Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection
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
Affiliations
Natalie E. Nieuwenhuizen
Department of Immunology, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, Germany
Geraldine Nouailles
Department 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, Germany
Jayne S. Sutherland
Vaccines and Immunity Theme, Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia
Joanna Zyla
Department of Data Science and Engineering, Silesian University of Technology, Gliwice, Poland
Arja H. Pasternack
Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Jan Heyckendorf
Department of Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
Björn C. Frye
Department of Pneumology, Clinic, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Kerstin Höhne
Department of Pneumology, Clinic, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Ulrike Zedler
Department of Immunology, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, Germany
Silke Bandermann
Department of Immunology, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, Germany
Ulrike Abu Abed
Microscopy Core Facility, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, Germany
Volker Brinkmann
Microscopy Core Facility, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, Germany
Birgitt Gutbier
Department 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, Germany
Martin Witzenrath
Department 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, Germany
Norbert Suttorp
Department 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, Germany
Gernot Zissel
Department of Pneumology, Clinic, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Christoph Lange
Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
Olli Ritvos
Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Stefan H. E. Kaufmann
Department of Immunology, Max Planck Institute for Infection Biology, Chariteplatz, Berlin, Germany
ABSTRACT Activin 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.
