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© The Rockefeller University Press, 0021-9525/2003/12/1123 $8.00
The Journal of Cell Biology, Volume 163, Number 5, 1123-1131

A Salmonella protein causes macrophage cell death by inducing autophagy

¹ Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510
² Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510
³ Section of Immunobiology and the Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510

Address correspondence to J.E. Galán, Section of Microbial Pathogenesis, Yale University School of Medicine, BCMM 354, 295 Congress Ave., New Haven, CT 06536-0812. Tel.: (203) 737-2404. Fax: (203) 737-2630. email: jorge.galan{at}yale.edu

Salmonella enterica, the causative agent of food poisoning and typhoid fever, induces programmed cell death in macrophages, a process found to be dependent on a type III protein secretion system, and SipB, a protein with membrane fusion activity that is delivered into host cells by this system. When expressed in cultured cells, SipB caused the formation of and localized to unusual multimembrane structures. These structures resembled autophagosomes and contained both mitochondrial and endoplasmic reticulum markers. A mutant form of SipB devoid of membrane fusion activity localized to mitochondria, but did not induce the formation of membrane structures. Upon Salmonella infection of macrophages, SipB was found in mitochondria, which appeared swollen and devoid of christae. Salmonella-infected macrophages exhibited marked accumulation of autophagic vesicles. We propose that Salmonella, through the action of SipB, kills macrophages by disrupting mitochondria, thereby inducing autophagy and cell death.

Key Words: apoptosis; bacterial pathogenesis; membrane fusion; host–pathogen interactionl; type III protein secretion

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