Journal
JOURNAL OF INFECTION
Volume 80, Issue 6, Pages E19-E26Publisher
W B SAUNDERS CO LTD
DOI: 10.1016/j.jinf.2020.03.003
Keywords
Tuberculosis; Host-directed therapy; Ibrutinib; Autophagy
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Funding
- Thirteen-Fifth Mega-Scientific Project on Prevention and Treatment of AIDS, Viral Hepatitis and Other Infectious Diseases [2017ZX10201301]
- National Natural Science Foundation of China [81800010, 81525016, 81671984]
- Provincial Natural Sciencice Foundation of Guandong [2018A030310642, 2020A1515010415]
- Guangdong Provincial Science and Technology Program [2019B030301009]
- Shenzhen Science and Technology Innovation Foundation [JCYJ20180305163440858]
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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. (C) 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
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