TY - JOUR
T1 - Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection
AU - CAPNETZ Study group
AU - DZIF TB study group
AU - Nieuwenhuizen, Natalie E.
AU - Nouailles, Geraldine
AU - Sutherland, Jayne S.
AU - Zyla, Joanna
AU - Pasternack, Arja H.
AU - Heyckendorf, Jan
AU - Frye, Björn C.
AU - Höhne, Kerstin
AU - Zedler, Ulrike
AU - Bandermann, Silke
AU - Abed, Ulrike Abu
AU - Brinkmann, Volker
AU - Gutbier, Birgitt
AU - Witzenrath, Martin
AU - Suttorp, Norbert
AU - Zissel, Gernot
AU - Lange, Christoph
AU - Ritvos, Olli
AU - Kaufmann, Stefan H.E.
N1 - Publisher Copyright:
© 2024 Nieuwenhuizen et al.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - activin A
KW - ActRIIB
KW - CD103
KW - IP-10
KW - latent TB infection
KW - pneumonia
KW - resident memory T cells
KW - sarcoidosis
KW - T
KW - treatment monitoring
KW - tuberculosis
KW - 11832 Microbiology and virology
KW - 1184 Genetics, developmental biology, physiology
U2 - 10.1128/mbio.03408-23
DO - 10.1128/mbio.03408-23
M3 - Article
C2 - 38376260
AN - SCOPUS:85187793178
SN - 2161-2129
VL - 15
JO - mBio
JF - mBio
IS - 3
M1 - e0340823
ER -