title: Salmonella exploits caspase-1 to colonize Peyer's patches in a murine typhoid model.
abstract: 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]-1beta-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-1beta 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 (LD(50)) 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 LD(50). 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.
authors.affiliation: Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, California 94305, USA. dmonack@leland.stanford.edu
authors.forename: D M
authors.initials: DM
authors.lastname: Monack
authors.forename: D
authors.initials: D
authors.lastname: Hersh
authors.forename: N
authors.initials: N
authors.lastname: Ghori
authors.forename: D
authors.initials: D
authors.lastname: Bouley
authors.forename: A
authors.initials: A
authors.lastname: Zychlinsky
authors.forename: S
authors.initials: S
authors.lastname: Falkow
mesh_terms: D000818:Animals; D017209:Apoptosis; D020170:Caspase 1 / Q000502:physiology*; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010581:Peyer's Patches / Q000382:microbiology*; D012486:Salmonella typhimurium / Q000472:pathogenicity*; D014435:Typhoid Fever / Q000276:immunology* / Q000469:parasitology / Q000473:pathology
chemical_list: D020170:Caspase 1