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.
Highlights
Tuberculosis (TB) remains the leading cause of deaths worldwide due to a single infectious agent
Post-marketing surveillance data suggested that Mycobacterium tuberculosis (Mtb) protective immunity is unequally impacted by different tumor necrosis factor (TNF)-α-targeting drugs used to treat inflammatory disorders
We explore the capability of such human, in-vitro granuloma model to assess the latent TB infection (LTBI)-reactivation risk of several TNF-α- and non-TNF-α-targeting biologics licensed for the treatment of various immune-mediated inflammatory disorders
Summary
Tuberculosis (TB) remains the leading cause of deaths worldwide due to a single infectious agent. It is estimated that a quarter of the world’s population presents an immune memory against Mycobacterium tuberculosis (Mtb)-specific antigens in the absence of clinical symptoms, and is inferred to be latently infected. Current thinking holds that immune activation and hypoxia within granulomas favor a switching of mycobacterial physiology into a lipid-rich, low-metabolic, and potentially non-replicating, dormant state that may persist for decades. While latency and reactivation respectively refer to absence or presence of clinical symptoms, dormancy and resuscitation describe bacterial phenotypes characterized by repressed or revived levels of replication and metabolic activity, respectively [5,6]. The metabolic switch leading to dormancy or non-replicating persistence can be induced in vitro upon exposure to various stresses including hypoxia. Under hypoxic conditions Mtb accumulates intracellular triacylglycerides into lipid inclusions, and undergoes transcriptional changes leading to a shift in carbon and energy metabolism [7]
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