Caspase-1 mediates resistance in murine melioidosis.
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. Moreover, caspase-1-dependent IFN-gamma production is likely to contribute to resistance in murine melioidosis.
Breitbach
Katrin
K
Friedrich Loeffler Institute of Medical Microbiology, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
Sun
Guang Wen
GW
Köhler
Jens
J
Eske
Kristin
K
Wongprompitak
Patimaporn
P
Tan
Gladys
G
Liu
Yichun
Y
Gan
Yunn-Hwen
YH
Steinmetz
Ivo
I
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D016957:Burkholderia pseudomallei / Q000254:growth & development / Q000472:pathogenicity* / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000382:microbiology; D008297:Male; D008554:Melioidosis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL
D020382:Interleukin-18; D007371:Interferon-gamma; D020170:Caspase 1