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. 2009 Apr;77(4):1589-95.
doi: 10.1128/IAI.01257-08. Epub 2009 Jan 29.

Caspase-1 mediates resistance in murine melioidosis

Katrin Breitbach  1 , Guang Wen Sun, Jens Köhler, Kristin Eske, Patimaporn Wongprompitak, Gladys Tan, Yichun Liu, Yunn-Hwen Gan, Ivo Steinmetz
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Caspase-1 mediates resistance in murine melioidosis (V体育平台登录)

"VSports" Katrin Breitbach et al. Infect Immun. 2009 Apr.

Abstract

The gram-negative rod Burkholderia pseudomallei is the causative agent of melioidosis, a potentially fatal disease which is endemic in tropical and subtropical areas. The bacterium multiplies intracellularly within the cytosol, induces the formation of actin tails, and can spread directly from cell to cell. Recently, it has been shown that B. pseudomallei can induce caspase-1-dependent cell death in macrophages. The aim of the present study was to further elucidate the role of caspase-1 during B. pseudomallei infection. In vivo experiments with caspase-1(-/-) mice revealed a high susceptibility to B. pseudomallei challenge. This phenotype was associated with a significantly higher bacterial burden 2 days after infection and decreased gamma interferon (IFN-gamma) and interleukin-18 cytokine levels 24 h after infection compared to control animals. caspase-1(-/-) bone marrow-derived macrophages (BMM) exhibited strong caspase-3 expression and reduced cell damage compared to wild-type (WT) cells during early B. pseudomallei infection, indicating "classical" apoptosis, whereas WT BMM showed signs of rapid caspase-1-dependent cell death. Moreover, we found that caspase-1(-/-) BMM had a strongly increased bacterial burden compared to WT cells 3 h after infection under conditions where no difference in cell death could be observed between both cell populations at this time point. We therefore suggest that caspase-1-dependent rapid cell death might contribute to resistance by reducing the intracellular niche for B. pseudomallei, but, in addition, caspase-1 might also have a role in controlling intracellular replication of B. pseudomallei in macrophages VSports手机版. Moreover, caspase-1-dependent IFN-gamma production is likely to contribute to resistance in murine melioidosis. .

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Figures

FIG. 1.
FIG. 1.
(A and B) Survival curves of C57BL/6 WT and caspase-1−/− mice after intranasal infection with B. pseudomallei KHW (A) and E8 (B). Mice received ∼100 CFU per animal. All WT mice survived for at least 2 weeks (data not shown). Statistical analyses were performed by using a Kaplan-Meier test. (C) Bacterial loads in spleens, livers, and lungs of B. pseudomallei E8-infected mice were determined 24 h and 48 h after infection. Each dot represents the bacterial count of the respective organ of a single animal. The horizontal line represents the median of each group. Statistical analyses were performed by using a Mann-Whitney test. For all panels, data were obtained and pooled from two independent experiments. n.s., nonsignificant. *, P < 0.05; **, P < 0.01.
FIG. 2.
FIG. 2.
Detection of IFN-γ (n = 4) (A) and IL-18 (n = 7) (B) release in the serum of caspase-1−/− and C57BL/6 WT mice 24 h after intranasal infection with B. pseudomallei E8. Uninfected mice revealed either no detectable or negligible amounts of IFN-γ and IL-18 release (data not shown). Values are the means ± standard deviations. Statistical analysis was performed by using a Student's t test. **, P < 0.01; ***, P < 0.001.
FIG. 3.
FIG. 3.
Course of cell damage in C57BL/6 WT and caspase-1−/− BMM after B. pseudomallei E8 infection at the indicated MOIs. Values are the means ± standard deviations from triplicate determinations. One out of at least three independent experiments with similar results is shown. Statistical analyses were performed by using a Student's t test. n.s., not significant. **, P < 0.01; ***, P < 0.001.
FIG. 4.
FIG. 4.
(A) Release of IL-1β from C57BL/6 WT and caspase-1−/− BMM 6 h after B. pseudomallei E8 infection (MOI of ∼30). Values are the means ± standard deviations from triplicate determinations. One out of three independent experiments with similar results is shown. Statistical analysis was performed by using a Student's t test. (B) Caspase-3 activity of caspase-1−/− and C57BL/6 WT macrophages 4 h after B. pseudomallei E8 infection (MOI of ∼30). Data were obtained from three independent experiments. Statistical analysis was performed by two-way analysis of variance. **, P < 0.01; ***, P < 0.001.
FIG. 5.
FIG. 5.
(A to D) Course of the bacterial burden in C57BL/6 WT and caspase-1−/− BMM after B. pseudomallei infection. (A) Unstimulated BMM infected at an MOI of ∼3. (B) IFN-γ-stimulated macrophages infected at an MOI of ∼3. (C) Unstimulated BMM infected at an MOI of ∼30. (D) IFN-γ-stimulated BMM infected at an MOI of ∼30. (E) Bacterial load in caspase-1-inhibited (Ac-YVAD-cmk [Ac-YVAD] treated) BMM from BALB/c and C57BL/6 mice 6 h after infection with B. pseudomallei E8 (MOI of 30). Bacterial uptake after infection was comparable for all types of macrophages (data not shown). Values are the means ± standard deviations from triplicate determinations. One out of at least three independent experiments with similar results is shown. Statistical analyses were performed by using a Student's t test. **, P < 0.01; ***, P < 0.001. w/o, without.
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References

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