Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI194710.15789/2220-7619-MBM-1947REVIEWSОБЗОРЫReview ArticleMetabolic biological markers for diagnosing and monitoring the course of tuberculosisМетаболические биологические маркеры диагностики и мониторинга течения туберкулезаKorotetskayaM. V.КоротецкаяМ. В.
Russian Federation

PhD (Biology), Senior Researcher, Laboratory of Immunogenetics

к.б.н., старший научный сотрудник лаборатории иммуногенетики отдела иммунологии

mkorotetskaya@gmail.comRubakovaE. I.РубаковаЭ. И.
Russian Federation

PhD (Biology), Senior Researcher, Laboratory of Immunogenetics, Department of Immunology

к.б.н., старший научный сотрудник лаборатории иммуногенетики отдела иммунологии

rubakova@mail.ruCentral Research Institute of TuberculosisФГБНУ Центральный научно-исследовательский институт туберкулезаLomonosov Moscow State UniversityМосковский государственный университет имени М.В. Ломоносова29062022161120221258278361105202219062022Copyright ©; 2022, Korotetskaya M.V., Rubakova E.I.Copyright ©; 2022, Коротецкая М.В., Рубакова Э.И.2022Korotetskaya M.V., Rubakova E.I.Коротецкая М.В., Рубакова Э.И.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/1947

The international biomedical community has been currently facing a need to find a simple and most accessible type of analysis that helps to diagnose tuberculosis (TB) with the maximum reliability even before the onset of clinical manifestations. Tuberculosis results in more deaths than any other pathogen, second only to pneumonia caused by the SARS-CoV-2 virus, but the majority of infected people remain asymptomatic. In addition, it is important to develop methods to distinguish various forms of tuberculosis infection course at early stages and to reliably stratify patients into appropriate groups (persons with a rapidly progressing infection, chronic course, latent infection carriers). Immunometabolism investigates a relationship between bioenergetic pathways and specific functions of immune cells that has recently become increasingly important in scientific research. The host anti-mycobacteria immune response in tuberculosis is regulated by a number of metabolic networks that can interact both cooperatively and antagonistically, influencing an outcome of the disease. The balance between inflammatory and immune reactions limits the spread of mycobacteria in vivo and protects from developing tuberculosis. Cytokines are essential for host defense, but if uncontrolled, some mediators may contribute to developing disease and pathology. Differences in plasma levels of metabolites between individuals with advanced infection, LTBI and healthy individuals can be detected long before the onset of the major related clinical signs. Changes in amino acid and cortisol level may be detected as early as 12 months before the onset of the disease and become more prominent at verifying clinical diagnosis. Assessing serum level of certain amino acids and their ratios may be used as additional diagnostic markers of active pulmonary TB. Metabolites, including serum fatty acids, amino acids and lipids may contribute to detecting active TB. Metabolic profiles indicate about increased indolamine 2.3-dioxygenase 1 (IDO1) activity, decreased phospholipase activity, increased adenosine metabolite level, and fibrous lesions in active vs. latent infection. TB treatment can be adjusted based on individual patient metabolism and biomarker profiles. Thus, exploring immunometabolism in tuberculosis is necessary for development of new therapeutic strategies.

Перед международным медико-биологическим сообществом в настоящее время стоит вопрос о поиске наиболее простого и доступного типа анализа, помогающего с максимальной достоверностью диагностировать туберкулез (ТБ) еще до появления клинических проявлений. Туберкулез вызывает больше смертей, чем любое другое заболевание, уступая только пневмонии, вызванной вирусом SARS-CoV-2, однако большинство инфицированных людей переносят его бессимптомно. Кроме того, важно разработать методы, позволяющие отличить на ранних стадиях различные формы течения туберкулезной инфекции и достоверно разделить пациентов по соответствующим группам (лица с быстро прогрессирующей инфекцией, хроническим течением, латентные носители инфекции). В последнее время все большее значение в научных исследованиях придается изучению иммунометаболизма, т. е. взаимосвязи между биоэнергетическими путями и специфическими функциями иммунных клеток. Иммунный ответ хозяина на микобактерии при туберкулезе регулируется рядом метаболических сетей, которые могут действовать как совместно, так и антагонистически, влияя на исход заболевания. Баланс воспалительных и иммунных реакций ограничивает распространение микобактерий в организме и обеспечивает протекцию организма от развития туберкулеза. Цитокины необходимы для защиты хозяина, но если не контролировать их концентрацию, некоторые медиаторы могут способствовать развитию заболевания и патологии. Различия в содержании метаболитов в плазме крови между лицами с прогрессирующей инфекцией, ЛТБИ и здоровыми могут выявляться задолго до появления основных клинических признаков заболевания. Изменения содержания аминокислот и кортизола могут быть обнаружены еще за 12 месяцев до начала заболевания и становятся сильнее на стадии постановки клинического диагноза. Определение содержания некоторых аминокислот и их соотношений в плазме крови может быть использовано в качестве дополнительных диагностических маркеров активного ТБ легких. Метаболиты, включающие жирные кислоты, аминокислоты и липиды в плазме крови, могут способствовать выявлению активного ТБ. Метаболические профили указывают на повышенную активность индоламин-2,3-диоксигеназы 1 (IDO1), снижение активности фосфолипазы, увеличение количества продуктов метаболизма аденозина, а также на показатели фиброзных поражений при активном заболевании по сравнению с латентной инфекцией. Лечение туберкулеза может быть скорректировано на основе индивидуальных особенностей метаболизма пациентов и профиля биомаркеров. Изучение иммунометаболизма при туберкулезе необходимо для разработки новых терапевтических стратегий.

tuberculosisimmune responsemetabolismenzymeslipid mediatorseicosanoidsтуберкулезиммунный ответметаболизмферментылипидные медиаторыэйкозаноидыAdu-Gyamfi C.G., Snyman T., Makhathini L., Otwombe K., Darboe F., Penn-Nicholson A., Fisher M., Savulescu D., Hoffmann C., Chaisson R., Martinson N., Scriba T.J., George J.A., Suchard M.S. Diagnostic accuracy of plasma kynurenine/tryptophan ratio, measured by enzyme-linked immunosorbent assay, for pulmonary tuberculosis. Int. J. Infect. Dis., 2020, vol. 99, pp. 441–448. doi: 10.1016/j.ijid.2020.08.028Almeida A.S., Lago P.M., Boechat N., Huard R.C., Lazzarini L.C., Santos A.R., Nociari M., Zhu H., Perez-Sweeney B.M., Bang H., Ni Q., Huang J., Gibson A.L., Flores V.C., Pecanha L.R., Kritski A.L., Lapa e Silva J.R., Ho J.L. Tuberculosis is associated with a down-modulatory lung immune response that impairs Th1-type immunity. J. Immunol., 2009, vol. 183, no. 1, pp. 718–731. doi: 10.4049/jimmunol.0801212Apt A.S., Logunova N.N., Kondratieva T.K. Host genetics in susceptibility to and severity of mycobacterial diseases. Tuberculosis (Edinb.), 2017, vol. 106, pp. 1–8. doi: 10.1016/j.tube.2017.05.004Bafica A., Scanga C.A., Serhan C., Machado F., White S., Sher A., Aliberti J. Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. J. Clin. Invest., 2005, vol. 115, no. 6, pp. 1601–1606. doi: 10.1172/JCI23949Behar S.M., Divangahi M., Remold H.G. Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy? Nat. Rev. Microbiol., 2010, vol. 8, no. 9, pp. 668–674. doi: 10.1038/nrmicro2387Behr M.A., Wilson M.A., Gill W.P., Salamon H., Schoolnik G.K., Rane S., Small P.M. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science, 1999, vol. 284, no. 5419, pp. 1520–1523. doi: 10.1126/science.284.5419.1520Blumenthal A., Nagalingam G., Huch J.H., Walker L., Guillemin G.J., Smythe G.A., Ehrt S., Britton W.J., Saunders B.M. M. tuberculosis induces potent activation of IDO-1, but this is not essential for the immunological control of infection. PLoS One, 2012, vol. 7, no. 5: e37314. doi: 10.1371/journal.pone.0037314Byrne S.T., Denkin S.M., Zhang Y. Aspirin and ibuprofen enhance pyrazinamide treatment of murine tuberculosis. J. Antimicrob. Chemother., 2007, vol. 59, no. 2, pp. 313–316. doi: 10.1093/jac/dkl486Ca J., Bm M., Pinnelli V.B., Kandi V., As S., Mathew H.A., Gundreddy H., Afreen F., Vadakedath S. The association of pulmonary tuberculosis, abnormal glucose tolerance, and type 2 diabetes mellitus: a hospital-based cross-sectional study. Cureus, 2021, vol. 13, no. 11: e19758. doi: 10.7759/cureus.19758Cai Y., Yang Q., Tang Y., Zhang M., Liu H., Zhang G., Deng Q., Huang J., Gao Z., Zhou B., Feng C.G., Chen X. Increased complement C1q level marks active disease in human tuberculosis. PLoS One, 2014, vol. 9, no. 3: e92340. doi: 10.1371/journal.pone.0092340Calder P.C. Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance. Biochim. Biophys. Acta, 2015, vol. 1851, no. 4, pp. 469–484. doi: 10.1016/j.bbalip.2014.08.010Chen M., Divangahi M., Gan H., Shin D.S., Hong S., Lee D.M., Serhan C.N., Behar S.M., Remold H.G. Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death. J. Exp. Med., 2008, vol. 205, no. 12, pp. 2791–2801. doi: 10.1084/jem.20080767Chendi B.H., Snyders C.I., Tonby K., Jenum S., Kidd M., Walzl G., Chegou N.N., Dyrhol-Riise A.M. A plasma 5-marker host biosignature identifies tuberculosis in high and low endemic countries. Front. Immunol., 2021, vol. 12: 608846. doi: 10.3389/fimmu.2021.608846Cho Y., Park Y., Sim B., Kim J., Lee H., Cho S.N., Kang Y.A., Lee S.G. Identification of serum biomarkers for active pulmonary tuberculosis using a targeted metabolomics approach. Sci. Rep., 2020, vol. 10, no. 1: 3825. doi: 10.1038/s41598-020-60669-0Conde R., Laires R., Gonçalves L.G., Rizvi A., Barroso C., Villar M., Macedo R., Simões M.J., Gaddam S., Lamosa P., Puchades-Carrasco L., Pineda-Lucena A., Patel A.B., Mande S.C., Banerjee S., Matzapetakis M., Coelho A.V. Discovery of serum biomarkers for diagnosis of tuberculosis by NMR metabolomics including cross-validation with a second cohort. Biomed. J., 2022, vol. 45, iss. 4, pp. 654–664. doi: 10.1016/j.bj.2021.07.006Cooper A.M. Cell-mediated immune responses in tuberculosis. Annu. Rev. Immunol., 2009, vol. 27, pp. 393–422. doi: 10.1146/annurev.immunol.021908.132703Cooper A.M., Magram J., Ferrante J., Orme I.M. Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with mycobacterium tuberculosis. J. Exp. Med., 1997, vol. 186, no. 1, pp. 39–45. doi: 10.1084/jem.186.1.39Cooper A.M., Mayer-Barber K.D., Sher A. Role of innate cytokines in mycobacterial infection. Mucosal Immunol., 2011, vol. 4, no. 3, pp. 252–260. doi: 10.1038/mi.2011.13Corbel M., Theret N., Caulet-Maugendre S., Germain N., Lagente V., Clement B., Boichot E. Repeated endotoxin exposure induces interstitial fibrosis associated with enhanced gelatinase (MMP-2 and MMP-9) activity. Inflamm. Res., 2001, vol. 50, no. 3, pp. 129–135. doi: 10.1007/s000110050736Coussens A., Timms P.M., Boucher B.J., Venton T.R., Ashcroft A.T., Skolimowska K.H., Newton S.M., Wilkinson K.A., Davidson R.N., Griffiths C.J., Wilkinson R.J., Martineau A.R. 1alpha,25-dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection. Immunology, 2009, vol. 127, no. 4, pp. 539–548. doi: 10.1111/j.1365-2567.2008.03024.xCumming B.M., Pacl H.T., Steyn A.J.C. Relevance of the Warburg effect in tuberculosis for host-directed therapy. Front. Cell Infect. Microbiol., 2020, vol. 10: 576596. doi: 10.3389/fcimb.2020.576596Dey B., Bishai W.R. Crosstalk between Mycobacterium tuberculosis and the host cell. Semin Immunol., 2014, vol. 26, no. 6, pp. 486–496. doi: 10.1016/j.smim.2014.09.002Ding Y., Raterink R.J., Marín-Juez R., Veneman W.J., Egbers K., van den Eeden S., Haks M.C., Joosten S.A., Ottenhoff T.H.M., Harms A.C., Alia A., Hankemeier T., Spaink H.P. Tuberculosis causes highly conserved metabolic changes in human patients, mycobacteria-infected mice and zebrafish larvae. Sci. Rep., 2020, vol. 10, no. 1: 11635. doi: 10.1038/s41598-020-68443-yDorhoi A., Yeremeev V., Nouailles G., Weiner J. 3rd, Jörg S., Heinemann E., Oberbeck-Müller D., Knaul J.K., Vogelzang A., Reece S.T., Hahnke K., Mollenkopf H.J., Brinkmann V., Kaufmann S.H. Type I IFN signaling triggers immunopathology in tuberculosis-susceptible mice by modulating lung phagocyte dynamics. Eur. J. Immunol., 2014, vol. 44, no. 8, pp. 2380–2393. doi: 10.1002/eji.201344219Dutta N.K., Annadurai S., Mazumdar K., Dastidar S.G., Kristiansen J.E., Molnar J., Martins M., Amaral L. Potential management of resistant microbial infections with a novel non-antibiotic: the anti-inflammatory drug diclofenac sodium. Int. J. Antimicrob. Agents, 2007, vol. 30, no. 3, pp. 242–249. doi: 10.1016/j.ijantimicag.2007.04.018Dutta N.K., Karakousis P.C. Latent tuberculosis infection: myths, models, and molecular mechanisms. Microbiol. Mol. Biol. Rev., 2014, vol. 78, no. 3, pp. 343–371. doi: 10.1128/MMBR.00010-14Ehlers S., Schaible U.E. The granuloma in tuberculosis: dynamics of a host-pathogen collusion. Front. Immunol., 2013, vol. 3: 411. doi: 10.3389/fimmu.2012.00411Elkington P.T., Ugarte-Gil C.A., Friedland J.S. Matrix metalloproteinases in tuberculosis. Eur. Respir. J., 2011, vol. 38, no. 2, pp. 456–464. doi: 10.1183/09031936.00015411Flores J., Cancino J.C., Chavez-Galan L. Lipoarabinomannan as a point-of-care assay for diagnosis of tuberculosis: how far are we to use it? Front. Microbiol., 2021, vol. 12: 638047. doi: 10.3389/fmicb.2021.638047Flynn J.L., Chan J., Triebold K.J., Dalton D.K., Stewart T.A., Bloom B.R. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J. Exp. Med., 1993, vol. 178, no. 6, pp. 2249–2254. doi: 10.1084/jem.178.6.2249Flynn J.L., Goldstein M.M., Chan J., Triebold K.J., Pfeffer K., Lowenstein C.J., Schreiber R., Mak T.W., Bloom B.R. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity, 1995, vol. 2, no. 6, pp. 561–572. doi: 10.1016/1074-7613(95)90001-2Ganguly N., Siddiqui I., Sharma P. Role of M. tuberculosis RD-1 region encoded secretory proteins in protective response and virulence. Tuberculosis (Edinb.), 2008, vol. 88, no. 6, pp. 510–517. doi: 10.1016/j.tube.2008.05.002Gey Van Pittius N.C., Gamieldien J., Hide W., Brown G.D., Siezen R.J., Beyers A.D. The ESAT-6 gene cluster of Mycobacterium tuberculosis and other high G+C Gram-positive bacteria. Genome Biol., 2001, vol. 2, no. 10: RESEARCH0044. doi: 10.1186/gb-2001-2-10-research0044Guggino G., Orlando V., Cutrera S., La Manna M.P., Di Liberto D., Vanini V., Petruccioli E., Dieli F., Goletti D., Caccamo N. Granzyme A as a potential biomarker of Mycobacterium tuberculosis infection and disease. Immunol. Lett., 2015, vol. 166, no. 2, pp. 87–91. doi: 10.1016/j.imlet.2015.05.019Hamasur B., Bruchfeld J., Haile M., Pawlowski A., Bjorvatn B., Källenius G., Svenson S.B. Rapid diagnosis of tuberculosis by detection of mycobacterial lipoarabinomannan in urine. J. Microbiol. Methods, 2001, vol. 45, no. 1, pp. 41–52. doi: 10.1016/s0167-7012(01)00239-1Hayashi S., Takeuchi M., Hatsuda K., Ogata K., Kurata M., Nakayama T., Ohishi Y., Nakamura H. The impact of nutrition and glucose intolerance on the development of tuberculosis in Japan. Int. J. Tuberc. Lung Dis., 2014, vol. 18, no. 1, pp. 84–88. doi: 10.5588/ijtld.13.0495Hunter R.L. Pathology of post primary tuberculosis of the lung: an illustrated critical review. Tuberculosis (Edinb.), 2011, vol. 91, no. 6, pp. 497–509. doi: 10.1016/j.tube.2011.03.007Juffermans N.P., Florquin S., Camoglio L., Verbon A., Kolk A.H., Speelman P., van Deventer S.J., van der Poll T. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J. Infect. Dis., 2000, vol. 182, no. 3, pp. 902–908. doi: 10.1086/315771Kapina M.A., Shepelkova G.S., Avdeenko V.G., Guseva A.N., Kondratieva T.K., Evstifeev V.V., Apt A.S. Interleukin-11 drives early lung inflammation during Mycobacterium tuberculosis infection in genetically susceptible mice. PLoS One, 2011, vol. 6, no. 7: e21878. doi: 10.1371/journal.pone.0021878Karim A.F., Sande O.J., Tomechko S.E., Ding X., Li M., Maxwell S., Ewing R.M., Harding C.V., Rojas R.E., Chance M.R., Boom W.H. Proteomics and network analyses reveal inhibition of Akt-mTOR signaling in CD4+ T cells by Mycobacterium tuberculosis mannose-capped lipoarabinomannan. Proteomics, 2017, vol. 17, no. 22: 1700233. doi: 10.1002/pmic.201700233Karinch A.M., Pan M., Lin C.M., Strange R., Souba W.W. Glutamine metabolism in sepsis and infection. J. Nutr., 2001, vol. 131 (9 Suppl), pp. 2535S–2538S; discussion 2550S–2551S. doi: 10.1093/jn/131.9.2535SKeane J., Remold H.G., Kornfeld H. Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages. J. Immunol., 2000, vol. 164, no. 4, pp. 2016–20. doi: 10.4049/jimmunol.164.4.2016Kroesen V.M., Gröschel M.I., Martinson N., Zumla A., Maeurer M., van der Werf T.S., Vilaplana C. Non-steroidal anti-inflammatory drugs as host-directed therapy for tuberculosis: a systematic review. Front. Immunol., 2017, vol. 8: 772. doi: 10.3389/fimmu.2017.00772Krug S., Parveen S., Bishai W.R. Host-directed therapies: modulating inflammation to treat tuberculosis. Front. Immunol., 2021, vol. 12: 660916. doi: 10.3389/fimmu.2021.660916Kübler A., Luna B., Larsson C., Ammerman N.C., Andrade B.B., Orandle M., Bock K.W., Xu Z., Bagci U., Mollura D.J., Marshall J., Burns J., Winglee K., Ahidjo B.A., Cheung L.S., Klunk M., Jain S.K., Kumar N.P., Babu S., Sher A., Friedland J.S., Elkington P.T., Bishai W.R. Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. J. Pathol., 2015, vol. 235, no. 3, pp. 431–444. doi: 10.1002/path.4432Lewinsohn D.M., Grotzke J.E., Heinzel A.S., Zhu L., Ovendale P.J., Johnson M., Alderson M.R. Secreted proteins from Mycobacterium tuberculosis gain access to the cytosolic MHC class-I antigen-processing pathway. J. Immunol., 2006, vol. 177, no. 1, pp. 437–442. doi: 10.4049/jimmunol.177.1.437Linge I., Tsareva A., Kondratieva E., Dyatlov A., Hidalgo J., Zvartsev R., Apt A. Pleiotropic Effect of IL-6 produced by B-lymphocytes during early phases of adaptive immune responses against TB infection. Front. Immunol., 2022, vol. 13: 750068. doi: 10.3389/fimmu.2022.750068Logunova N., Korotetskaya M., Apt A. Analysis of gene expression in the lung tissue in mice congenic as per H2-line complex with various severity of tuberculous infection course. Tuberculosis and Lung Diseases, 2015, vol. 12, pp. 44–49.Lubbers R., Sutherland J.S., Goletti D., de Paus R.A., van Moorsel C.H.M., Veltkamp M., Vestjens S.M.T., Bos W.J.W., Petrone L., Del Nonno F., Bajema I.M., Dijkman K., Verreck F.A.W., Walzl G., Gelderman K.A., Groeneveld G.H., Geluk A., Ottenhoff T.H.M., Joosten S.A., Trouw L.A. Complement component C1q as serum biomarker to detect active tuberculosis. Front. Immunol., 2018, vol. 9: 2427. doi: 10.3389/fimmu.2018.02427Maurya R., Bhattacharya P., Dey R., Nakhasi H.L. Leptin functions in infectious diseases. Front. Immunol., 2018, vol. 9: 2741. doi: 10.3389/fimmu.2018.02741Mayer-Barber K.D., Andrade B.B., Barber D.L., Hieny S., Feng C.G., Caspar P., Oland S., Gordon S., Sher A. Innate and adaptive interferons suppress IL-1 and IL-1 production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection. Immunity, 2011, vol. 35, no. 6, pp. 1023–1034. doi: 10.1016/j.immuni.2011.12.002Mayer-Barber K.D., Andrade B.B., Oland S.D., Amaral E.P., Barber D.L., Gonzales J., Derrick S.C., Shi R., Kumar N.P., Wei W., Yuan X., Zhang G., Cai Y., Babu S., Catalfamo M., Salazar A.M., Via L.E., Barry C.E. 3rd, Sher A. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature, 2014, vol. 511, no. 7507, pp. 99–103. doi: 10.1038/nature13489Mayer-Barber K.D., Sher A. Cytokine and lipid mediator networks in tuberculosis. Immunol. Rev., 2015, vol. 264, no. 1, pp. 264–275. doi: 10.1111/imr.12249Mehrotra P., Jamwal S.V., Saquib N., Sinha N., Siddiqui Z., Manivel V., Chatterjee S., Rao K.V. Pathogenicity of Mycobacterium tuberculosis is expressed by regulating metabolic thresholds of the host macrophage. PLoS Pathog., 2014, vol. 10, no. 7: e1004265. doi: 10.1371/journal.ppat.1004265Nienaber A., Baumgartner J., Dolman R.C., Ozturk M., Zandberg L., Hayford F.E.A., Brombacher F., Blaauw R., Parihar S.P., Smuts C.M., Malan L. Omega-3 fatty acid and iron supplementation alone, but not in combination, lower inflammation and anemia of infection in Mycobacterium tuberculosis-infected mice. Nutrients, 2020, vol. 12, no. 9: 2897. doi: 10.3390/nu12092897Nienaber A., Hayford F.E.A., Variava E., Martinson N., Malan L. The manipulation of the lipid mediator metabolism as adjunct host-directed therapy in tuberculosis. Front. Immunol., 2021, vol. 12: 623941. doi: 10.3389/fimmu.2021.623941Novikov A., Cardone M., Thompson R., Shenderov K., Kirschman K.D., Mayer-Barber K.D., Myers T.G., Rabin R.L., Trinchieri G., Sher A., Feng C.G. Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL-1 production in human macrophages. J. Immunol., 2011, vol. 187, no. 5, pp. 2540–2547. doi: 10.4049/jimmunol.1100926O’Garra A., Redford P.S., McNab F.W., Bloom C.I., Wilkinson R.J., Berry M.P. The immune response in tuberculosis. Annu. Rev. Immunol. 2013, vol. 31, pp. 475–527. doi: 10.1146/annurev-immunol-032712-095939Oliveira G.P., de Abreu M.G., Pelosi P., Rocco P.R. Exogenous glutamine in respiratory diseases: myth or reality? Nutrients, 2016, vol. 8, no. 2: 76. doi: 10.3390/nu8020076Ong C.W., Elkington P.T., Friedland J.S. Tuberculosis, pulmonary cavitation, and matrix metalloproteinases. Am. J. Respir. Crit. Care Med., 2014, vol. 190, no. 1, pp. 9–18. doi: 10.1164/rccm.201311-2106PPOsawa T., Watanabe M., Morimoto K., Okumura M., Yoshiyama T., Ogata H., Goto H., Kudoh S., Ohta K., Sasaki Y. Serum procalcitonin levels predict mortality risk in patients with pulmonary tuberculosis: a single-center prospective observational study. J. Infect. Dis., 2020, vol. 222, no. 10, pp. 1651–1654. doi: 10.1093/infdis/jiaa275Pathak S.K., Basu S., Basu K.K., Banerjee A., Pathak S., Bhattacharyya A., Kaisho T., Kundu M., Basu J. Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. Nat. Immunol., 2007, vol. 8, no. 6, pp. 610–618. doi: 10.1038/ni1468Palčeková Z., Gilleron M., Angala S.K., Belardinelli J.M., McNeil M., Bermudez L.E., Jackson M. Polysaccharide succinylation enhances the intracellular survival of Mycobacterium abscessus. ACS Infect. Dis., 2020, vol. 6, no. 8, pp. 2235–2248. doi: 10.1021/acsinfecdis.0c00361Pavlicek R.L., Fine-Coulson K., Gupta T., Quinn F.D., Posey J.E., Willby M., Castro-Garza J., Karls R.K. Rv3351c, a Mycobacterium tuberculosis gene that affects bacterial growth and alveolar epithelial cell viability. Can. J. Microbiol., 2015, vol. 61, no. 12, pp. 938–947. doi: 10.1139/cjm-2015-0528Rasmussen T.A., Søgaard O.S., Camara C., Andersen P.L., Wejse C. Serum procalcitonin in pulmonary tuberculosis. Int. J. Tuberc. Lung Dis., 2011, vol. 15, no. 2, pp. 251–256.Ritter K., Rousseau J., Hölscher C. The role of gp130 cytokines in tuberculosis. Cells, 2020, vol. 9, no. 12: 2695. doi: 10.3390/cells9122695Rodrigues T.S., Conti B.J., Fraga-Silva T.F.C., Almeida F., Bonato V.L.D. Interplay between alveolar epithelial and dendritic cells and Mycobacterium tuberculosis. J. Leukoc. Biol., 2020, vol. 108, no. 4, pp. 1139–1156. doi: 10.1002/JLB.4MR0520-112RRussell D.G. Who puts the tubercle in tuberculosis? Nat. Rev. Microbiol., 2007, vol. 5, no. 1, pp. 39–47. doi: 10.1038/nrmicro1538Sada E., Aguilar D., Torres M., Herrera T. Detection of lipoarabinomannan as a diagnostic test for tuberculosis. J. Clin. Microbiol., 1992, vol. 30, no. 9, pp. 2415–2418. doi: 10.1128/jcm.30.9.2415-2418.1992Sande O.J., Karim A.F., Li Q., Ding X., Harding C.V., Rojas R.E., Boom W.H. Mannose-capped lipoarabinomannan from Mycobacterium tuberculosis induces CD4+ T cell anergy via GRAIL. J. Immunol., 2016, vol. 196, no. 2, pp. 691–702. doi: 10.4049/jimmunol.1500710Selvaraj P., Jawahar M.S., Rajeswari D.N., Alagarasu K., Vidyarani M., Narayanan P.R. Role of mannose binding lectin gene variants on its protein levels and macrophage phagocytosis with live Mycobacterium tuberculosis in pulmonary tuberculosis. FEMS Immunol. Med. Microbiol., 2006, vol. 46, no. 3, pp. 433–437. doi: 10.1111/j.1574-695X.2006.00053.xShi L., Eugenin E.A., Subbian S. Immunometabolism in tuberculosis. Front. Immunol., 2016, vol. 7: 150. doi: 10.3389/fimmu.2016.00150Singh V., Donini S., Pacitto A., Sala C., Hartkoorn R.C., Dhar N., Keri G., Ascher D.B., Mondésert G., Vocat A., Lupien A., Sommer R., Vermet H., Lagrange S., Buechler J., Warner D.F., McKinney J.D., Pato J., Cole S.T., Blundell T.L., Rizzi M., Mizrahi V. The inosine monophosphate dehydrogenase, guaB2, is a vulnerable new bactericidal drug target for tuberculosis. ACS Infect. Dis., 2017, vol. 3, no. 1, pp. 5–17. doi: 10.1021/acsinfecdis.6b00102Singh V., Kaur C., Chaudhary V.K., Rao K.V., Chatterjee S. M. tuberculosis secretory protein ESAT-6 induces metabolic flux perturbations to drive foamy macrophage differentiation. Sci. Rep., 2015, vol. 5: 12906. doi: 10.1038/srep12906Søborg C., Madsen H.O., Andersen A.B., Lillebaek T., Kok-Jensen A., Garred P. Mannose-binding lectin polymorphisms in clinical tuberculosis. J. Infect. Dis., 2003, vol. 188, no. 5, pp. 777–782. doi: 10.1086/377183Stanley S.A., Raghavan S., Hwang W.W., Cox J.S. Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system. Proc. Natl. Acad. Sci. USA, 2003, vol. 100, no. 22, pp. 13001–13006. doi: 10.1073/pnas.2235593100Suzuki Y., Miwa S., Akamatsu T., Suzuki M., Fujie M., Nakamura Y., Inui N., Hayakawa H., Chida K., Suda T. Indoleamine 2,3-dioxygenase in the pathogenesis of tuberculous pleurisy. Int. J. Tuberc. Lung Dis., 2013, vol. 17, no. 11, pp. 1501–1506. doi: 10.5588/ijtld.13.0082Suzuki Y., Suda T., Asada K., Miwa S., Suzuki M., Fujie M., Furuhashi K., Nakamura Y., Inui N., Shirai T., Hayakawa H., Nakamura H., Chida K. Serum indoleamine 2,3-dioxygenase activity predicts prognosis of pulmonary tuberculosis. Clin. Vaccine Immunol., 2012, vol. 19, no. 3, pp. 436–442. doi: 10.1128/CVI.05402-11Tobin D.M., Roca F.J., Oh S.F., McFarland R., Vickery T.W., Ray J.P., Ko D.C., Zou Y., Bang N.D., Chau T.T., Vary J.C., Hawn T.R., Dunstan S.J., Farrar J.J., Thwaites G.E., King M.C., Serhan C.N., Ramakrishnan L. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell, 2012, vol. 148, no. 3, pp. 434–446. doi: 10.1016/ j.cell.2011.12.023Tonby K., Wergeland I., Lieske N.V., Kvale D., Tasken K., Dyrhol-Riise A.M. The COX-inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection. BMC Infect. Dis., 2016, vol. 16, no. 1: 599. doi: 10.1186/s12879-016-1938-8Weiner J. 3rd, Maertzdorf J., Sutherland J.S., Duffy F.J., Thompson E., Suliman S., McEwen G., Thiel B., Parida S.K., Zyla J., Hanekom W.A., Mohney R.P., Boom W.H., Mayanja-Kizza H., Howe R., Dockrell H.M., Ottenhoff T.H.M., Scriba T.J., Zak D.E., Walzl G., Kaufmann S.H.E.; GC6-74 consortium. Metabolite changes in blood predict the onset of tuberculosis. Nat. Commun., 2018, vol. 9, no. 1: 5208. doi: 10.1038/s41467-018-07635-7Weiner J. 3rd, Parida S.K., Maertzdorf J., Black G.F., Repsilber D., Telaar A., Mohney R.P., Arndt-Sullivan C., Ganoza C.A., Faé K.C., Walzl G., Kaufmann S.H. Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients. PLoS One, 2012, vol. 7, no. 7: e40221. doi: 10.1371/journal.pone.0040221Yamada H., Mizumo S., Horai R., Iwakura Y., Sugawara I. Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Lab. Invest., 2000, vol. 80, no. 5, pp. 759–767. doi: 10.1038/labinvest.3780079