Ibrutinib suppresses intracellular mycobacterium tuberculosis growth by inducing macrophage autophagy

Abstract

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. The host-directed therapy is a promising strategy for TB treatment that synergize with anti-TB treatment drugs. In this study, we found that the anti-chronic lymphocytic leukemia drug, ibrutinib, inhibited the growth of intracellular Mtb in human macrophages. Mechanisms studies showed that ibrutinib treatment significantly decreased p62 and increased LC3b proteins in Mtb infected macrophages. In addition, ibrutinib increased LC3b colocalization with intracellular Mtb and auto-lysosome fusion. Furthermore, inhibition of autophagy by using siRNA targeting ATG7 abolished the effect of ibrutinib-mediated suppression of intracellular Mtb. Next, we found that ibrutinib induced autophagy was through inhibition of BTK/Akt/mTOR pathway. Finally, we confirmed that ibrutinib treatment significantly reduced Mtb load in mediastinal node and spleen of Mtb infected mice. In conclusion, our data suggest that ibrutinib is a potential host-directed therapy candidate against TB.

Host‐directed therapy to combat mycobacterial infections*

“…68 Inhibition of protein-kinase C-beta (PKC-B), another important regulator of the PI3K-Akt-mTOR pathway, by ibrutinib also enhanced autophagy and restricted intracellular growth of Mtb in macrophages and mice in the spleen, although not in the lungs. 69 Alleviating the Mtb-mediated suppression of sirtuin-1, a class-III histone deacetylase that also modulates autophagy via 5'AMP-activated protein-kinase (AMPK), using resveratrol restricted intracellular Mtb growth by stimulating autophagy and phagosome-lysosome fusion. 70 Metformin, a well-established stimulator of AMPK-mediated inhibition of mTOR signaling, is widely used for the treatment of type-2 diabetes, but also induces ROS production, phagosome maturation, and autophagy in vitro and prevents mitochondrial membrane depolarization.…”

High-Content Screening of Eukaryotic Kinase Inhibitors Identify CHK2 Inhibitor Activity Against Mycobacterium tuberculosis

“…One signaling pathway that is both well-characterized in M.tb infections and enriched in our analysis is the PI3K-Akt-GSK3-mTOR pathway. Previous work from our lab (Poirier et al, 2014) and others (Singh and Subbian, 2018;Hu et al, 2020), as well as this work, highlight this pathway's inhibition in controlling intracellular infection via control of cellular apoptosis and autophagy. Since signaling pathways commonly interreact with each other, upscaling our screen and analysis can highlight those sub-paths relevant to M.tb inhibition, providing a complimentary and unbiased approach to classical biochemical pathway characterization techniques.…”

An Interplay Between Autophagy and Immunometabolism for Host Defense Against Mycobacterial Infection

“…Several drugs/agents inhibit mTOR pathway activation, thereby promoting antimicrobial effects during Mtb infection. For example, the anti-chronic lymphocytic leukemia drug ibrutinib inhibited Mtb growth both in vitro and in vivo , activating autophagy via inhibition of the BTK/Akt/mTOR pathway ( 92 ). The effects of ibrutinib on M2 polarization and immunosuppression of nurse-like cells have been described; these cells are a subset of tumor-associated macrophages found in patients with chronic lymphocytic leukemia ( 93 ).…”