<jats:title>Abstract</jats:title> <jats:p>The Wnt/β-catenin pathway has been evolved in regulating cell proliferation, survival, and inflammation in cancer development. However, the role of β-catenin during infections remains elusive. Ehrlichia is obligate intracellular bacteria that cause life-threatening sepsis, characterized by liver injury and dysregulated inflammatory response with no effective therapy available. We examined here the contribution of Wnt pathway to the pathogenesis of Ehrlichia-induced sepsis employing murine models of mild and fatal ehrlichiosis caused by intraperitoneal infection with avirulent Ehrlichia muris (EM) and virulent Ixodes Ovatus Ehrlichia (IOE), respectively. We show that EM infection induces higher activation of the hepatic Wnt/β-catenin pathway and activates Wnt target genes; C-Myc and Cyclin D1 on day 7 post infection compared to uninfected controls. Notably, IOE infection attenuated Wnt/β-catenin pathway in liver tissue, which is associated with inflammasome activation, inhibition of autophagy in macrophages, host cell death, and increased number of replicating bacteria, suggesting that Wnt pathway is a host-protective mechanism that also enhances cell survival and attenuate inflammation during Ehrlichia infection. Notably, pharmacologic or genetic inhibition of mTORC1 activation in IOE-infected mice by rapamycin or MyD88 deficiency, respectively, enhanced Wnt signaling, induced autophagy, and decreased inflammation, suggesting that suppression of Wnt pathway during IOE infection is mediated by mTORC1. These novel findings unravel that virulent Ehrlichia may cause liver injury via mTORC1-mediated inhibition of Wnt pathway. Targeting of mTORC1 could provide a novel therapy for Ehrlichia-induced sepsis.</jats:p>