TNF-α antagonists differentially induce TGF-β1-dependent resuscitation of dormant-like Mycobacterium tuberculosis

Ainhoa Arbués; Dominique Brees; Salah-Dine Chibout; Todd Fox; Michael Kammüller; Damien Portevin

doi:10.1371/journal.ppat.1008312

TNF-α antagonists differentially induce TGF-β1-dependent resuscitation of dormant-like Mycobacterium tuberculosis

PLoS Pathog. 2020 Feb 18;16(2):e1008312. doi: 10.1371/journal.ppat.1008312. eCollection 2020 Feb.

Authors

Ainhoa Arbués^{1

2}, Dominique Brees³, Salah-Dine Chibout³, Todd Fox⁴, Michael Kammüller³, Damien Portevin^{1

2}

Affiliations

¹ Department of Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
² University of Basel, Basel, Switzerland.
³ Novartis Institutes for Biomedical Research, Basel, Switzerland.
⁴ Novartis Pharma AG, Basel, Switzerland.

Abstract

TNF-α- as well as non-TNF-α-targeting biologics are prescribed to treat a variety of immune-mediated inflammatory disorders. The well-documented risk of tuberculosis progression associated with anti-TNF-α treatment highlighted the central role of TNF-α for the maintenance of protective immunity, although the rate of tuberculosis detected among patients varies with the nature of the drug. Using a human, in-vitro granuloma model, we reproduce the increased reactivation rate of tuberculosis following exposure to Adalimumab compared to Etanercept, two TNF-α-neutralizing biologics. We show that Adalimumab, because of its bivalence, specifically induces TGF-β1-dependent Mycobacterium tuberculosis (Mtb) resuscitation which can be prevented by concomitant TGF-β1 neutralization. Moreover, our data suggest an additional role of lymphotoxin-α-neutralized by Etanercept but not Adalimumab-in the control of latent tuberculosis infection. Furthermore, we show that, while Secukinumab, an anti-IL-17A antibody, does not revert Mtb dormancy, the anti-IL-12-p40 antibody Ustekinumab and the recombinant IL-1RA Anakinra promote Mtb resuscitation, in line with the importance of these pathways in tuberculosis immunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adalimumab / pharmacology
Antibodies, Monoclonal, Humanized / immunology
Antibodies, Monoclonal, Humanized / metabolism
Antibodies, Monoclonal, Humanized / pharmacology
Etanercept / pharmacology
Granuloma / drug therapy
Granuloma / metabolism
Humans
Immunologic Factors / metabolism
Latent Tuberculosis / immunology
Models, Biological
Mycobacterium tuberculosis / immunology
Mycobacterium tuberculosis / metabolism*
Transforming Growth Factor beta1 / metabolism
Tuberculosis / immunology*
Tumor Necrosis Factor Inhibitors / metabolism
Tumor Necrosis Factor Inhibitors / pharmacology*
Tumor Necrosis Factor-alpha / immunology
Tumor Necrosis Factor-alpha / metabolism

Substances

Antibodies, Monoclonal, Humanized
Immunologic Factors
TGFB1 protein, human
Transforming Growth Factor beta1
Tumor Necrosis Factor Inhibitors
Tumor Necrosis Factor-alpha
secukinumab
Adalimumab
Etanercept

Grants and funding

DP received the funding to conduct the study under a research agreement contract between Novartis AG and the Swiss Tropical and Public Health Institute. The funders initiated study design e.g. decision to implement the assay and compare activity of the tested drugs. The funders later supported further study design initiated by the collaborators, and had no role in data collection and analysis.