NF-κB-dependent inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii infection

Abstract

The possibility that bacteria may have evolved strategies to overcome host cell apoptosis was explored by using Rickettsia rickettsii, an obligate intracellular Gram-negative bacteria that is the etiologic agent of Rocky Mountain spotted fever. The vascular endothelial cell, the primary target cell during in vivo infection, exhibits no evidence of apoptosis during natural infection and is maintained for a sufficient time to allow replication and cell-to-cell spread prior to eventual death due to necrotic damage. Prior work in our laboratory demonstrated that R. rickettsii infection activates the transcription factor NF-B and alters expression of several genes under its control. However, when R. rickettsiiinduced activation of NF-B was inhibited, apoptosis of infected but not uninfected endothelial cells rapidly ensued. In addition, human embryonic fibroblasts stably transfected with a superrepressor mutant inhibitory subunit IB that rendered NF-B inactivatable also underwent apoptosis when infected, whereas infected wild-type human embryonic fibroblasts survived. R. rickettsii, therefore, appeared to inhibit host cell apoptosis via a mechanism dependent on NF-B activation. Apoptotic nuclear changes correlated with presence of intracellular organisms and thus this previously unrecognized proapoptotic signal, masked by concomitant NF-B activation, likely required intracellular infection. Our studies demonstrate that a bacterial organism can exert an antiapoptotic effect, thus modulating the host cell's apoptotic response to its own advantage by potentially allowing the host cell to remain as a site of infection.

Activation of Akt/Protein Kinase B in Epithelial Cells by theSalmonella typhimurium Effector SigD

“…Thus it is possible that Salmonella-induced activation of Akt in epithelial cells would increase host cell survival, perhaps allowing the pathogen a greater intracellular time frame within which to replicate. Anti-apoptotic mechanisms are employed by at least two intracellular bacterial pathogens Chlamydia trachomatis (35) and Rickettsia ricketsii (36), although the bacterial factors mediating these processes have not been identified. In macrophages, Salmonella and other bacterial pathogens including Shigella specifically induce apoptosis (12,37).…”

Cell death in the host response to infection

“…By stimulating NF-kB signaling, Rickettsia prevents host cell death and continues to replicate unabated. 12 Another intracellular pathogen, Chlamidiae spp., also protects infected cells from death during the early invasive stages of the disease, presumably by blocking cytochrome c release from the mitochondria. 13 These instances clearly indicate that induction of cell death plays a beneficial role in the elimination of infection (Table 1).…”

Involvement of 5′-Flanking κB-like Sites withinbcl-x Gene in Silica-induced Bcl-x Expression

“…The nuclear transcription factor NF-B plays an important role in cell survival, proliferation, and transformation by regulating the expression of numerous genes (1)(2)(3)(4)(5). The finding that NF-B is activated during or immediately before cell apoptosis under certain stimulatory conditions has led to the suggestion that this transcription factor may function to promote apoptosis.…”