All ETDs from UAB

Advisory Committee Chair

Jannet Katz

Advisory Committee Members

Daniel Balkovetz

Mary-Ann Bjornsti

Peter D Burrows

Laurie Harrington

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Francisella tularensis is an intracellular pathogen and the etiologic agent of tularemia. Because virulent strains cause morbidity and lethality in human, the attenuated live vaccine strain (LVS) has been used to study F. tularensis pathogenesis in murine models, since the disease in mice resembles human tularemia. Despite growing knowledge about host responses to Francisella infection, there is scarce information on the cell signaling events involved in Francisella host cell entry and in early immune re-sponses. Therefore, the purpose of this dissertation was to assess the involvement of the mammalian target of rapamycin (mTOR) in these processes. First, we evaluated the role of mTOR on F. tularensis cell entry into murine macrophages and delineated signaling pathways associated with the mTOR pathway in this event. We showed that mTOR sig-naling is extremely important in F. tularensis LVS invasion of macrophages in a TLR2 dependent manner. Furthermore, within the context of the mTOR signaling cascade, PI3K, ERK, and p38, as well as PLC and Ca2+ signaling were also implicated in Francisella invasion. Second, we gained insight into the signaling pathways that play a role in the early host response following F. tularensis LVS invasion of macrophages and on the involvement of mTOR in this response. We showed that mTOR signaling is critical for the early, but not late, differential induction of cytokines following F. tularensis LVS infection. Nuclear translocation of IRF-1and IRF-5 was observed by inhibition of mTOR signaling, but Francisella infection rendered a differential regulation of these transcription factors. Translocation of these IRFs was associated with the activation of caspase 3 and 8, and furthermore, JNK signaling and the transcription factors Sp1 were also involved in the mTOR mediated regulation of caspase activation and IRF translocation. This dissertation demonstrates for the first time the importance of mTOR signaling in the internalization of F. tularensis LVS by murine macrophages, and in the early immune signaling events that take place as a consequence of this process.

Share

COinS