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Infection and Immunity, October 2000, p. 5702-5709, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Salmonella Pathogenicity Island 1-Independent Induction of Apoptosis in Infected Macrophages by Salmonella enterica Serotype Typhimurium

Adrianus W. M. van der Velden,1 Susanne W. Lindgren,1,2 Micah J. Worley,1 and Fred Heffron1,*

Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, Oregon 97201-3098,1 and Department of Biology, California State University, Sacramento, California 95819-60772

Received 14 April 2000/Accepted 30 June 2000

The enteric pathogen Salmonella enterica serotype Typhimurium induces apoptosis in infected macrophages. This process is rapid, specific, and depends on the type III protein secretion system encoded within Salmonella pathogenicity island 1 (SPI1). Here, we demonstrate that serotype Typhimurium can activate programmed macrophage cell death independently of SPI1. SPI1 independent induction of apoptosis in infected macrophages is observed as early as 12 to 13 h postinfection, even in the absence of intracellular bacterial replication. Delayed activation of programmed macrophage cell death is not observed with serotype Typhimurium strains mutated in ompR or SPI2. Even though SPI2 mutants have a defect in intracellular proliferation, our results indicate that long-term intracellular survival and growth are not required for delayed macrophage killing per se, since Salmonella mutants that are severely defective in intracellular growth still induce delayed apoptosis. Inactivation of genes required for either rapid or delayed induction of apoptosis results in a conditional noncytotoxic phenotype, whereas simultaneous inactivation of genes required for both rapid and delayed induction of apoptosis renders serotype Typhimurium noncytotoxic under all conditions tested. Our hypothesis is that differential activation of programmed macrophage cell death by serotype Typhimurium occurs under discrete physiological conditions at distinct locations within an infected host.


* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., L220, Portland, OR 97201-3098. Phone: (503) 494-6738. Fax: (503) 494-6862. E-mail: heffronf{at}ohsu.edu.


Infection and Immunity, October 2000, p. 5702-5709, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.



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