефензина-1 в качестве маркера тяжести туберкулеза также были включены в работу. Для получения собственных результатов в исследование были включены 100 больных туберкулезом и 20 здоровых людей. Уровень β-дефензина-1 в сыворотке был исследован у всех пациентов в начале лечения и у здоровых людей. U-критерий Манна-Уитни (для сравнения 2 независимых групп) и коэффициент корреляции Спирмена были использованы для статистической обработки данных. Было обнаружено, что уровень β-дефензина-1 был значительно выше у больных туберкулезом, чем у здоровых людей. Выявлена корреляция средней силы (r = + 0,53, р <0,05) между уровнем β-дефензина-1 и туберкулезного поражения. Полученные данные позволяют использовать β-дефензин-1 в качестве диагностического маркера течения туберкулеза.
Ключевые слова: туберкулез, β-дефензины, иммунитет, прогностический маркер
References
Global Tuberculosis Report. World Health Organization, 2020, 277 p.
WHO End TB Strategy. Available at: http://www.who.int/tb/post2015_strategy/en/
Hilchie, A.L., Wuerth, K., Hancock, R.E. (2013). Immune modulation by multifaceted cationic host defense (antimicrobial) peptides. Nat Chem Biol, 9(12), 761-768. doi: 10.1038/nchembio.1393
Chow, B.T., Soto, M., Lo, B.L., Crosby, D.C., Camerini, D. (2012). Antibacterial Activity of Four Human Beta-Defensins: HBD-19, HBD-23, HBD-27, and HBD-29. Polymers, 4, 747-758. doi: 10.3390/polym4010747.
Goldman, M.J., Anderson, G.M., Stolzenberg, E.D., Kari, U.P., Zasloff, M., Wilson J.M. (1997). Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell, 88(4), 553-60. doi: 10.1016/s0092-8674(00)81895-4
Harder, J., Meyer-Hoffert, U., Teran, L.M., Schwichtenberg, L., Bartels, J., Maune, S., Schroder, J.M. (2000). Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia. Am J Respir Cell Mol Biol, 22(6), 714-21. doi: 10.1165/ajrcmb.22.6.4023
Raj, P.A, Dentino, A.R. (2000). Current status of defensins and their role in innate and adaptive immunity. FEMS Microbiology Letters, 206, 9–18. doi: 10.1111/j.1574-6968.2002.tb10979.x
Dongsheng, L., Jiawen, L., Yiqun, D., Xiaoyong, Z. (2004), Expression of LL-37, human beta defensin-2, and CCR6 mRNA in patients with psoriasis vulgaris. J Huazhong Univ Sci Technolog Med Sci, 24, 404–406. doi: 10.1007/bf02861879
Méndez-Samperio, P., Miranda, E., Trejo, A. (2006). Mycobacterium bovis Bacillus Calmette-Guérin (BCG) stimulates human beta-defensin-2 gene transcription in human epithelial cells. Cell Immunol, 239(1), 61-66. doi: 10.1016/j.cellimm.2006.04.001
Lehrer, R.I., Lichtenstein, A.K., Ganz T. (1993). Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu Rev Immunol, 11, 105-128. doi: 10.1146/annurev.immunol.11.1.105
Sharma, S.I., Khuller G. (2001). DNA as the intracellular secondary target for antibacterial action of human neutrophil peptide-I against Mycobacterium tuberculosis H37Ra. Curr Microbiol, 43 (1), 74-76. doi: 10.1007/s002840010263
Dong, H., Lv, Y., Zhao, D., Barrow, P., Zhou, X. (2016). Defensins: The Case for Their Use against Mycobacterial Infections. J Immunol Res, 7515687. doi: 10.1155/2016/7515687
Sigal, G.B., Segal, M.R., Mathew, A., Jarlsberg, L., Wang, M., Barbero, S., … Nahid, P. (2017). Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial. EBioMedicine, 25, 112-121. doi: 10.1016/j.ebiom.2017.10.018.
Kalita, A., Verma, I., Khuller, G.K. (2004). Role of human neutrophil peptide-1 as a possible adjunct to antituberculosis chemotherapy. J Infect Dis, 190(8), 1476-80. doi: 10.1086/424463
Rivas-Santiago, B., Rivas-Santiago, C., Sada, E., Hernandez-Pando, R. (2015). Prophylactic potential of defensins and L-isoleucine in tuberculosis household contacts: an experimental model. Immunotherapy. 7(3), 207-13. doi: 10.2217/imt.14.119.
Rivas-Santiago, C.E., Rivas-Santiago, B., Leon, D.A., Castaneda-Delgado, J., Hernandez-Pando, R. (2011). Induction of β-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis. Clin Exp Immunol, 164(1), 80-89. doi: 10.1111/j.1365-2249.2010.04313.x.
Selsted, M.E., Harwig, S.S., Ganz, T., Schilling, J.W., Lehrer, R.I. (1985). Primary structures of three human neutrophil defensins. J Clin Invest, 76(4), 1436–1439. doi: 10.1172/JCI112121
Mao, X., Qi, S., Yu, B., He, J., Yu, J., Chen, D. (2013). Zn(2+) and L-isoleucine induce the expressions of porcine β-defensins in IPEC-J2 cells. Mol Biol Rep, 40(2), 1547-1552. doi: 10.1007/s11033-012-2200-0.
Tyrrell, C., De Cecco, M., Reynolds, N.L., Kilanowski, F., Campopiano, D., Barran, P., … Dorin, J.R. (2010). Isoleucine/leucine2 is essential for chemoattractant activity of beta-defensin Defb14 through chemokine receptor 6. Mol Immunol, 47(6), 1378-82. doi: 10.1016/j.molimm.2009.11.025.
Fehlbaum, P., Rao, M., Zasloff, M., Anderson, G.M. (2000). An essential amino acid induces epithelial beta-defensin expression. Proceedings of the National Academy of Sciences of the United States of America, 97(23), 12723-12728. doi: 10.1073/pnas.220424597
Kumar, N.P., Moideen, K., Viswanathan, V., Sivakumar, S., Menon, P.A., Kornfeld, H., Babu, S. (2017). Heightened circulating levels of antimicrobial peptides in tuberculosis-Diabetes co-morbidity and reversal upon treatment. PloS One, 12(9), e0184753. doi: 10.1371/journal.pone.0184753
Alvarez, A.H., Martinez Velazquez, M., Prado Montes de Oca, E. (2018). Human β-defensin 1 update: Potential clinical applications of the restless warrior. The International Journal of Biochemistry & Cell Biology, 104, 133–137. doi: 10.1016/j.biocel.2018.09.007
Castaneda-Delqado, J.E., Cervantes-Villagrana, A., Serrano-Escobedo, C.J., Frausto-Lujan, I., Rivas-Santiago, C., Ensico-Moreno, J.A., Rivas-Santiago, B. (2014). Tuberculin skin test and interferon-gamma release assay values are associated with antimicrobial peptides expression in polymorphonuclear cells during latent tuberculous infection. Memorias do Instituto Oswaldo Cruz, 109(3), 330-334. doi: 10.1590/0074-0276140348
Corrales-Garcia, L., Ortiz, E., Castaneda-Delgado, J., Rivas-Santiago, B., Corzo, G. (2013). Bacterial expression and antibiotic activities of recombinant variants of human β-defensins on pathogenic bacteria and M. tuberculosis. Protein Expression and Purification, 89(1), 33-43. doi: 10.1016/j.pep.2013.02.007
Jena, P., Mohanty, S., Mohanty, T., Kallert, S., Morgelin, M., Lindstorm, T., … Sorensen, O.E. (2012). Azurophil Granule Proteins Constitute the MajorMycobactericidal Proteins in Human Neutrophils and Enhance the Killing of Mycobacteria in Macrophages. PLoS One, 7(12), e50345. doi: 10.1371/journal.pone.0050345
Gonzalez-Curiel, I., Castaneda-Delgado, J., Lopez-Lopez, N., Araujo, Z., Hernandez-Pando, R., Gandara-Jasso, B. (2011). Differential expression of antimicrobial peptides in active and latent tuberculosis and its relationship with diabetes mellitus. Human Immunology, 72(8), 656-662. doi: 10.1016/j.humimm.2011.03.027
Zhu, L.M., Liu, C.H., Chen, P., Dai, A.-G., Li, C.-X., Xiao, K., … Chen, Y.-R. (2011). Multidrug-resistant tuberculosis is associated with low plasma concentrations of human neutrophil peptides 1-3. International Journal of Tuberculosis and Lung Disease, 15(3), 369-374.
Rivas-Santiago, B., Contreras, J.C., Sada, E., Hernandez-Pando, R. (2008). The potential role of lung epithelial cells and beta-defensins in experimental latent tuberculosis. Scandinavian Journal of Immunology, 67(5), 448-52. doi: 10.1111/j.1365-3083.2008.02088.x
Laube, D.M., Yim, S., Ryan, L.K., Kisich, K.O., Diamond, G. (2006). Antimicrobial peptides in the airway. Curr Top Microbiol Immunol, 306, 153-182. doi: 0.1007/3-540-29916-5_6
Fu, L.M. (2003). The potential of human neutrophil peptides in tuberculosis therapy. International Journal of Tuberculosis and Lung Disease, 7(11), 1027–1032.
Rekha, R.S., Mily, A., Sultana, T., Haq, A., Ahmed, S., Kamal, S.M.M., … Raqib, R. (2018). Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy. BMC Infectious Diseases, 18, 303. doi: 10.1186/s12879-018-3203-9
Sharma, R., Saikia, U.N., Sharma, S., Verma, I. (2017) Activity of human beta defensin-1 and its motif against active and dormant Mycobacterium tuberculosis. Applied Microbiology and Biotechnology, 101(19), 7239-7248. doi: 10.1007/s00253-017-8466-3
Mao, X., Gu, C., Ren, M., Chen, D., Yu, B., He, J., … Yang, Q. (2018). L-Isoleucine Administration Alleviates Rotavirus Infection and Immune Response in the Weaned Piglet Model. Frontiers in Immunology, 16(9), 1654. doi: 10.3389/fimmu.2018.01654
Du, F., Xhen, X., Liu, X., Liu, G., Zhang, Y. (2018). Expression of recombinant HBD3 protein that reduces Mycobacterial infection capacity. AMD Express, 8, 42. doi: 10.1186/s13568-018-0573-8
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