Ī well-established host factor controlling Mtb dormancy is tumor necrosis factor (TNF)‐α, as documented by the clinical association of anti‐TNF-α therapies with reactivation of LTBI. Under hypoxic conditions Mtb accumulates intracellular triacylglycerides into lipid inclusions, and undergoes transcriptional changes leading to a shift in carbon and energy metabolism. The metabolic switch leading to dormancy or non-replicating persistence can be induced in vitro upon exposure to various stresses including hypoxia. 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. The complex pathophysiology of Mtb infection suscitated the need to define an appropriate terminology. Consequently, dormant Mtb displays an increased tolerance to antibiotics that target metabolic pathways active during bacterial replication. 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. Despite having the potential to be sterilizing, in some instances granulomas may contain but not eliminate the infection. The hallmark of the host immune response against the tubercle bacillus is the formation of structurally-organized, multicellular clusters constituted mainly of macrophages and lymphocytes called granulomas. as a consequence of HIV co-infection or immunosuppressive drug treatments. Yet, in low endemic countries, the risk of progressing from latent to active TB can reach up to 10% if the immune system is weakened, e.g. Recent Mtb infection in high-transmission areas is the major contributor to the global TB burden. Therefore, so-defined latent TB infection (LTBI) does not necessarily reflect the presence of a continued Mtb infection as it encompasses cured as well quiescent, asymptomatic or subclinical infections. In addition, 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 thus inferred to be latently infected. Tuberculosis (TB) remains the leading cause of deaths worldwide due to a single infectious agent. The funders later supported further study design initiated by the collaborators, and had no role in data collection and analysis.Ĭompeting interests: DP has received a research grant from Novartis. decision to implement the assay and compare activity of the tested drugs. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the manuscript and its Supporting Information files.įunding: DP received the funding to conduct the study under a research agreement contract between Novartis AG and the Swiss Tropical and Public Health Institute. Received: JAccepted: JanuPublished: February 18, 2020Ĭopyright: © 2020 Arbués et al. Hawn, University of Washington, UNITED STATES 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.Ĭitation: Arbués A, Brees D, Chibout S-D, Fox T, Kammüller M, Portevin D (2020) TNF-α antagonists differentially induce TGF-β1-dependent resuscitation of dormant-like Mycobacterium tuberculosis. Moreover, our data suggest an additional role of lymphotoxin-α–neutralized by Etanercept but not Adalimumab–in the control of latent tuberculosis infection. 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. 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. 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. TNF-α- as well as non-TNF-α-targeting biologics are prescribed to treat a variety of immune-mediated inflammatory disorders.
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