Regulation of apoptosis and anti-apoptosis signalling by Francisella tularensis.
Francisella tularensis induces apoptosis within macrophages but the temporal and spatial modulation through activation of caspase-1, caspase-3, and the anti-apoptosis nuclear transcription factor B (NF-kappaB) is not known. Whether escape of the bacteria into the cytosol is sufficient and/or essential for activation of NF-kappaB is not known. Our results show that F. tularensis subsp. novicida induces sustained nuclear translocation of NF-kappaB at early time points after infection of human monocytes derived macrophages (hMDMs). The sustained nuclear translocation of NF-kappaB is defective in the iglC mutant that fails to escape into the cytosol of macrophages. Nuclear translocation of NF-kappaB by the wild type strain is abolished upon treatment with the NF-kappaB inhibitor caffein acid phenyl ester. While the wild type strain triggers caspase-3 and caspase-1 activation by 6 h post-infection the iglC mutant is defective in triggering both caspases. In hMDMs treated with the apoptosis-inducing agent, staurosporin, there is an induction of cell death in the iglC mutant-infected macrophages despite reduced frequency of caspase-1 and caspase-3 activity. The wt-infected macrophages are resistant to cell death-induced agent. We conclude that although caspase-1 and capsase-3 are triggered within F. tularensis-infected hMDMs during early stages of infection, cell death is delayed, which is correlated with simultaneous activation of NF-kappaB.
Santic
Marina
M
Department of Microbiology and Parasitology, University of Rijeka, Medical Faculty, Brace Branchetta 20, 51000 Rijeka, Croatia. marina@medri.hr
Pavokovic
Gordana
G
Jones
Snake
S
Asare
Rexford
R
Kwaik
Yousef Abu
YA
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004789:Enzyme Activation; D005604:Francisella tularensis / Q000472:pathogenicity*; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction
D051017:Apoptosis Regulatory Proteins; D016328:NF-kappa B; D053148:Caspase 3; D020170:Caspase 1