Regulation of Apoptosis by Gram-Positive Bacteria: Mechanistic Diversity and Consequences for Immunity

Abstract

Apoptosis, or programmed cell death (PCD), is an important physiological mechanism, through which the human immune system regulates homeostasis and responds to diverse forms of cellular damage. PCD may also be involved in immune counteraction to microbial infection. Over the past decade, the amount of research on bacteria-induced PCD has grown tremendously, and the implications of this mechanism on immunity are being elucidated. Some pathogenic bacteria actively trigger the suicide response in critical lineages of leukocytes that orchestrate both the innate and adaptive immune responses; other bacteria proactively prevent PCD to benefit their own survival and persistence. Currently, the microbial virulence factors, which represent the keys to unlocking the suicide response in host cells, are a primary focus of this field. In this review, we discuss these bacterial "apoptosis regulatory molecules" and the apoptotic events they either trigger or prevent, the host target cells of this regulatory activity, and the possible ramifications for immunity to infection. Gram-positive pathogens including Staphylococcus, Streptococcus, Bacillus, Listeria, and Clostridia species are discussed as important agents of human infection that modulate PCD pathways in eukaryotic cells.

Fig. (1)

Mechanisms of intrinsic and extrinsic programmed cell death (PCD) in eukaryotic cells. Shown on the left is the current paradigm for intrinsic PCD, a pathway characterized by mitochondrial dysfunction, loss of mitochondrial membrane integrity (potential), and integrated signal transduction through various BCL-2 family members. Numerous BCL-2 proteins reside in the inner mitochondrial membrane space and contribute to cytochrome c release, subsequent caspase-9 activation, apoptosome formation, procaspase-3 cleavage, and terminal PCD events. As shown on the upper right, membrane-displayed death receptors relay initial receptor ligation by apoptotic ligands that provoke extrinsic PCD through death-effector domain-containing intracellular adaptor molecules TRADD and FADD with their corresponding procaspase protein-docking regions; these regions act as signal transducers for initiator caspase-8 or -10 activation. Subsequent downstream effector caspase function results from cleavage of procaspase-3, -6, or -7 and then acts on suicide effectors such as PARP, which causes DNA breakdown and PCD. Various activators, inhibitors, and decoys regulate both intrinsic and extrinsic pathways; these regulators keep PCD pathways in check at various levels of early-, intermediate-, and late-stage events. Induction of the nuclear transcription factor NF-κB by its inducing kinase NIK (or MAPK) activates antiapoptotic gene transcription and regulates death pathways through factors such as IAPs and FLIPs. In this manner, NF-κB exerts prosurvival effects [189]. Normally, NF-κB activity is suppressed by I-κB, which is also regulated through interactions with IAPs.

Fig. (2)

Programmed cell death (PCD) regulatory activities of gram-positive bacterial apoptosis regulatory molecules (ARMs). Numerous bacterial ARMs commandeer different elements of the intrinsic and extrinsic PCD pathways to seize control of the apoptotic machinery of the host cell; an activity that may improve the microbe’s survival and persistence. In S. aureus infection (A), α-toxin causes pores to form in the host cell membrane, which disrupts ionic balance, and alters steady state intrinsic mitochondrial PCD activity. Additionally, SEB triggers activation-induced cell death in T cells by a mechanism centered on extrinsic PCD factors involving FAS-FASL signaling. LeTx produced by B. anthracis (B) inhibits MAPK activity in macrophages and triggers PCD by a mechanism that involves activation of caspase-8. PCD in activated T cells in response to L. monocytogenes listeriolysin O (C) is characterized by a variety of alterations in both the intrinsic and extrinsic PCD pathways. Perforin and IFN-γ appear to contribute to these alterations. Finally, PCD in intestinal enterocytes triggered by C. difficile exotoxin (D) is executed by inactivation of Rho GTPases and involves toxin-induced alterations in both the intrinsic and extrinsic PCD pathways.