Role of mTOR Downstream Effector Signaling Molecules in Francisella Tularensis Internalization by Murine Macrophages |
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Authors: | Michael W Edwards James A Aultman Gregory Harber Jay M Bhatt Elizabeth Sztul Qingan Xu Ping Zhang Suzanne M Michalek Jannet Katz |
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Institution: | 1. Department of Pediatric Dentistry, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.; 2. Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.; 3. Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.; University of Louisville, United States of America, |
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Abstract: | Francisella tularensis is an infectious, gram-negative, intracellular microorganism, and the cause of tularemia. Invasion of host cells by intracellular pathogens like Francisella is initiated by their interaction with different host cell membrane receptors and the rapid phosphorylation of different downstream signaling molecules. PI3K and Syk have been shown to be involved in F. tularensis host cell entry, and both of these signaling molecules are associated with the master regulator serine/threonine kinase mTOR; yet the involvement of mTOR in F. tularensis invasion of host cells has not been assessed. Here, we report that infection of macrophages with F. tularensis triggers the phosphorylation of mTOR downstream effector molecules, and that signaling via TLR2 is necessary for these events. Inhibition of mTOR or of PI3K, ERK, or p38, but not Akt signaling, downregulates the levels of phosphorylation of mTOR downstream targets, and significantly reduces the number of F. tularensis cells invading macrophages. Moreover, while phosphorylation of mTOR downstream effectors occurs via the PI3K pathway, it also involves PLCγ1 and Ca2+ signaling. Furthermore, abrogation of PLC or Ca2+ signaling revealed their important role in the ability of F. tularensis to invade host cells. Together, these findings suggest that F. tularensis invasion of primary macrophages utilize a myriad of host signaling pathways to ensure effective cell entry. |
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