Journal
PLOS ONE
Volume 4, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0007919
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Funding
- NCI NIH HHS [P01 CA095426] Funding Source: Medline
- NHLBI NIH HHS [R01 HL094586-01A1, R01 HL094586] Funding Source: Medline
- NIAID NIH HHS [1-U54-AI-057153, R21 AI083871-01, U54 AI057153, R01 AI059406, R21 AI083871] Funding Source: Medline
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Francisella tularensis infects macrophages and escapes phago-lysosomal fusion to replicate within the host cytosol, resulting in host cell apoptosis. Here we show that the Fas-mediated death pathway is activated in infected cells and correlates with escape of the bacterium from the phagosome and the bacterial burden. Our studies also demonstrate that constitutive activation of Akt, or deletion of SHIP, promotes phago-lysosomal fusion and limits bacterial burden in the host cytosol, and the subsequent induction of Fas expression and cell death. Finally, we show that phagosomal escape/intracellular bacterial burden regulate activation of the transcription factors sp1/sp3, leading to Fas expression and cell death. These data identify for the first time host cell signaling pathways that regulate the phagosomal escape of Francisella, leading to the induction of Fas and subsequent host cell death.
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