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Infection and Immunity, June 2008, p. 2304-2315, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01437-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Induction of Guanylate Binding Protein 5 by Gamma Interferon Increases Susceptibility to Salmonella enterica Serovar Typhimurium-Induced Pyroptosis in RAW 264.7 Cells{triangledown}

Adam C. Rupper* and James A. Cardelli

Department of Microbiology and Immunology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana

Received 25 October 2007/ Returned for modification 3 December 2007/ Accepted 12 March 2008

The regulation of caspase-1 activation in macrophages plays a central role in host defense against bacterial pathogens. The activation of caspase-1 by the detection of bacterial products through Nod-like receptors leads to the secretion of mature interleukin-1β (IL-1β) and IL-18 and the induction of rapid host cell death (pyroptosis). Here, we report that pyroptosis induced by Salmonella enterica serovar Typhimurium can be positively regulated by prior gamma interferon (IFN-{gamma}) stimulation of RAW 264.7 cells. This increase in cell death is dependent on both caspase-1 activation and, in part, Salmonella pathogenicity island 1 (SPI-1) expression by Salmonella. Furthermore, the exogenous expression of the IFN-{gamma}-induced protein guanylate binding protein 5 (GBP-5) is sufficient to induce a heightened susceptibility of RAW 264.7 cells to Salmonella-induced pyroptosis, and the endogenous expression of GBP-5 is important for this phenomenon. RAW 264.7 cells with decreased expression of GBP-5 mRNA (inhibited by short hairpin RNA against GBP-5) release twofold less lactate dehydrogenase (a marker of membrane permeability) upon infection by invasive S. enterica serovar Typhimurium than do infected control cells. Importantly, 3x FLAG-tagged GBP-5 is localized to membrane ruffles, which contact invasive Salmonella, and is found on the membranes of spacious phagosomes containing Salmonella (although it is also found in the cytoplasm and on other cellular membranes), placing 3x FLAG GBP-5 at the interface of secreted SPI-1 effectors and host protein machinery. The regulation of pyroptosis by the IFN-{gamma}-induced protein GBP-5 may play an important role in the host defense against Salmonella enterica serovar Typhimurium and perhaps other invasive bacterial pathogens.

* Corresponding author. Present address: Department of Microbiology and Molecular Biology, Brigham Young University, 775 WIDB, Provo, UT 84602-5253. Phone: (801) 422-5314. Fax: (801) 422-0519. E-mail: arupper{at}gmail.com

{triangledown} Published ahead of print on 24 March 2008.

Editor: B. A. McCormick

Infection and Immunity, June 2008, p. 2304-2315, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01437-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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