cardiovascularКардиоваскулярная терапия и профилактикаCardiovascular Therapy and Prevention1728-88002619-0125«SILICEA-POLIGRAF» LLC10.15829/1728-8800-2023-3711UOWPDTcardiovascular-3711Research ArticleБИОБАНКИРОВАНИЕBIOBANKINGИсследование особенностей метаболома пациентов с COVID-19Study of the metabolome features of patients with COVID-19https://orcid.org/0000-0003-1762-3055РусскихЯ. В.RusskikhY. V.

Яна Владимировна Русских — кандидат химических наук, специалист.

Сестрорецк

Sestroretsk

YANARUSSK@GMAIL.COMhttps://orcid.org/0000-0002-5100-5229СушенцеваН. Н.SushentsevaN. N.

Наталья Николаевна Сушенцева — начальник научно- исследовательской лаборатории трансляционной биомедицины научно- исследовательского отдела инновационных и конверсионных программ.

Сестрорецк

Sestroretsk

navicula@yandex.ruhttps://orcid.org/0000-0003-1778-0165ПоповО. С.PopovO. S.

Олег Сергеевич Попов — специалист, магистрант.

Сестрорецк, Санкт- Петербург

Sestroretsk

ospopov@outlook.comhttps://orcid.org/0000-0002-3853-4185АпалькоС. В.ApalkoS. V.

Светлана Вячеславовна Апалько — кандидат биологических наук, начальник научно- исследовательского отдела инновационных и конверсионных программ, старший научный сотрудник.

Сестрорецк, Санкт- Петербург

Sestroretsk

svetlana.apalko@gmail.comhttps://orcid.org/0000-0001-5642-621XАнисенковаА. Ю.AnisenkovaA. Yu.

Анна Юрьевна Анисенкова — врач-терапевт, кардиолог, доцент кафедры последипломного медицинского образования.

Сестрорецк, Санкт- Петербург

Sestroretsk

anna_anisenkova@list.ruhttps://orcid.org/0000-0002-1357-4324МосенкоС. В.MosenkoS. V.

Сергей Викторович Мосенко — врач-невролог, старший научный сотрудник.

Сестрорецк, Санкт- Петербург

Sestroretsk

neurologist@mail.ruhttps://orcid.org/0000-0003-3198-8990СаранаА. М.SaranaA. M.

Андрей Михайлович Сарана — доцент кафедры последипломного мед. образования, и.о. декана медицинского факультета, первый заместитель председателя Комитета по здравоохранению Правительства Санкт-Петербурга.

Санкт- Петербург

Sestroretsk

asarana@mail.ruhttps://orcid.org/0000-0001-5047-2792ЩербакС. Г.ShcherbakS. G.

Сергей Григорьевич Щербак — главный врач, профессор кафедры последипломного медицинского образования, заведующий кафедрой.

Сестрорецк, Санкт- Петербург

Sestroretsk

sgsherbak@mail.ruСПбГБУЗ "Городская больница № 40 Курортного района" Отдела здравоохранения Администрации Курортного района   г. Санкт-ПетербургаCity Hospital № 40 of the Kurortny DistrictСПбГБУЗ "Городская больница № 40 Курортного района" Отдела здравоохранения Администрации Курортного района   г. Санкт-Петербурга; ФГБОУ ВО "Санкт- Петербургский государственный университет"City Hospital № 40 of the Kurortny District; Saint­ Petersburg State UniversityФГБОУ ВО "Санкт- Петербургский государственный университет"; Комитет по здравоохранению Санкт-ПетербургаSaint­Petersburg State University; Health Committee of Saint­Petersburg2023101220232211Биобанкирование37113711Copyright © Русских Я.В., Сушенцева Н.Н., Попов О.С., Апалько С.В., Анисенкова А.Ю., Мосенко С.В., Сарана А.М., Щербак С.Г., 20232023Русских Я.В., Сушенцева Н.Н., Попов О.С., Апалько С.В., Анисенкова А.Ю., Мосенко С.В., Сарана А.М., Щербак С.Г.Russkikh Y.V., Sushentseva N.N., Popov O.S., Apalko S.V., Anisenkova A.Y., Mosenko S.V., Sarana A.M., Shcherbak S.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cardiovascular.elpub.ru/jour/article/view/3711Цель

Цель. Комплексный анализ особенностей метаболомного профиля пациентов с COVID-19 (COrona VIrus Disease 2019, новая коронавирусная инфекция) с использованием методов массспектрометрии и с учетом клинико-лабораторного анамнеза. Изучение связи между тяжестью симптомов COVID-19 и концентрацией первичных метаболитов, прежде всего аминокислот.

Материал и методы

Материал и методы. В ретроспективное исследование включены образцы сыворотки крови в общей сложности 935 человек (445 мужчин и 490 женщин) из коллекции биобанка СПб ГБУЗ "Городская больница № 40" из числа заболевших COVID-19. Во всех образцах хромато-масс-спектрометрическим методом было проведено исследование метаболомного профиля. Для статистической обработки данных использовался язык программирования R.

Результаты

Результаты. На основании проведенного анализа выявлено различие метаболического профиля пациентов с COVID-19 в зависимости от тяжести заболевания — для 52 из 84 обнаруженных соединений наблюдались различия с достоверностью p<0,01. Статистически значимые различия в концентрации зафиксированы для органических кислот, аминокислот и их производных.

Заключение

Заключение. С использованием образцов из коллекции биобанка было проведено метаболомное исследование биоматериала пациентов, госпитализированных с диагнозом COVID-19. Согласно полученным результатам, с тяжестью протекания COVID-19 ассоциированы кинуренин, фенилаланин и ацетилкарнитин. Выявлены различия метаболомного профиля у пациентов с цитокиновым штормом на момент взятия крови, определены метаболиты, подходящие под потенциальные биомаркеры развития цитокинового шторма.

Aim

Aim. To analyze the metabolomic profile of patients with coronavirus disease 2019 (COVID-19) using mass spectrometry methods and taking into account clinical and laboratory history. Studying the relationship between the severity of COVID-19 symptoms and the concentration of primary metabolites, primarily amino acids.

Material and methods

Material and methods. The retrospective study included serum samples from a total of 935 people (445 men and 490 women) with COVID-19 from the collection of the biobank of the City Hospital № 40. A metabolomic profile was studied in all samples using chromatography-mass spectrometry. The R language was used for statistical data processing.

Results

Results. Based on the analysis, a difference in the metabolic profile of patients with COVID-19 was identified depending on the disease severity — for 52 of the 84 detected compounds, differences were observed with a significance of p<0,01. Significant differences in concentration were recorded for organic acids, amino acids and their derivatives.

Conclusion

Conclusion. Using samples from the biobank collection, a metabolomic study of the biomaterial of patients hospitalized with a diagnosis of COVID-19 was carried out. According to the results obtained, kynurenine, phenylalanine and acetylcarnitine are associated with COVID-19 severity. Differences in the metabolomic profile were identified in patients with cytokine storm at the time of blood collection. Potential biomarkers for cytokine storm were identified.

биобанкCOVID-19метаболомный профильхромато-масс-спектрометрический анализцитокиновый штормbiobankCOVID-19metabolomic profilegas chromatography-mass spectrometry analysiscytokine stormReferencesChen X, Gu M, Li T, et al. Metabolite reanalysis revealed potential biomarkers for COVID­19: a potential link with immune response. Future Microbiol. 2021;16:577­88. doi:10.2217/fmb­2021­0047.Chen X, Gu M, Li T, et al. Metabolite reanalysis revealed potential biomarkers for COVID-19: a potential link with immune response. Future Microbiol. 2021;16:577-588. doi: 10.2217/fmb-2021-0047.Mierzchala­ Pasierb M, Lipinska­ Gediga M, Fleszar MG, et al. Altered profiles of serum amino acids in patients with sepsis and septic shock — Preliminary findings. Arch Biochem Biophys. 2020;30;691:108508. doi:10.1016/j.abb.2020.108508.Mierzchala-Pasierb M, Lipinska-Gediga M, Fleszar MG, et al. Altered profiles of serum amino acids in patients with sepsis and septic shock - Preliminary findings. Arch Biochem Biophys. 2020;30;691:108508. doi: 10.1016/j.abb.2020.108508.Costanzo M, Caterino M, Fedele R, et al. COVIDomics: The Proteomic and Metabolomic Signatures of COVID­19. Int J Mol Sci. 2022;22;23(5):2414. doi:10.3390/ijms23052414.Costanzo M, Caterino M, Fedele R, et al. COVIDomics: The Proteomic and Metabolomic Signatures of COVID-19. Int J Mol Sci. 2022; 22;23(5):2414. doi: 10.3390/ijms23052414.Beloborodova NV, Olenin AY, Pautova AK. Metabolomic findings in sepsis as a damage of host­microbial metabolism integration. J Crit Care. 2018;43:246­55. doi:10.1016/j.jcrc.2017.09.014.Beloborodova NV, Olenin AY, Pautova AK. Metabolomic findings in sepsis as a damage of host-microbial metabolism integration. J Crit Care. 2018;43:246-255. doi: 10.1016/j.jcrc.2017.09.014.Wan S, Xiang Y, Fang W, et al. Clinical features and treatment of COVID­19 patients in northeast Chongqing. J Med Virol. 2020;92(7):797­806. doi:10.1002/jmv.25783.Wan S, Xiang Y, Fang W, et al. Clinical features and treatment of COVID-19 patients in northeast Chongqing. J Med Virol. 2020;92(7):797-806. doi: 10.1002/jmv.25783.Atila A, Alay H, Yaman ME, et al. The serum amino acid profile in COVID­19. Amino Acids. 2021;53(10):1569­88. doi:10.1007/S00726­021­03081­w.Atila A, Alay H, Yaman ME, et al. The serum amino acid profile in COVID-19. Amino Acids. 2021;53(10):1569-1588. doi: 10.1007/s00726-021-03081-w.Whittaker A, Anson M, Harky A. Neurological Manifestations of COVID­19: A systematic review and current update. Acta Neurol Scand. 2020;142(1):14­22. doi:10.1111/ane.13266.Whittaker A, Anson M, Harky A. Neurological Manifestations of COVID-19: A systematic review and current update. Acta Neurol Scand. 2020 Jul;142(1):14-22. doi: 10.1111/ane.13266.Synakiewicz A, Stanislawska­ Sachadyn A, Sawicka­ Zukowska M, et al. Plasma free amino acid profiling as metabolomic diagnostic and prognostic biomarker in pediatric cancer patients: a follow­up study. Amino Acids. 2021;53(1):133­8. doi:10.1007/s00726­020­02910­8.Synakiewicz A, Stanislawska-Sachadyn A, Sawicka-Zukowska M, et al. Plasma free amino acid profiling as metabolomic diagnostic and prognostic biomarker in pediatric cancer patients: a follow-up study. Amino Acids. 2021;53(1):133-138. doi: 10.1007/s00726-020-02910-8.Philips AM, Khan N. Amino acid sensing pathway: a major check point in the pathogenesis of obesity and COVID­19. Obes Rev. 2021;22(4):e13221. doi:10.1111/obr.13221.Philips AM, Khan N. Amino acid sensing pathway: a major check point in the pathogenesis of obesity and COVID-19. Obes Rev. 2021;22(4):e13221. doi: 10.1111/obr.13221.Rees CA, Rostad CA, Mantus G, et al. Altered amino acid profile in patients with SARS­CoV­2 infection. Proc Natl Acad Sci USA. 2021;118(25):e2101708118. doi:10.1073/pnas.2101708118.Rees CA, Rostad CA, Mantus G, et al. Altered amino acid profile in patients with SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 2021;118(25):e2101708118. doi: 10.1073/pnas.2101708118.Paez­ Franco JC, Torres­ Ruiz J, Sosa­ Hernandez VA, et al. Metabolomics analysis reveals a modified amino acid metabolism that correlates with altered oxygen homeostasis in COVID­19 patients. Sci Rep. 2021;11(1):6350. doi:10.1038/s41598­021­85788­0.Paez-Franco JC, Torres-Ruiz J, Sosa-Hernandez VA, et al. Metabolomics analysis reveals a modified amino acid metabolism that correlates with altered oxygen homeostasis in COVID-19 patients. Sci Rep. 2021;11(1):6350. doi: 10.1038/s41598-021-85788-0.Song JW, Lam SM, Fan X, et al. Omics­driven systems interrogation of metabolic dysregulation in covid­19 pathogenesis. Cell Metab. 2020;32:1­15. doi:10.1016/j.cmet.2020.06.016.Song JW, Lam SM, Fan X, et al. Omics-driven systems interrogation of metabolic dysregulation in covid-19 pathogenesis. Cell Metab. 2020;32:1–15. doi: 10.1016/j.cmet.2020.06.016.Barberis E, Timo S, Amede E, et al. Large­ Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS­CoV­2. Int J Mol Sci. 2020;21(22):8623. doi:10.3390/ijms21228623.Barberis E, Timo S, Amede E, et al. Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2. Int J Mol Sci. 2020;21(22):8623. doi: 10.3390/ijms21228623.Danlos FX, Grajeda­ Iglesias C, Durand S, et al. Metabolomic analyses of COVID­19 patients unravel stage­ dependent and prognostic biomarkers. Cell Death Dis. 2021;12(3):258. doi:10.1038/S41419­021­03540­y.Danlos FX, Grajeda-Iglesias C, Durand S, et al. Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers. Cell Death Dis. 2021;12(3):258. doi: 10.1038/s41419-021-03540-y.Caterino M, Costanzo M, Fedele R, et al. The Serum Metabolome of Moderate and Severe COVID­19 Patients Reflects Possible Liver Alterations Involving Carbon and Nitrogen Metabolism. Int J Mol Sci. 2021;22(17):9548. doi:10.3390/ijms22179548.Caterino M, Costanzo M, Fedele R, et al. The Serum Metabolome of Moderate and Severe COVID-19 Patients Reflects Possible Liver Alterations Involving Carbon and Nitrogen Metabolism. Int J Mol Sci. 2021;22(17):9548. doi: 10.3390/ijms22179548.Shen B, Yi X, Sun Y, et al. Proteomic and Metabolomic Characterization of COVID­19 Patient Sera. Cell. 2020;182(1):59­72. e15. doi:10.1016/j.cell.2020.05.032.Shen B, Yi X, Sun Y, et al. Proteomic and Metabolomic Characterization of COVID-19 Patient Sera. Cell. 2020;182(1):59-72.e15. doi: 10.1016/j.cell.2020.05.032.Thomas T, Stefanoni D, Reisz JA, et al. COVID­19 infection alters kynurenine and fatty acid metabolism, correlating with IL­6 levels and renal status. JCI Insight. 2020;5(14):e140327. doi:10.1172/jci.insight.140327.Thomas T, Stefanoni D, Reisz JA, et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight. 2020;5(14):e140327. doi: 10.1172/jci.insight.140327.Ceballos FC, Virseda­ Berdices A, Resino S, et al. Metabolic Profiling at COVID­19 Onset Shows Disease Severity and Sex­ Specific Dysregulation. Front. Immunol. 2022;13:925558. doi:10.3389/fimmu.2022.925558.Ceballos FC, Virseda-Berdices A, Resino S, et al. Metabolic Profiling at COVID-19 Onset Shows Disease Severity and Sex-Specific Dysregulation. Front. Immunol. 2022;13:925558. doi: 10.3389/fimmu.2022.925558.Valdés A, Moreno LO, Rello SR, et al. Metabolomics study of COVID­19 patients in four different clinical stages. Sci Rep. 2022;12(1):1650. doi:10.1038/s41598­022­05667­0.Valdés A, Moreno LO, Rello SR, et al. Metabolomics study of COVID-19 patients in four different clinical stages. Sci Rep. 2022;12(1):1650. doi: 10.1038/s41598-022-05667-0.Maltais­ Payette I, Lajeunesse­ Trempe F, Pibarot P, et al. Association between Circulating Amino Acids and COVID­19 Severity. Metabolites. 2023;13(2):201. doi:10.3390/metabo13020201.Maltais-Payette I, Lajeunesse-Trempe F, Pibarot P, et al. Association between Circulating Amino Acids and COVID-19 Severity. Metabolites. 2023;13(2):201. doi: 10.3390/metabo13020201.Ozturk A, Bayraktar N, Bayraktar M, et al. Evaluation of amino acid profile in serum of patients with Covid­19 for providing a new treatment strategy. J Med Biochem. 2022;41(4):526­33. doi:10.5937/jomb0­37514.Ozturk A, Bayraktar N, Bayraktar M, et al. Evaluation of amino acid profile in serum of patients with Covid-19 for providing a new treatment strategy. J Med Biochem. 2022;41(4):526-533. doi: 10.5937/jomb0-37514.Stanifer ML, Kee C, Cortese M, et al. Critical Role of Type III Interferon in Controlling SARS­CoV­2 Infection in Human Intestinal Epithelial Cells. Cell Rep. 2020;32(1):107863. doi:10.1016/j.celrep.2020.107863.Stanifer M.L., Kee C., Cortese M., et al. Critical Role of Type III Interferon in Controlling SARS-CoV-2 Infection in Human Intestinal Epithelial Cells. Cell Rep. 2020;32(1):107863. doi: 10.1016/j.celrep.2020.107863.Danchin A, Marlière P. Cytosine drives evolution of SARS­CoV­2. Environ Microbiol. 2020;22(6):1977­85. doi:10.1111/1462­2920.15025.Danchin A, Marlière P. Cytosine drives evolution of SARS-CoV-2. Environ Microbiol. 2020 Jun;22(6):1977-1985. doi: 10.1111/1462-2920.15025.Perła­ Kaján J, Jakubowski H. COVID­19 and One­ Carbon Metabolism. Int J Mol Sci. 2022; 23(8):4181. doi:10.3390/ijms23084181.Perła-Kaján J, Jakubowski H. COVID-19 and One-Carbon Metabolism. International Journal of Molecular Sciences. 2022; 23(8):4181. doi: 10.3390/ijms23084181.Silvagno F, Vernone A, Pescarmona GP. The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID­19. Antioxidants. 2020;9(7):624. doi:10.3390/antiox9070624.Silvagno F, Vernone A, Pescarmona GP. The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19. Antioxidants. 2020; 9(7):624. doi: 10.3390/antiox9070624.Bramer LM, Hontz RD, Eisfeld AJ, et al. Multi­omics of NET formation and correlations with CNDP1, PSPB, and L­cystine levels in severe and mild COVID­19 infections. Heliyon. 2023;9(3):e13795. doi:10.1016/j.heliyon.2023.e13795.Bramer LM, Hontz RD, Eisfeld AJ, et al. Multi-omics of NET formation and correlations with CNDP1, PSPB, and L-cystine levels in severe and mild COVID-19 infections. Heliyon. 2023;9(3):e13795. doi: 10.1016/j.heliyon.2023.e13795.Páez­ Franco JC, Maravillas­ Montero JL, Mejía­ Domínguez NR, et al. Metabolomics analysis identifies glutamic acid and cystine imbalances in COVID­19 patients without comorbid conditions. Implications on redox homeostasis and COVID­19 pathophysiology. PLoS One. 2022;17(9):e0274910. doi:10.1371/journal.pone.0274910.Páez-Franco JC, Maravillas-Montero JL, Mejía-Domínguez NR, et al. Metabolomics analysis identifies glutamic acid and cystine imbalances in COVID-19 patients without comorbid conditions. Implications on redox homeostasis and COVID-19 pathophysiology. PLoS One. 2022;17(9):e0274910. doi: 10.1371/journal.pone.0274910.Galli F, Marcantonini G, Giustarini D, et al. How Aging and Oxidative Stress Influence the Cytopathic and Inflammatory Effects of SARS­CoV­2 Infection: The Role of Cellular Glutathione and Cysteine Metabolism. Antioxidants (Basel). 2022;11(7):1366. doi:10.3390/antiox11071366.Galli F, Marcantonini G, Giustarini D, et al. How Aging and Oxidative Stress Influence the Cytopathic and Inflammatory Effects of SARS-CoV-2 Infection: The Role of Cellular Glutathione and Cysteine Metabolism. Antioxidants (Basel). 2022;11(7):1366. doi: 10.3390/antiox11071366.Kryukov EV, Ivanov AV, Karpov VO, et al. Plasma S­Adenosylmethionine Is Associated with Lung Injury in COVID­19. Dis Markers. 2021;2021:7686374. doi:10.1155/2021/7686374.Kryukov EV, Ivanov AV, Karpov VO, et al.. Plasma S-Adenosylmethionine Is Associated with Lung Injury in COVID-19. Dis Markers. 2021;2021:7686374. doi: 10.1155/2021/7686374.Cai Y, Kim DJ, Takahashi T, et al. Kynurenic acid may underlie sexspecific immune responses to COVID­19. Sci Signal. 2021;14. eabf8483. doi:10.1126/scisignal.abf8483.Cai Y, Kim DJ, Takahashi T, et al. Kynurenic acid may underlie sex-specific immune responses to COVID-19.Sci. Signal. 2021;14,eabf8483. doi: 10.1126/scisignal.abf8483.

The authors declare that there are no conflicts of interest present.