Caian L Vinhaes1, Deivide Oliveira-de-Souza1, Paulo S Silveira-Mattos1, Betania Nogueira2, Ruiru Shi3, Wang Wei3, Xing Yuan3, Guolong Zhang4, Ying Cai5, Clifton E Barry5, Laura E Via5, Kiyoshi F Fukutani1, Bruno B Andrade6, Katrin D Mayer-Barber7. 1. Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador 40210-320, Brazil; Curso de Medicina, Faculdade de Tecnologia e Ciências (FTC), Salvador 40290-150, Brazil. 2. Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador 40210-320, Brazil. 3. Henan Chest Hospital, Zhengzhou 450000, China. 4. Henan Anti-TB Institute, Sino-US Joint Research Laboratory for Tuberculosis of Henan CDC, Zhengzhou 450000, China. 5. Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda 20892, MD, USA. 6. Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador 40210-320, Brazil; Curso de Medicina, Faculdade de Tecnologia e Ciências (FTC), Salvador 40290-150, Brazil; Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador 40290-000, Brazil; Universidade Salvador (UNIFACS), Laureate Universities, Salvador 41720-200, Brazil; Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa; Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: bruno.andrade@fiocruz.br. 7. Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda 20892, MD, USA. Electronic address: mayerk@niaid.nih.gov.
Abstract
BACKGROUND: The identification of meaningful biomarkers of tuberculosis (TB) has potential to improve diagnosis, disease staging and prediction of treatment outcomes. It has been shown that active pulmonary TB (PTB) is associated with qualitative and quantitative changes in systemic immune profile, suggesting a chronic inflammatory imbalance. Here we characterized the profile of PTB and extrapulmonary TB (EPTB) in a prospective cohort study. METHODS: We measured a panel of 27 inflammatory cytokines, soluble receptors, and lipid mediators in peripheral blood from patients with PTB or EPTB from a prospective clinical study in China. Multidimensional analyses were performed to describe associations between plasma levels of biomarkers and different TB disease presentation profiles. RESULTS: Mycobacterium tuberculosis infection induced changes in both the expression and correlation profiles of plasma mediators of inflammation in patients with PTB compared to those with EPTB. Increases in mycobacterial loads in sputum smears were associated with rises in concentrations of several molecules involved in TB pathogenesis, such as IL-1β, IFN-α, IL-10 and PGF2α. Moreover, PTB patients presenting with severe disease exhibited a distinct inflammatory profile hallmarked by heightened levels of TNF-α, IL-1β, IL17, IL-18 and IL-27. Interestingly, while antitubercular treatment (ATT) resulted in early changes of plasma concentrations of markers in PTB, changes were delayed in EPTB patients. Exploratory analyses of the molecular degree of perturbation (MDP) of the inflammatory mediators before and during ATT suggested the occurrence of infection and/or treatment-induced long lasting "inflammatory imprinting" of biomarker profiles in TB. At 24 weeks post ATT commencement, markers underlying the observed increases in MDP scores were IL-27 in PTB and IL-1β in EPTB patients. CONCLUSION: Our findings describe systemic and durable changes in the concentrations of inflammatory cytokines and lipid mediators in both PTB and EPTB and emphasize the role of M. tuberculosis bacterial burden and site of disease in modulating patient immune biomarkers.
BACKGROUND: The identification of meaningful biomarkers of tuberculosis (TB) has potential to improve diagnosis, disease staging and prediction of treatment outcomes. It has been shown that active pulmonary TB (PTB) is associated with qualitative and quantitative changes in systemic immune profile, suggesting a chronic inflammatory imbalance. Here we characterized the profile of PTB and extrapulmonary TB (EPTB) in a prospective cohort study. METHODS: We measured a panel of 27 inflammatory cytokines, soluble receptors, and lipid mediators in peripheral blood from patients with PTB or EPTB from a prospective clinical study in China. Multidimensional analyses were performed to describe associations between plasma levels of biomarkers and different TB disease presentation profiles. RESULTS:Mycobacterium tuberculosisinfection induced changes in both the expression and correlation profiles of plasma mediators of inflammation in patients with PTB compared to those with EPTB. Increases in mycobacterial loads in sputum smears were associated with rises in concentrations of several molecules involved in TB pathogenesis, such as IL-1β, IFN-α, IL-10 and PGF2α. Moreover, PTB patients presenting with severe disease exhibited a distinct inflammatory profile hallmarked by heightened levels of TNF-α, IL-1β, IL17, IL-18 and IL-27. Interestingly, while antitubercular treatment (ATT) resulted in early changes of plasma concentrations of markers in PTB, changes were delayed in EPTBpatients. Exploratory analyses of the molecular degree of perturbation (MDP) of the inflammatory mediators before and during ATT suggested the occurrence of infection and/or treatment-induced long lasting "inflammatory imprinting" of biomarker profiles in TB. At 24 weeks post ATT commencement, markers underlying the observed increases in MDP scores were IL-27 in PTB and IL-1β in EPTBpatients. CONCLUSION: Our findings describe systemic and durable changes in the concentrations of inflammatory cytokines and lipid mediators in both PTB and EPTB and emphasize the role of M. tuberculosis bacterial burden and site of disease in modulating patient immune biomarkers.
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