Regulation of apoptosis and anti-apoptosis signalling by Francisella tularensis

Abstract

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-κB) is not known. Whether escape of the bacteria into the cytosol is sufficient and/or essential for activation of NF-κB is not known. Our results show that F. tularensis subsp. novicida induces sustained nuclear translocation of NF-κB at early time points after infection of human monocytes derived macrophages (hMDMs). The sustained nuclear translocation of NF-κB is defective in the iglC mutant that fails to escape into the cytosol of macrophages. Nuclear translocation of NF-κB by the wild type strain is abolished upon treatment with the NF-κB 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-κB.

Production of Outer Membrane Vesicles and Outer Membrane Tubes by Francisella novicida

“…A number of studies have shown that Francisella spp. actively interfere with intracellular signaling pathways and innate immune responses of host cells (7,9,(15)(16)(17). In addition, fully virulent strains of F. tularensis are capable of inducing a broad immunosuppression during early stages of infection (18).…”

“…1 to 4 h escape into the host cell cytosol, where bacterial replication occurs (7,8). The intracellular bacteria eventually activate host cell death pathways, leading to the release and spread of Francisella (9,10).…”

“…In contrast to typical lipopolysaccharide (LPS), the LPS expressed by Francisella has low proinflammatory activity and does not signal host cells through Toll-like receptor 4 (TLR4) (13,14). In addition, the bacteria actively interfere with intracellular signaling pathways and the innate immune responses of host cells (7,9,(15)(16)(17)(18).…”

Prison Break: Pathogens' Strategies To Egress from Host Cells

“…In the case of Francisella, it is well documented that the bacterium first escapes its vacuole, a phagosome with features of a late endosomal compartment, within the first 30 min of infection (124). It then multiplies in the cytosol of its host macrophage, of mammalian or arthropod origin (122), and is able to trigger pyroptosis and cell lysis, possibly as a primary strategy for dissemination (123,125). However, at least in murine macrophages, it is subsequently taken up again into a membranous compartment by autophagy.…”

“…It is therefore considered a potent innate defense mechanism. Despite this, some pathogens, such as Francisella (123,125) and Legionella (131), exit host cells that have undergone this type of cell death. As another example, Salmonella enterica induces the extrusion of infected cells from the intestinal epithelium for dissemination into the gut and the environment.…”