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.Author summaryMycobacterium tuberculosis (Mtb) is the world's leading infectious killer. Multi-cellular immune structures called granulomas may constitute a latent form of Mtb infection and a potential reservoir for future cases. Post-marketing surveillance data suggested that Mtb protective immunity is unequally impacted by different TNF-alpha-targeting drugs used to treat inflammatory disorders. We used an in-vitro granuloma model to reproduce these clinical observations and gain mechanistic insights and, in addition, to assess the risk of tuberculosis reactivation associated with the use of other immunomodulatory drugs. These results may inspire pharmacologists to design future drug-development strategies of biologics in particular, while immunologists and microbiologists will find a relevant experimental approach to disentangle the complex interactions involved in Mtb protective immunity and immunopathogenesis.