2020
DOI: 10.1371/journal.ppat.1008312
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TNF-α antagonists differentially induce TGF-β1-dependent resuscitation of dormant-like Mycobacterium tuberculosis

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 A… Show more

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Cited by 35 publications
(35 citation statements)
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“…In contrast, however, TNFa inhibitors are well-known to impair bacterial containment when used without accompanying multidrug anti-TB therapy (18,22). While TNFa antagonists have the potential to improve TB therapy when used as adjunctive agents, there have been concerns about their expense, their need to be given parenterally, and the potential for disease worsening if administered without adequate anti-TB chemotherapy, and due to these concerns advanced clinical trials to test them as adjunctive HDTs for TB have not been performed (18,60,67).…”
Section: Tnf Antagonistsmentioning
confidence: 99%
“…In contrast, however, TNFa inhibitors are well-known to impair bacterial containment when used without accompanying multidrug anti-TB therapy (18,22). While TNFa antagonists have the potential to improve TB therapy when used as adjunctive agents, there have been concerns about their expense, their need to be given parenterally, and the potential for disease worsening if administered without adequate anti-TB chemotherapy, and due to these concerns advanced clinical trials to test them as adjunctive HDTs for TB have not been performed (18,60,67).…”
Section: Tnf Antagonistsmentioning
confidence: 99%
“…A phase II trial is scheduled to commence shortly to investigate this (NCT03891901). TNF-α inhibitors and LT-α inhibitors, highly successful in cancer treatment, also show potential for repurposing, as an in vitro granuloma model reveals their ability to resuscitate dormant TB via controlled immunosuppression [ 64 ]. There is a recent burst of exploration into similar molecules, such as nilotinib, gefitinib and fostamatinib, each showing varied mechanisms of action, for example, enhancing autophagy [ 65 , 66 , 67 ].…”
Section: Repurposing Immunomodulatory Compoundsmentioning
confidence: 99%
“…On the other hand, Mtb displays features associated with dormancy such as accumulation of intracellular triacylglycerides into lipid inclusions, loss of acid-fastness, transcriptional changes leading to a shift in carbon and energy metabolisms, and increase in antibiotic tolerance (Kapoor et al, 2013). Remarkably, this model was also able to reproduce the differential rate of latent TB reactivation observed in the clinic upon treatment with different TNF-αneutralizing biologics (Arbués et al, 2020). Some particular limitations of this model to take into account are the difficulty of adding new immune cells for dynamic studies or its relatively low throughput.…”
mentioning
confidence: 91%
“…Bio-protocol 10(22): e3820. DOI:10.21769/BioProtoc.3820 independent groups have reported in vitro models based on the infection of human peripheral blood mononuclear cells (PBMCs) with virulent Mtb (Kapoor et al, 2013;Guirado et al, 2015;Agrawal et al, 2016;Arbués et al, 2020;Tezera et al, 2017). Despite lacking some relevant cell types (e.g., neutrophils) and the full tissue conditions (such as lung structure or vascularization), such models are able to mimic the organization of human nascent granulomas, orchestrated by relevant cytokines.…”
mentioning
confidence: 99%
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