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Open AccessArticle

Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy

1
Key Laboratory of Animal Epidemiology and Zoonosis of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
2
Department of Pathology, Faculty of Veterinary Science, Cholistan University of Veterinary and Animal Sciences, Bahawalpur 63100, Pakistan
*
Author to whom correspondence should be addressed.
Cells 2019, 8(5), 506; https://doi.org/10.3390/cells8050506
Received: 2 May 2019 / Revised: 20 May 2019 / Accepted: 23 May 2019 / Published: 26 May 2019
Nilotinib, a tyrosine kinase inhibitor, has been studied extensively in various tumor models; however, no information exists about the pharmacological action of nilotinib in bacterial infections. Mycobacterium bovis (M. bovis) and Mycobacterium avium subspecies paratuberculosis (MAP) are the etiological agents of bovine tuberculosis and Johne’s disease, respectively. Although M. bovis and MAP cause distinct tissue tropism, both of them infect, reside, and replicate in mononuclear phagocytic cells of the infected host. Autophagy is an innate immune defense mechanism for the control of intracellular bacteria, regulated by diverse signaling pathways. Here we demonstrated that nilotinib significantly inhibited the intracellular survival and growth of M. bovis and MAP in macrophages by modulating host immune responses. We showed that nilotinib induced autophagic degradation of intracellular mycobacterium occurred via the inhibition of PI3k/Akt/mTOR axis mediated by abelson (c-ABL) tyrosine kinase. In addition, we observed that nilotinib promoted ubiquitin accumulation around M. bovis through activation of E3 ubiquitin ligase parkin. From in-vivo experiments, we found that nilotinib effectively controlled M. bovis growth and survival through enhanced parkin activity in infected mice. Altogether, our data showed that nilotinib regulates protective innate immune responses against intracellular mycobacterium, both in-vitro and in-vivo, and can be exploited as a novel therapeutic remedy for the control of M. bovis and MAP infections. View Full-Text
Keywords: nilotinib; Mycobacterium bovis (M. bovis); Mycobacterium avium subspecies paratuberculosis (MAP); macrophage; autophagy nilotinib; Mycobacterium bovis (M. bovis); Mycobacterium avium subspecies paratuberculosis (MAP); macrophage; autophagy
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Hussain, T.; Zhao, D.; Shah, S.Z.A.; Sabir, N.; Wang, J.; Liao, Y.; Song, Y.; Dong, H.; Hussain Mangi, M.; Ni, J.; Yang, L.; Zhou, X. Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy. Cells 2019, 8, 506.

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