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Ingram JP , Tursi S , Zhang T , Guo W , Yin C , AWynosky-Dolfi M , van der Heijden J , Cai KQ , Yamamoto M , Finlay BB , Brodsky IE , Grivennikov SI , Tukel C , Balachandran S
A Nonpyroptotic IFN-gamma-Triggered Cell Death Mechanism in Nonphagocytic Cells Promotes Salmonella Clearance In Vivo
J Immunol. 2018 May15;200(10) :3626-3634
PMID: 29654208    PMCID: PMC6034694    URL: https://www.ncbi.nlm.nih.gov/pubmed/29654208
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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.
1550-6606 Ingram, Justin P Tursi, Sarah Zhang, Ting Guo, Wei Yin, Chaoran A Wynosky-Dolfi, Meghan van der Heijden, Joris Cai, Kathy Q Yamamoto, Masahiro Finlay, B Brett Brodsky, Igor E ORCID: http://orcid.org/0000-0001-7970-872X Grivennikov, Sergei I Tukel, Cagla ORCID: http://orcid.org/0000-0001-7073-0226 Balachandran, Siddharth Journal Article United States R01 CA168621/CA/NCI NIH HHS/ R00 DK088589/DK/NIDDK NIH HHS/ R01 CA190542/CA/NCI NIH HHS/ R01 AI135025/AI/NIAID NIH HHS/ R21 AI113469/AI/NIAID NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ J Immunol. 2018 May 15;200(10):3626-3634. doi: 10.4049/jimmunol.1701386. Epub 2018 Apr 13.