Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI1820110.15789/2220-7619-MMB-18201ORIGINAL ARTICLESОРИГИНАЛЬНЫЕ СТАТЬИUnknownMOLECULAR MIMICRY BETWEEN CHLAMYDIA PNEUMONIAE ANTIGENS AND PROTEINS INVOLVED IN ATHEROGENESIS AND ARTERITIDES WITH EXPERIMENTAL PATHOMORPHOLOGICAL CORRELATESМОЛЕКУЛЯРНАЯ МИМИКРИЯ МЕЖДУ АНТИГЕНАМИ CHLAMYDIA PNEUMONIAE И БЕЛКАМИ, ВОВЛЕЧЕННЫМИ В АТЕРОГЕНЕЗ И АРТЕРИИТЫ: ЭКСПЕРИМЕНТАЛЬНЫЕ ПАТОМОРФОЛОГИЧЕСКИЕ КОРРЕЛЯТЫhttps://orcid.org/0000-0001-6359-002666029536418879-0875ChurilovLeonid PavlovichЧуриловЛеонид Павлович
Russian Federation

M.D., Ph.D., Associate Professor, Head of the Department of Pathology

кандидат медицинских наук, доцент, заведующий кафедрой патологии

elpach@mail.ruhttps://med.spbu.ru/kafedra-patologii/tpost/kg4myifgk1-churilov-leonid-pavlovich2414-0069NovitskaiaTatiana AleksandrovnaНовицкаяТатьяна Александровна
Russian Federation

M.D., Ph.D., Associate Professor, Associate Professor of the Department of Pathology.

кандидат медицинских наук, доцент кафедры патологии.

nta0666@rambler.ruhttps://med.spbu.ru/kafedra-patologii/tpost/am7t5paou1-novitskaya-tatyana-aleksandrovnahttps://orcid.org/0000-0002-1307-0513579034838009235-3589NormatovMuslimbek GhulomovichНорматовМуслимбек Гуломович
Russian Federation

postgraduate student, department of pathology

аспирант кафедры патологии

muslimbek_normatov@mail.ruhttps://pureportal.spbu.ru/ru/persons/--(7dfebe33-a155-4476-9fe5-31a0e467b62e).htmlhttps://orcid.org/0000-0003-1843-2808573833956005353-0280ShapkinaValeriia AleksandrovnaШапкинаВалерия Александровна
Russian Federation

assistant, department of pathology

ассистент кафедры патологии

valshapkina@gmail.comhttps://pureportal.spbu.ru/ru/persons/--(188d71a1-3dec-47fa-9b01-7ac8e450f3dd).htmlhttps://orcid.org/0000-0002-0192-1931566776467006494-2319IablonskiiPavel PetrovichЯблонскийПавел Петрович
Russian Federation

M.D., Ph.D., Associate Professor, Associate Professor of the Department of Hospital Surgery

кандидат медицинских наук, доцент кафедры госпитальной хирургии

pavel.yablonski@gmail.comhttps://med.spbu.ru/kafedra-gospitalnoj-khirurgii/tpost/396ohklc71-yablonskii-pavel-petrovichInstitute of Medicine, Saint Petersburg State University, St. Petersburg, RussiaMедицинский институт, Санкт-Петербургский государственный университет, Санкт-Петербург, РоссияSaint Petersburg State University, St. Petersburg, RussiaСанкт-Петербургский государственный университет, Санкт-Петербург, РоссияSt. Petersburg Research Institute of Phthisiopulmonology, St. Petersburg, RussiaСанкт-Петербургский научно-исследовательский институт фтизиопульмонологии, Санкт-Петербург, РоссияClinic of High Technologies “Beloostrov”, Leningrad region, Vsevolozhsky distr., Yukkovskoye village, RussiaКлиника высоких технологий «Белоостров», Ленинградская область, Всеволожский район, Юкковское сельское поселение, Россия060920261104202628072026Copyright ©; , Churilov L.P., Novitskaia T.A., Normatov M.G., Shapkina V.A., Iablonskii P.P.Copyright ©; , Чурилов Л.П., Новицкая Т.А., Норматов М.Г., Шапкина В.А., Яблонский П.П.Churilov L.P., Novitskaia T.A., Normatov M.G., Shapkina V.A., Iablonskii P.P.Чурилов Л.П., Новицкая Т.А., Норматов М.Г., Шапкина В.А., Яблонский П.П.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/18201

A series of epidemiological and experimental data suggest a link between Chlamydia pneumoniae and development of atherosclerosis as a variant of chronic productive inflammation of large and medium-sized arteries of the elastic and muscular-elastic types in response to accumulating atherogenic lipoprotein cholesterol. Atherogenesis consists of immunopathological and autoimmune components, being promoted in autoimmune vasculitis. Atherogenesis-related autoimmune manifestations may be enabled via molecular mimicry. The presence of homologous peptides between infectious agent antigens and human autoantigens may eventually activate autoreactive immune cells. The study investigated a relationship between Chlamydia pneumoniae, molecular mimicry, and development of atherosclerosis, a disease characterized by lipid accumulation and chronic inflammation of the arteries. Materials and Methods: We present a comprehensive bioinformatics analysis aimed at understanding the pathogenesis of atherosclerosis and arteritis by analyzing key antigenic proteins. Candidate protein amino acid sequences were retrieved from the UniProt and NCBI databases. The “Alignmentaj” application was used to identify mimicking pentapeptides. In addition, an infectious model of atherosclerosis was created using Chlamydia pneumoniae administered endotracheally to male rabbits. Pathohistological examination of animal aorta and carotid arteries was carried out. Results: Significant homology between chlamydial antigens and apoprotein B (84 pentapeptides) was revealed. Moreover, we found 23 mimicking pentapeptides in protein tenascin, which dually plays pathogenic and sanogenic role in atherogenesis. Fewer shared pentapeptides were identified in other autoantigens involved in atherogenesis and/or arteritis pathogenesis. Experimental chlamydial infection induced atherosclerotic changes in the aortic intima, including foam cell and plaque formation. The carotid artery wall had uniform thickness with preserved endothelium; however, degenerative changes and a mononuclear inflammatory infiltrates were observed in the vasa vasorum of the adventitia. Conclusion: Bioinformatic analysis underlines a potential for molecular mimicry as a mechanism of autoimmune atherogenic risk associated with Chlamydia infection. Experimental studies in rabbits confirmed the atherogenicity of Chlamydia infection and the induction of vasa vasorum vasculitis potentially due to mimicry between chlamydial antigens and atherogenic autoantigens.

Ряд эпидемиологических и экспериментальных данных указывают на связь Chlamydia pneumoniae с развитием атеросклероза. Последний представляет собой разновиидность хронического продуктивного воспаления крупных и средних артерий эластического и мышечно эластического типа в ответ на накопление холестерина атерогенных липопротеидов. Атерогенез включает иммунопатологические и аутоиммунные звенья, ускоряясь при наличии аутоиммунных васкулитов. Аутоиммунные проявления при атеросклерозе могут реализовываться через феномен молекулярной мимикрии. Наличие мимикрирующих пептидов между антигенами инфекционного агента и аутоантигенами человека может приводить к активации аутореактивных иммунных клеток. В данном исследовании изучалась взаимосвязь между Chlamydia pneumoniae, молекулярной мимикрией и развитием атеросклероза — заболевания, характеризующегося накоплением липидов и хроническим воспалением артерий. Материалы и методы: Представлен комплексный биоинформатический анализ, направленный на понимание патогенеза атеросклероза и артериитов путем изучения ключевых антигенных белков. Аминокислотные последовательности белков-кандидатов были получены из баз данных UniProt и NCBI. Для выявления мимикрирующих пентапептидов использовали авторскую программу «Alignmentaj». Кроме того, была создана инфекционная модель атеросклероза с использованием Chlamydia pneumoniae, вводимых эндотрахеально самцам кроликов. Было проведено патогистологическое исследование аорты и сонных артерий животных. Результаты: Выявилено значительная гомология между антигенами Chlamydia pneumoniae и апопротеином В (84 пентапептида). Кроме того, обнаружено 23 имитирующих пентапептида в белке тенасцине, играющем двоякую как патогенную, так и саногенную роль в атерогенезе. В других аутоантигенах – участниках атерогенеза и патогенеза артериитов было выявлено меньшее количество имитирующих пентапептидов. Экспериментальная хламидийная инфекция вызывала атеросклеротические изменения в интиме аорты, включая образование пенистых клеток и бляшек. Стенка сонной артерии имела равномерную толщину с сохраненным эндотелием; однако в сосудах vasa vasorum в адвентиции наблюдались дегенеративные изменения и мононуклеарные воспалительные инфильтраты. Вывод: биоинформатический анализ подчеркивает потенциал молекулярной мимикрии как механизма аутоиммунного атерогенного риска, связанного с хдамидийной инфекцией. Экспериментальные исследования на кроликах подтвердили атерогенность хламидийной инфекции и индукцию васкулита vasa vasorum, которая может быть обусловлен мимикрией между хламидийными антигенами и атерогенными аутоантигенами.

chlamydia pneumoniaemolecular mimicryatherosclerosisautoimmunityautoantigensvasa vasorum.chlamydia pneumoniaeмолекулярная мимикрияатеросклерозаутоиммунитетаутоантигеныvasa vasorum.Funding. This work was supported by the grant of the Government of the Russian Federation for the state support of scientific research carried out under the supervision of leading scientists, agreement No. 075-15-2022-1110 dated 30 June 2022.Шенфельд И., Мерони П.Л., Чурилов Л.П. Руководство по аутоиммунным заболеваниям для врачей общей практики. Санкт-Петербург: Медкнига «ЭЛБИ», 2017. 416 с. Shoenfeld Y., Meroni P.L., Churilov L.P. Guide in Autoimmune Diseases for General Medical Practice. ELBI. 2017. https://elibrary.ru/item.asp?id=29379651Bachmaier K., Neu N., de La Maza L. M., Pal S., Hessel A., Penninger J. M. Chlamydia infections and heart disease linked through antigenic mimicry. Science, 1999, vol. 283, no. 5406, pp. 1335‑1339. https://www.science.org/doi/10.1126/science.283.5406.1335Campbell L. A., Kuo C. Chlamydia pneumoniae – an infectious risk factor for atherosclerosis? Nat. Rev. Microbiol., 2004, vol. 2, no. 1, pp. 23‑32. https://www.nature.com/articles/nrmicro796Chahine M.N., Deniset J., Dibrov E., Hirono S., Blackwood D.P., Austria J.A., Pierce G.N. Oxidized LDL promotes the mitogenic actions of Chlamydia pneumoniae in vascular smooth muscle cells. Cardiovasc. Res., 2011, vol. 92, no. 3, pp. 476‑483. https://academic.oup.com/cardiovascres/article-abstract/92/3/476/268702?redirectedFrom=fulltextChakravarti R., Gupta K., Swain M., Willard B., Scholtz J., Svensson L.G., Roselli E.E., Pettersson G., Johnston D.R., Soltesz E.G., Yamashita M., Stuehr D., Daly T.M., Hoffman G.S. 14‑3‑3 in Thoracic Aortic Aneurysms: Identification of a Novel Autoantigen in Large Vessel Vasculitis. Arthritis Rheumatol., 2015, vol. 67, no. 7, pp. 1913‑1921. https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.39130Chen W., Wang Y., Ren C., Yu S., Wang C., Xing J., Xu J., Yan S., Zhang T., Li Q., Peng X., Shao Y., Zhang R., Zhang D., Xing D. The role of TNC in atherosclerosis and drug development opportunities. Int. J. Biol. Sci., 2024, 20, no. 1, pp. 127‑136. https://www.ijbs.com/v20p0127.htmde Boer O. J., van der Wal A. C., Becker A. E. Atherosclerosis, inflammation, and infection. J. Pathol., 2000, vol. 190, no. 3, pp. 237‑243. https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/(SICI)1096-9896(200002)190:3%3C237::AID-PATH541%3E3.0.CO;2-NDi Pietro M., Filardo S., De Santis F., Sessa R. Chlamydia pneumoniae infection in atherosclerotic lesion development through oxidative stress: a brief overview. Int. J. Mol. Sci., 2013, vol. 14, no. 7, pp. 15105‑15120. https://www.mdpi.com/1422-0067/14/7/15105Edsfeldt A., Nilsson J. Understanding autoimmunity in atherosclerosis paves the way for novel therapies. Nat. Cardiovasc. Res., 2023, vol. 2, no. 3, pp. 227‑229. https://www.nature.com/articles/s44161-023-00230-0Fong I.W., Chiu B., Viira E., Jang D., Mahony J.B. De Novo induction of atherosclerosis by Chlamydia pneumoniae in a rabbit model. Infect. Immun., 1999, vol. 67, no. 11, pp. 6048‑55. https://journals.asm.org/doi/10.1128/iai.67.11.6048-6055.1999Gabriel A.S., Gnarpe H., Gnarpe J., Hallander H., Nyquist O., Martinsson A. The prevalence of chronic Chlamydia pneumoniae infection as detected by polymerase chain reaction in pharyngeal samples from patients with ischaemic heart disease. Eur. Heart. J., 1998, vol. 19, no. 9, pp. 1321‑1327. https://academic.oup.com/eurheartj/article-abstract/19/9/1321/578465?redirectedFrom=fulltextGaydos C.A., Summersgill J.T., Sahney N.N., Ramirez J.A., Quinn T.C. Replication of Chlamydia pneumoniae in vitro in human macrophages, endothelial cells, and aortic artery smooth muscle cells. Infect. Immun., 1996, vol. 64, no. 5, pp. 1614‑1620. https://journals.asm.org/doi/10.1128/iai.64.5.1614-1620.1996Getz G.S., Reardon C.A. Atherosclerosis: cell biology and lipoproteins. Curr. Opin. Lipidol., 2020, vol. 31, no.1, pp. 35‑37. https://journals.lww.com/co-lipidology/fulltext/2020/02000/atherosclerosis__cell_biology_and_lipoproteins.8.aspxGrayston J.T., Belland R.J., Byrne G.I., Kuo C.C., Schachter J., Stamm W.E., Zhong G. Infection with Chlamydia pneumoniae as a cause of coronary heart disease: the hypothesis is still untested. Pathog. Dis., 2015, vol. 73, no. 1, pp. 1‑9. https://academic.oup.com/femspd/article/73/1/1/2911545Hartley A., Haskard D., Khamis R. Oxidized LDL and anti‑oxidized LDL antibodies in atherosclerosis - Novel insights and future directions in diagnosis and therapy. Trends in Cardiovasc. Med., 2019, vol. 29, no. 1, pp. 22‑26. https://www.sciencedirect.com/science/article/abs/pii/S1050173818300835?via%3DihubHu C.J., Pan J.B., Song G., Wen X.T., Wu Z.Y., Chen S., Mo W.X., Zhang F.C., Qian J., Zhu H., Li Y.Z. Identification of Novel Biomarkers for Behcet Disease Diagnosis Using Human Proteome Microarray Approach. Mol. Cell. Proteomics, 2017, vol. 16, no. 2, pp. 147‑156. https://www.mcponline.org/article/S1535-9476(20)32432-4/fulltextHu H., Pierce G. N., Zhong G. The atherogenic effects of chlamydia are dependent on serum cholesterol and specific to Chlamydia pneumoniae. J. Clin. Invest., 1999, vol. 103, no. 5, pp. 747‑753. https://www.jci.org/articles/view/4582Kanduc D. Pentapeptides as minimal functional units in cell biology and immunology. Curr. Protein Pept. Sci., 2013, vol. 14, no. 2, pp. 111–120. https://www.eurekaselect.com/article/50579Kattoor A.J., Kanuri S.H., Mehta J.L. Role of Ox‑LDL and LOX‑1 in Atherogenesis. Curr. Med. Chem., 2019, vol. 26, no. 9, pp. 1693‑1700. https://www.eurekaselect.com/article/90252Khoshbayan A., Taheri F., Moghadam M.T., Chegini Z., Shariati A. The association of Chlamydia pneumoniae infection with atherosclerosis: Review and update of in vitro and animal studies. Microb. Pathog., 2021, vol. 154, pp. 104803. https://www.sciencedirect.com/science/article/abs/pii/S0882401021000759?via%3DihubLaitinen K., Laurila A., Pyhälä L., Leinonen M., Saikku P. Chlamydia pneumoniae infection induces inflammatory changes in the aortas of rabbits. Infect. Immun., 1997, vol. 65, no. 11, pp. 4832‑4835. https://journals.asm.org/doi/10.1128/iai.65.11.4832-4835.1997Lenz D. C., Lu L., Conant S.B., Wolf N.A., Gérard H.C., Whittum‑Hudson J.A., Hudson A.P., Swanborg R.H. A Chlamydia pneumoniae‑specific peptide induces experimental autoimmune encephalomyelitis in rats. The Journal of Immunology, 2001, vol. 167, no. 3, pp. 1803‑1808. https://academic.oup.com/jimmunol/article-abstract/167/3/1803/8025732?redirectedFrom=fulltextLu S., White J.V., Nwaneshiudu I., Nwaneshiudu A., Monos D.S., Solomides C.C., Oleszak E.L., Platsoucas C.D. Human abdominal aortic aneurysm (AAA): Evidence for an autoimmune antigen‑driven disease. Autoimmun. Rev., 2022, vol. 21, no. 10, pp. 103164. https://www.sciencedirect.com/science/article/abs/pii/S1568997222001343?via%3DihubMaoz‑Segal R., Andrade P. Molecular Mimicry and Autoimmunity. Infection and Autoimmunity, 2015, pp. 27‑44. https://www.sciencedirect.com/science/chapter/edited-volume/pii/B9780444632692000544?via%3DihubMatsunaga A., Harita Y., Shibagaki Y., Shimizu N., Shibuya K., Ono H., Kato H., Sekine T., Sakamoto N., Igarashi T., Hattori S. Identification of 4‑Trimethylaminobutyraldehyde Dehydrogenase (TMABA‑DH) as a Candidate Serum Autoantibody Target for Kawasaki Disease. PLoS One, 2015, vol. 10, no. 5, pp. e0128189. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128189Moazed T. C., Campbell L. A., Rosenfeld M. E., Grayston J. T., Kuo C. C. Chlamydia pneumoniae infection accelerates the progression of atherosclerosis in apolipoprotein E – deficient mice. J. Infect. Dis., 1999, vol. 180, no. 1, pp. 238‑241. https://academic.oup.com/jid/article-abstract/180/1/238/991320?redirectedFrom=fulltextMosorin M., Surcel H.M., Laurila A., Lehtinen M., Karttunen R., Juvonen J., Paavonen J., Morrison R.P., Saikku P., Juvonen T. Detection of Chlamydia pneumoniae–reactive T lymphocytes in human atherosclerotic plaques of carotid artery. Arteriosclerosis, thrombosis, and vascular biology, 2000, vol. 20, no. 4, pp. 1061‑1067. https://www.ahajournals.org/doi/10.1161/01.atv.20.4.1061?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmedMuhlestein J. B., Anderson J. L., Hammond E. H., Zhao L., Trehan S., Schwobe E. P., Carlquist J. F. Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation, 1998, vol. 97, no. 7, pp. 633‑636. https://www.ahajournals.org/doi/10.1161/01.CIR.97.7.633Mutoh T., Shirai T., Ishii T., Shirota Y., Fujishima F., Takahashi F., Kakuta Y., Kanazawa Y., Masamune A., Saiki Y., Harigae H., Fujii H. Identification of two major autoantigens negatively regulating endothelial activation in Takayasu arteritis. Nat. Commun., 2020, vol. 11, no. 1, pp. 1253. https://www.nature.com/articles/s41467-020-15088-0Nicholls S.J., Hazen S.L. Myeloperoxidase, modified lipoproteins, and atherogenesis. J. Lipid. Res., 2009, vol. 50, pp. S346‑S351. https://www.sciencedirect.com/science/article/pii/S0022227520306374Normatov M.G., Pakhomov V.A., Churilov L.P. “Alignmentaj” – a Tool For In Silico Prediction Of Similar Peptides Potentially Involved In Molecular Mimicry Phenomenon. Vestnik of Saint Petersburg University. Medicine, 2025, vol. 20, no. 1, pp. 96–101. https://medicine-journal.spbu.ru/article/view/18248Ozkan H. S., Kayikcioglu M. Atherosclerosis associated with Chlamydia pneumoniae: Dissecting the etiology: Chlamydia pneumoniae and atherosclerosis. European Atherosclerosis Journal, 2024, vol. 3, no. 2, pp. 30‑37. https://www.eathj.org/index.php/eaj/article/view/57Peabody M. A., Laird M. R., Vlasschaert C., Lo, R., Brinkman F. S. PSORTdb: expanding the bacteria and archaea protein subcellular localization database to better reflect diversity in cell envelope structures. Nucleic acids research, 2016, vol. 44, no. D1, pp. D663‑D668. https://academic.oup.com/nar/article/44/D1/D663/2503083Porsch F., Binder C.J. Autoimmune diseases and atherosclerotic cardiovascular disease. Nat. Rev. Cardiol., 2024, vol. 21, no. 11, pp. 780‑807. https://www.nature.com/articles/s41569-024-01045-7Ramos M., Alvarez I., Sesma L., Logean A., Rognan D., de Castro J. A. L. Molecular mimicry of an HLA‑B27‑derived ligand of arthritis‑linked subtypes with chlamydial proteins. Journal of Biological Chemistry, 2002, vol. 277, no. 40, pp. 37573‑37581. https://www.sciencedirect.com/science/article/pii/S0021925818364810Ravnskov U., McCully K. S. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann. Clin. Lab. Sci., 2009, vol. 39, no. 1, pp. 3‑16. https://www.annclinlabsci.org/content/39/1/3.longRojas M., Restrepo‑Jiménez P., Monsalve D.M., Pacheco Y., Acosta‑Ampudia Y., Ramírez‑Santana C., Leung P., Ansari A.A., Gershwin ME, Anaya JM. Molecular mimicry and autoimmunity. J. Autoimmun., 2018, vol. 95, pp. 100‑123. https://www.sciencedirect.com/science/article/pii/S0896841118305365?via%3DihubSanjadi M., Rezvanie Sichanie Z., Totonchi H., Karami J., Rezaei R., Aslani S. Atherosclerosis and autoimmunity: a growing relationship. Int. J. Rheum. Dis., 2018, vol. 21, no. 5, pp. 908‑921. https://onlinelibrary.wiley.com/doi/10.1111/1756-185X.13309Singh K., Prabhakaran D. Apolipoprotein B - An ideal biomarker for atherosclerosis? Indian Heart J., 2024, vol. 76, pp. S121‑S129.Tilson M.D. Similarities of an autoantigen in aneurysmal disease of the human abdominal aorta to a 36‑kDa microfibril‑associated bovine aortic glycoprotein. Biochem. Biophys. Res. Commun., 1995, vol. 213, no. 1, pp. 40‑43.Vink A., Pasterkamp G., Poppen M., Schoneveld A. H., de Kleijn D. P., Roholl P. J., Fontijn J., Plomp S., Borst C. The adventitia of atherosclerotic coronary arteries frequently contains Chlamydia pneumoniae. Atherosclerosis, 2001, vol. 157, no. 1, pp. 117‑122.Xia S., Ozsvath K., Hirose H., Tilson M.D. Partial amino acid sequence of a novel 40-kDa human aortic protein, with vitronectin-like, fibrinogen-like, and calcium binding domains: aortic aneurysm-associated protein-40 (AAAP-40) [human MAGP-3, proposed]. Biochem. Biophys. Res. Commun., 1996, vol. 219, pp. 36-39.Zhao X., Miao G., Zhang L., Zhang Y., Zhao H., Xu Z., Wang B., Zhang L. Chlamydia pneumoniae Infection Induces Vascular Smooth Muscle Cell Migration and Atherosclerosis Through Mitochondrial Reactive Oxygen Species-Mediated JunB-Fra-1 Activation. Front. Cell Dev. Biol., 2022, vol. 10, pp. 879023.