Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection
ABSTRACTActivin A strongly influences immune responses; yet, few studies have examined its role in infectious diseases. We measured serum activin A levels in two independent tuberculosis (TB) patient cohorts and in patients with pneumonia and sarcoidosis. Serum activin A levels were increased in TB...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2024-03-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03408-23 |
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| author | Natalie E. Nieuwenhuizen Geraldine Nouailles Jayne S. Sutherland Joanna Zyla Arja H. Pasternack Jan Heyckendorf Björn C. Frye Kerstin Höhne Ulrike Zedler Silke Bandermann Ulrike Abu Abed Volker Brinkmann Birgitt Gutbier Martin Witzenrath Norbert Suttorp Gernot Zissel Christoph Lange Olli Ritvos Stefan H. E. Kaufmann |
| author_facet | Natalie E. Nieuwenhuizen Geraldine Nouailles Jayne S. Sutherland Joanna Zyla Arja H. Pasternack Jan Heyckendorf Björn C. Frye Kerstin Höhne Ulrike Zedler Silke Bandermann Ulrike Abu Abed Volker Brinkmann Birgitt Gutbier Martin Witzenrath Norbert Suttorp Gernot Zissel Christoph Lange Olli Ritvos Stefan H. E. Kaufmann |
| author_sort | Natalie E. Nieuwenhuizen |
| collection | DOAJ |
| description | ABSTRACTActivin A strongly influences immune responses; yet, few studies have examined its role in infectious diseases. We measured serum activin A levels in two independent tuberculosis (TB) patient cohorts and in patients with pneumonia and sarcoidosis. Serum activin A levels were increased in TB patients compared to healthy controls, including those with positive tuberculin skin tests, and paralleled severity of disease, assessed by X-ray scores. In pneumonia patients, serum activin A levels were also raised, but in sarcoidosis patients, levels were lower. To determine whether blockade of the activin A signaling axis could play a functional role in TB, we harnessed a soluble activin type IIB receptor fused to human IgG1 Fc, ActRIIB-Fc, as a ligand trap in a murine TB model. The administration of ActRIIB-Fc to Mycobacterium tuberculosis-infected mice resulted in decreased bacterial loads and increased numbers of CD4 effector T cells and tissue-resident memory T cells in the lung. Increased frequencies of tissue-resident memory T cells corresponded with downregulated T-bet expression in lung CD4 and CD8 T cells. Altogether, the results suggest a disease-exacerbating role of ActRIIB signaling pathways. Serum activin A may be useful as a biomarker for diagnostic triage of active TB or monitoring of anti-tuberculosis therapy.IMPORTANCETuberculosis remains the leading cause of death by a bacterial pathogen. The etiologic agent of tuberculosis, Mycobacterium tuberculosis, can remain dormant in the infected host for years before causing disease. Significant effort has been made to identify biomarkers that can discriminate between latently infected and actively diseased individuals. We found that serum levels of the cytokine activin A were associated with increased lung pathology and could discriminate between active tuberculosis and tuberculin skin-test-positive healthy controls. Activin A signals through the ActRIIB receptor, which can be blocked by administration of the ligand trap ActRIIB-Fc, a soluble activin type IIB receptor fused to human IgG1 Fc. In a murine model of tuberculosis, we found that ActRIIB-Fc treatment reduced mycobacterial loads. Strikingly, ActRIIB-Fc treatment significantly increased the number of tissue-resident memory T cells. These results suggest a role for ActRIIB signaling pathways in host responses to Mycobacterium tuberculosis and activin A as a biomarker of ongoing disease. |
| first_indexed | 2024-04-25T00:09:58Z |
| format | Article |
| id | doaj.art-3d3667d5541a46edbd2bf30cc823eefc |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-25T00:09:58Z |
| publishDate | 2024-03-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-3d3667d5541a46edbd2bf30cc823eefc2024-03-13T14:01:04ZengAmerican Society for MicrobiologymBio2150-75112024-03-0115310.1128/mbio.03408-23Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infectionNatalie E. Nieuwenhuizen0Geraldine Nouailles1Jayne S. Sutherland2Joanna Zyla3Arja H. Pasternack4Jan Heyckendorf5Björn C. Frye6Kerstin Höhne7Ulrike Zedler8Silke Bandermann9Ulrike Abu Abed10Volker Brinkmann11Birgitt Gutbier12Martin Witzenrath13Norbert Suttorp14Gernot Zissel15Christoph Lange16Olli Ritvos17Stefan H. E. Kaufmann18Department of Immunology, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, GermanyDepartment of Infectious Diseases, Respiratory Medicine and Critical Care, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyVaccines and Immunity Theme, Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The GambiaDepartment of Data Science and Engineering, Silesian University of Technology, Gliwice, PolandDepartment of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, FinlandDepartment of Medicine I, University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Pneumology, Clinic, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyDepartment of Pneumology, Clinic, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyDepartment of Immunology, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, GermanyDepartment of Immunology, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, GermanyMicroscopy Core Facility, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, GermanyMicroscopy Core Facility, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, GermanyDepartment of Infectious Diseases, Respiratory Medicine and Critical Care, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyDepartment of Infectious Diseases, Respiratory Medicine and Critical Care, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyDepartment of Infectious Diseases, Respiratory Medicine and Critical Care, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyDepartment of Pneumology, Clinic, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyDivision of Clinical Infectious Diseases, Research Center Borstel, Borstel, GermanyDepartment of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, FinlandDepartment of Immunology, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, GermanyABSTRACTActivin A strongly influences immune responses; yet, few studies have examined its role in infectious diseases. We measured serum activin A levels in two independent tuberculosis (TB) patient cohorts and in patients with pneumonia and sarcoidosis. Serum activin A levels were increased in TB patients compared to healthy controls, including those with positive tuberculin skin tests, and paralleled severity of disease, assessed by X-ray scores. In pneumonia patients, serum activin A levels were also raised, but in sarcoidosis patients, levels were lower. To determine whether blockade of the activin A signaling axis could play a functional role in TB, we harnessed a soluble activin type IIB receptor fused to human IgG1 Fc, ActRIIB-Fc, as a ligand trap in a murine TB model. The administration of ActRIIB-Fc to Mycobacterium tuberculosis-infected mice resulted in decreased bacterial loads and increased numbers of CD4 effector T cells and tissue-resident memory T cells in the lung. Increased frequencies of tissue-resident memory T cells corresponded with downregulated T-bet expression in lung CD4 and CD8 T cells. Altogether, the results suggest a disease-exacerbating role of ActRIIB signaling pathways. Serum activin A may be useful as a biomarker for diagnostic triage of active TB or monitoring of anti-tuberculosis therapy.IMPORTANCETuberculosis remains the leading cause of death by a bacterial pathogen. The etiologic agent of tuberculosis, Mycobacterium tuberculosis, can remain dormant in the infected host for years before causing disease. Significant effort has been made to identify biomarkers that can discriminate between latently infected and actively diseased individuals. We found that serum levels of the cytokine activin A were associated with increased lung pathology and could discriminate between active tuberculosis and tuberculin skin-test-positive healthy controls. Activin A signals through the ActRIIB receptor, which can be blocked by administration of the ligand trap ActRIIB-Fc, a soluble activin type IIB receptor fused to human IgG1 Fc. In a murine model of tuberculosis, we found that ActRIIB-Fc treatment reduced mycobacterial loads. Strikingly, ActRIIB-Fc treatment significantly increased the number of tissue-resident memory T cells. These results suggest a role for ActRIIB signaling pathways in host responses to Mycobacterium tuberculosis and activin A as a biomarker of ongoing disease.https://journals.asm.org/doi/10.1128/mbio.03408-23activin AActRIIBtuberculosislatent TB infectionpneumoniasarcoidosis |
| spellingShingle | Natalie E. Nieuwenhuizen Geraldine Nouailles Jayne S. Sutherland Joanna Zyla Arja H. Pasternack Jan Heyckendorf Björn C. Frye Kerstin Höhne Ulrike Zedler Silke Bandermann Ulrike Abu Abed Volker Brinkmann Birgitt Gutbier Martin Witzenrath Norbert Suttorp Gernot Zissel Christoph Lange Olli Ritvos Stefan H. E. Kaufmann Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection mBio activin A ActRIIB tuberculosis latent TB infection pneumonia sarcoidosis |
| title | Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection |
| title_full | Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection |
| title_fullStr | Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection |
| title_full_unstemmed | Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection |
| title_short | Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection |
| title_sort | activin a levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to m tuberculosis infection |
| topic | activin A ActRIIB tuberculosis latent TB infection pneumonia sarcoidosis |
| url | https://journals.asm.org/doi/10.1128/mbio.03408-23 |
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