A Nonpyroptotic IFN-γ-Triggered Cell Death Mechanism in Nonphagocytic Cells Promotes Salmonella Clearance In Vivo

The cytokine IFN-gamma has well-established antibacterial properties against the bacterium Salmonella enterica in phagocytes, but less is known about the effects of IFN-gamma on Salmonella-infected nonphagocytic cells, such as intestinal epithelial cells (IECs) and fibroblasts. In this article, we show that exposing human and murine IECs and fibroblasts to IFN-gamma following infection with Salmonella triggers a novel form of cell death that is neither pyroptosis nor any of the major known forms of programmed cell death. Cell death required IFN-gamma-signaling via STAT1-IRF1-mediated induction of guanylate binding proteins and the presence of live Salmonella in the cytosol. In vivo, ablating IFN-gamma signaling selectively in murine IECs led to higher bacterial burden in colon contents and increased inflammation in the intestine of infected mice. Together, these results demonstrate that IFN-gamma signaling triggers release of Salmonella from the Salmonella-containing vacuole into the cytosol of infected nonphagocytic cells, resulting in a form of nonpyroptotic cell death that prevents bacterial spread in the gut.