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Salmonella exploits caspase-1 to colonize Peyer's patches in a murine typhoid model.

Monack DM, Hersh D, Ghori N, Bouley D, Zychlinsky A, Falkow S - J. Exp. Med. (2000)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, California 94305, USA. dmonack@leland.stanford.edu

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.

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(continues on facing page). S. typhimurium induces inflammation in wild-type PP but not in casp-1−/− PP. Transmission electron micrographs of infected PP revealed bacterial invasion of M cells at 0.5 h in wild-type (a) and casp-1−/− (b) PP, and at 1 h in (c) extracellular Salmonella in wild-type and (d) intracellular bacteria in casp-1−/− PP. At 3 h, wild-type PP dome revealed an infiltration of PMNs and intracellular Salmonella (e), whereas casp-1−/− PP revealed an absence of PMNs and bacteria (f). Hematoxylin and eosin stains of PP from casp-1+/+ (g) mice infected for 3 h revealed clusters of PMNs (black arrows) and pyknotic cells (arrowheads), whereas casp-1−/− PP did not (h). Uninfected, wild-type PP are shown for comparison (i). Yellow arrows point to the PP dome area. Serial tissue sections were stained with anti-Salmonella antibody to confirm that the PP shown was infected. All sections are oriented with intestinal lumen at the top and lymphoid follicle at the bottom.
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Figure 3: (continues on facing page). S. typhimurium induces inflammation in wild-type PP but not in casp-1−/− PP. Transmission electron micrographs of infected PP revealed bacterial invasion of M cells at 0.5 h in wild-type (a) and casp-1−/− (b) PP, and at 1 h in (c) extracellular Salmonella in wild-type and (d) intracellular bacteria in casp-1−/− PP. At 3 h, wild-type PP dome revealed an infiltration of PMNs and intracellular Salmonella (e), whereas casp-1−/− PP revealed an absence of PMNs and bacteria (f). Hematoxylin and eosin stains of PP from casp-1+/+ (g) mice infected for 3 h revealed clusters of PMNs (black arrows) and pyknotic cells (arrowheads), whereas casp-1−/− PP did not (h). Uninfected, wild-type PP are shown for comparison (i). Yellow arrows point to the PP dome area. Serial tissue sections were stained with anti-Salmonella antibody to confirm that the PP shown was infected. All sections are oriented with intestinal lumen at the top and lymphoid follicle at the bottom.

Mentions: Bacterial colony counts and tissue samples for microscopic examination were obtained from the ligated loops of wild-type and casp-1−/− mice infected for 0.5, 1, and 3 h. At 0.5 h after infection in both wild-type and casp-1−/− mice, Salmonella invaded M cells and produced the characteristic membrane ruffles followed by the destruction of M cells (28; Fig. 3, a and b). At 1 h, the macrophages in the dome area of wild-type PP were killed and extruded into the intestinal lumen, and bacteria were extracellular (Fig. 3 c). By 3 h, the epithelium overlying the PP in wild-type mice was virtually destroyed by invading Salmonella and there were many PMNs containing bacteria that were localized to the dome area (Fig. 3e and Fig. g). In contrast, in PP from casp-1−/− mice infected for 1 h, the majority of bacteria were inside monocytes (Fig. 3 d). By 3 h, very few bacteria were observed and the casp-1−/− PP, which showed little inflammation, were devoid of PMNs (Fig. 3f and Fig. h). Thus, Salmonella initiates an inflammatory response in casp-1+/+ mice, presumably due in part to Casp-1–mediated IL-1β and IL-18 activation.


Salmonella exploits caspase-1 to colonize Peyer's patches in a murine typhoid model.

Monack DM, Hersh D, Ghori N, Bouley D, Zychlinsky A, Falkow S - J. Exp. Med. (2000)

(continues on facing page). S. typhimurium induces inflammation in wild-type PP but not in casp-1−/− PP. Transmission electron micrographs of infected PP revealed bacterial invasion of M cells at 0.5 h in wild-type (a) and casp-1−/− (b) PP, and at 1 h in (c) extracellular Salmonella in wild-type and (d) intracellular bacteria in casp-1−/− PP. At 3 h, wild-type PP dome revealed an infiltration of PMNs and intracellular Salmonella (e), whereas casp-1−/− PP revealed an absence of PMNs and bacteria (f). Hematoxylin and eosin stains of PP from casp-1+/+ (g) mice infected for 3 h revealed clusters of PMNs (black arrows) and pyknotic cells (arrowheads), whereas casp-1−/− PP did not (h). Uninfected, wild-type PP are shown for comparison (i). Yellow arrows point to the PP dome area. Serial tissue sections were stained with anti-Salmonella antibody to confirm that the PP shown was infected. All sections are oriented with intestinal lumen at the top and lymphoid follicle at the bottom.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193260&req=5

Figure 3: (continues on facing page). S. typhimurium induces inflammation in wild-type PP but not in casp-1−/− PP. Transmission electron micrographs of infected PP revealed bacterial invasion of M cells at 0.5 h in wild-type (a) and casp-1−/− (b) PP, and at 1 h in (c) extracellular Salmonella in wild-type and (d) intracellular bacteria in casp-1−/− PP. At 3 h, wild-type PP dome revealed an infiltration of PMNs and intracellular Salmonella (e), whereas casp-1−/− PP revealed an absence of PMNs and bacteria (f). Hematoxylin and eosin stains of PP from casp-1+/+ (g) mice infected for 3 h revealed clusters of PMNs (black arrows) and pyknotic cells (arrowheads), whereas casp-1−/− PP did not (h). Uninfected, wild-type PP are shown for comparison (i). Yellow arrows point to the PP dome area. Serial tissue sections were stained with anti-Salmonella antibody to confirm that the PP shown was infected. All sections are oriented with intestinal lumen at the top and lymphoid follicle at the bottom.
Mentions: Bacterial colony counts and tissue samples for microscopic examination were obtained from the ligated loops of wild-type and casp-1−/− mice infected for 0.5, 1, and 3 h. At 0.5 h after infection in both wild-type and casp-1−/− mice, Salmonella invaded M cells and produced the characteristic membrane ruffles followed by the destruction of M cells (28; Fig. 3, a and b). At 1 h, the macrophages in the dome area of wild-type PP were killed and extruded into the intestinal lumen, and bacteria were extracellular (Fig. 3 c). By 3 h, the epithelium overlying the PP in wild-type mice was virtually destroyed by invading Salmonella and there were many PMNs containing bacteria that were localized to the dome area (Fig. 3e and Fig. g). In contrast, in PP from casp-1−/− mice infected for 1 h, the majority of bacteria were inside monocytes (Fig. 3 d). By 3 h, very few bacteria were observed and the casp-1−/− PP, which showed little inflammation, were devoid of PMNs (Fig. 3f and Fig. h). Thus, Salmonella initiates an inflammatory response in casp-1+/+ mice, presumably due in part to Casp-1–mediated IL-1β and IL-18 activation.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, California 94305, USA. dmonack@leland.stanford.edu

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.

Show MeSH
Related in: MedlinePlus