Abstract

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) andMycobacterium aviumsubspeciesparatuberculosis(MAP) are the etiological agents of bovine tuberculosis and Johne’s disease, respectively. AlthoughM. bovisand 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 ofM. bovisand 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 aroundM. bovisthrough activation of E3 ubiquitin ligase parkin. From in-vivo experiments, we found that nilotinib effectively controlledM. bovisgrowth 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 ofM. bovisand MAP infections.Keywords:nilotinib;Mycobacterium bovis(M. bovis);Mycobacterium aviumsubspeciesparatuberculosis(MAP);macrophage;autophagy