TNF-? antagonists differentially induce TGF-?1-dependent resuscitation of dormant-like Mycobacterium tuberculosis.

ABSTRACT: TNF-?- as well as non-TNF-?-targeting biologics are prescribed to treat a variety of immune-mediated inflammatory disorders. The well-documented risk of tuberculosis progression associated with anti-TNF-? treatment highlighted the central role of TNF-? 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-?-neutralizing biologics. We show that Adalimumab, because of its bivalence, specifically induces TGF-?1-dependent Mycobacterium tuberculosis (Mtb) resuscitation which can be prevented by concomitant TGF-?1 neutralization. Moreover, our data suggest an additional role of lymphotoxin-?-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.

SUBMITTER: Arbues A 

PROVIDER: S-EPMC7048311 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature