LRRK2 Kinase Plays an Important Role in the Intracellular Survival of Brucella abortus 2308 in Murine Macrophages and in a Mouse Infection Model

Abstract

Received: Revised: Accepted: Published online: December 28, 2018 February 23, 2019 March 08, 2019 April 06, 2019 Brucella species are facultative, intracellular bacteria that cause serious diseases in animals and people. Persistent survival inside macrophages is a major cause of chronic infections with Brucella. Leucine-rich repeat kinase 2 (LRRK2), a large multidomain protein kinase, is associated with Parkinson’s disease, chronic inflammation and intracellular infections. Hence, we monitored the activation of the LRRK2 kinase in Brucella-infected cells and evaluated the function of LRRK2 kinase in the intracellular survival of Brucella. Our results show that Brucella abortus 2308 activated the LRRK2 kinase and that the kinase activity was inhibited by a LRRK2-specific inhibitor in a dose-dependent manner. LRRK2 silencing significantly increased the Th1 immune response and reduced the replication of Brucella abortus 2308, both in vitro and in vivo. LRRK2 also enhanced the phosphorylation level of Akt, thereby inhibiting Akt-mediated humoral immune responses during Brucella infection. Collectively, these findings confirm that LRRK2 acts to reduce innate immune responses by activation of PI3K-Akt pathway, thereby contributing to the intracellular survival of Brucella abortus 2308 in murine macrophages and in a mouse infection model. Therefore, LRRK2 kinase play a key role in infections with Brucella abortus 2308, which will provide new insights into the pathogenic mechanisms used by Brucella. ©2019 PVJ. All rights reserved