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

Autor: Tariq Hussain, Deming Zhao, Syed Zahid Ali Shah, Naveed Sabir, Jie Wang, Yi Liao, Yinjuan Song, Haodi Dong, Mazhar Hussain Mangi, Jiamin Ni, Lifeng Yang, Xiangmei Zhou
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Cells, Vol 8, Iss 5, p 506 (2019)
Druh dokumentu: article
ISSN: 2073-4409
DOI: 10.3390/cells8050506
Popis: 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.
Databáze: Directory of Open Access Journals
Nepřihlášeným uživatelům se plný text nezobrazuje