TNF-[alpha] antagonists differentially induce TGF-[beta]1-dependent resuscitation of dormant-like Mycobacterium tuberculosis

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