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Review
. 2008 Apr;16(4):173-80.
doi: 10.1016/j.tim.2008.02.001. Epub 2008 Mar 18.

Staying Alive: Bacterial Inhibition of Apoptosis During Infection

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Free PMC article
Review

Staying Alive: Bacterial Inhibition of Apoptosis During Infection

Christina S Faherty et al. Trends Microbiol. .
Free PMC article

Abstract

The ability of bacterial pathogens to inhibit apoptosis in eukaryotic cells during infection is an emerging theme in the study of bacterial pathogenesis. Prevention of apoptosis provides a survival advantage because it enables the bacteria to replicate inside host cells. Bacterial pathogens have evolved several ways to prevent apoptosis by protecting the mitochondria and preventing cytochrome c release, by activating cell survival pathways, or by preventing caspase activation. This review summarizes the most recent work on bacterial anti-apoptotic strategies and suggests new research that is necessary to advance the field.

Figures

Figure 1
Figure 1
The apoptosis pathway. Apoptosis is activated by intrinsic and extrinsic pathways. In the intrinsic pathway, certain apoptotic stimuli alter the normal status of the Bcl-2 family of proteins (Box 1), which leads to permeabilization of the mitochondrial membrane. Under normal circumstances, the pro-survival proteins of the Bcl-2 family protect the mitochondrial membrane. Once cytochrome c (CytoC) is released into the cytosol, it binds to the apoptosome [1], a complex of proteins made up of the apoptosis activating factor-1 (Apaf1) protein and the initiator caspase-9. A morphological change in the apoptosome results from cytochrome c binding, which causes caspase-9 to become activated. Caspase-9 activates the effector caspase-3, leading to apoptosis [1]. Caspase-3 is known as the ‘executioner caspase’, because it activates or cleaves various protein targets, which is detrimental to the cell and results in death [1]. Activation of caspase-9 and caspase-3 are normally inhibited by a family of proteins known as the inhibitor of apoptosis proteins (IAPs), and XIAP (X-linked IAP) is the most potent IAP [1]. In the extrinsic pathway, ligands such as Fas ligand (FasL) or tumor necrosis factor α (TNF-α) bind to death receptors on the membrane of the host cell. Trimerization of the death receptors follows, forming what is known as the death-inducing signaling complex (DISC), which includes the Fas-associated death domain (FADD) adaptor protein, the Flice-like inhibitory protein (FLIP), and procaspase-8 [2]. Caspase-8 is activated, which in turn directly activates caspase-3 [1]. In addition, caspase-8 activates the pro-apoptotic protein Bid, which stimulates the intrinsic pathway to enhance the apoptotic signal, because Bid activation eventually leads to cytochrome c release [1].
Figure 2
Figure 2
Mechanisms by which bacterial pathogens inhibit apoptosis at different points along the apoptotic pathway. Chlamydia secretes the chlamydial proteasome-like activity factor (CPAF) to inhibit and degrade the pro-apoptotic proteins with one BH3 domain. These pro-apoptotic proteins inhibit the pro-survival Bcl-2 proteins upon activation. The outer membrane protein porin PorB of Neisseria meningitidis prevents cytochrome c (CytoC) release. Salmonella secretes the effector SopB through a type III secretion system, resulting in the activation of the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway. This pathway prevents cytochrome c release. Anaplasma also activates the PI3K/Akt pathway in addition to activating nuclear factor kappa B (NF-κB). NF-κB prevents the release of cytochrome c and activates the inhibitor of apoptosis proteins (IAPs). Bartonella, Ehrlichia, and Rickettsia activate NF-κB as well. Shigella inhibits caspase-3 activation. Legionella directly activates caspase-3 to enhance infection, but inhibits apoptosis through NF-κB. Red lines indicate inhibition in the pathway while green arrows indicate activation. The bacterial proteins that specifically participate in apoptosis inhibition are shown, where known. The shapes of the bacteria, all shown in red, represent their morphology. P, phosphate.

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