The Journal of Experimental Medicine
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Published online 17 July 2000.
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© The Rockefeller University Press, 0022-1007/2000/7/249/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 2, July 17, 2000 249-258

Original Article

Salmonella Exploits Caspase-1 to Colonize Peyer's Patches in a Murine Typhoid Model

Denise M. Monacka, David Hershc, Nafisa Ghoria, Donna Bouleyb, Arturo Zychlinskyc, and Stanley Falkowa
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

Correspondence to: Denise M. Monack, Dept. of Microbiology and Immunology, Stanford School of Medicine, 299 Campus Dr., Fairchild Bldg. D 037, Stanford, CA 94305. Tel:650-498-6953 Fax:650-723-1837 E-mail: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]-1ß–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-1ß 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


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