Natalie E. Nieuwenhuizen (Würzburg / DE; Berlin / DE), Geraldine Nouailles (Berlin / DE), Jayne S. Sutherland (Fajara / GM), Joanna Zyla (Gliwice / DE), Arja H. Pasternack (Helsinki / FI), Jan Heyckendorf (Kiel / DE), Björn C Frye (Freiburg i. Br. / DE), Kerstin Höhne (Freiburg i. Br. / DE), Ulrike Zedler (Berlin / DE), Silke Bandermann (Berlin / DE), Ulrike Abu Abed (Berlin / DE), Volker Brinkmann (Berlin / DE), Birgitt Gutbier (Berlin / DE), Martin Witzenrath (Berlin / DE; Hannover / DE; Giessen / DE), Norbert Suttorp (Berlin / DE; Hannover / DE; Giessen / DE), Gernot Zissel (Freiburg i. Br. / DE), Christoph Lange (Borstel / DE; Lübeck / DE; Houston, TX / US), Olli Ritvos (Helsinki / FI), Stefan H.E. Kaufmann (Berlin / DE; Göttingen / DE; College Station, TX / US)
Introduction: The TGF-beta superfamily member activin A is an important immunomodulatory cytokine, but few studies have examined its roles in infectious diseases. Activin A has been implicated in lung pathophysiology, driving us to examine whether it is increased in tuberculosis (TB) and pneumonia, as well as sarcoidosis, a granulomatous inflammatory disease of unknown aetiology that mainly affects the lungs.
Goals: We aimed to determine whether serum activin A levels are increased during pulmonary TB, pneumonia and sarcoidosis. Furthermore, we aimed to investigate whether the activin signaling axis plays a role in experimental TB.
Materials & Methods: Serum activin A levels were measured in patients with TB, pneumonia (including bacterial and viral pneumonia), and sarcoidosis. A soluble activin type IIB receptor fused to human IgG1 Fc (sActRIIB-Fc) was used to inhibit the activin signaling axis in a murine TB model.
Results: In two independent cohorts of TB patients from Gambia and Germany, serum activin A levels were increased during active TB, and levels were associated with increased X-ray scores. In the Gambian cohort, Activin A levels were strongly increased in patients with active TB compared to healthy household contacts, and were reduced in most patients by six months of therapy. Many pneumonia patients also had elevated activin A levels, but activin A levels remained low in sarcoidosis patients. Administration of a soluble ActRIIB-Fc complex to M. tuberculosis-infected mice decreased lung bacterial loads, altered cytokine profiles and increased numbers of CD103+ T cells. The decreased frequencies of CD103+ T cells corresponded with downregulated T-bet expression in both CD4 and CD8 T cells, without changes to TGF-beta expression.
Summary: Activin A shows potential as a useful cytokine biomarker for diagnosis of active TB. The activin signalling axis appears to play a functional role during murine TB.