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Original Article

^a Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, California 94305
^b Department of Comparative Medicine, Stanford School of Medicine, Stanford University, Stanford, California 94305
^c Skirball Institute, Department of Microbiology and Kaplan Cancer Center, New York University School of Medicine, New York, New York 10016
Dept. of Microbiology and Immunology, Stanford School of Medicine, 299 Campus Dr., Fairchild Bldg. D 037, Stanford, CA 94305.650-723-1837650-498-6953

dmonack{at}leland.stanford.edu

Salmonella typhimurium invades host macrophages and induces apoptosis and the release of mature proinflammatory cytokines. SipB, a protein translocated by Salmonella into the cytoplasm of macrophages, is required for activation of Caspase-1 (Casp-1, an interleukin [IL]-1β–converting enzyme), which is a member of a family of cysteine proteases that induce apoptosis in mammalian cells. Casp-1 is unique among caspases because it also directly cleaves the proinflammatory cytokines IL-1β and IL-18 to produce bioactive cytokines. We show here that mice lacking Casp-1 (casp-1^–/– mice) had an oral S. typhimurium 50% lethal dose (LD₅₀) that was 1,000-fold higher than that of wild-type mice. Salmonella breached the M cell barrier of casp-1^–/– mice efficiently; however, there was a decrease in the number of apoptotic cells, intracellular bacteria, and the recruitment of polymorphonuclear lymphocytes in the Peyer's patches (PP) as compared with wild-type mice. Furthermore, Salmonella did not disseminate systemically in the majority of casp-1^–/– mice, as demonstrated by significantly less colonization in the PP, mesenteric lymph nodes, and spleens of casp-1^–/– mice after an oral dose of S. typhimurium that was 100-fold higher than the LD₅₀. The increased resistance in casp-1^–/– animals appears specific for Salmonella infection since these mice were susceptible to colonization by another enteric pathogen, Yersinia pseudotuberculosis, which normally invades the PP. These results show that Casp-1, which is both proapoptotic and proinflammatory, is essential for S. typhimurium to efficiently colonize the cecum and PP and subsequently cause systemic typhoid-like disease in mice.

Key Words: apoptosis • pathogenesis • intestine • inflammation • macrophages

© 2000 The Rockefeller University Press

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