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.

Infection and Cellular Defense Dynamics in a Novel 17β-Estradiol Murine Model of Chronic Human Group B Streptococcus Genital Tract Colonization Reveal a Role for Hemolysin in Persistence and Neutrophil Accumulation

“…A novel function of secreted GBS GAPDH as an inducer of macrophage apoptosis also has been shown recently (76). Induction of apoptosis represents a possible mechanism of immune suppression by GBS, as occurs for other Gram-positive pathogens (77). Although the role of GM-CSF in macrophage responses to GBS appears to be beneficial for bacterial killing, studies are now required to define its role in macrophage antimicrobial responses in the GBS-colonized genital tract (e.g., the F4/80 + cell response).…”

Enterococcus faecalis Infection Activates Phosphatidylinositol 3-Kinase Signaling To Block Apoptotic Cell Death in Macrophages

“…Gram-positive pathogens known to modulate apoptosis in host cells include Streptococcus, Staphylococcus, Bacillus, Listeria, and Clostridia species, although there appears to be limited conservation of the mechanisms involved (35). Among those more closely related to Enterococcus, group A streptococcus (GAS) induces rapid, dose-dependent apoptosis in primary and cultured macrophages and neutrophils, and it has been shown that the pore-forming cytolysin streptolysin O is necessary and sufficient for the apoptosis-inducing phenotype (36).…”

Genome-Wide Mapping of Cystitis Due to Streptococcus agalactiae and Escherichia coli in Mice Identifies a Unique Bladder Transcriptome That Signifies Pathogen-Specific Antimicrobial Defense against Urinary Tract Infection

“…Chemokine and chemokine receptor gene expression, including that of Cxcl10 (25.4, 0.006), Cxcl5 (4.27, 0.071), Cxcl9 (3.99, 0.075), and Ccl12 (2.9, 0.078), was also prominent. Other responses of note were related to apoptosis regulators and effectors, including PARP family members 9 (2.8, 0.058), 12 (2.5, 0.053), and 14 (3.1, 0.088), CARD 5 (3.0, 0.035), and neutrophil apoptosis (3.3, 0.093), given the ability of GBS to induce apoptosis and PARP cleavage (79). Unexpectedly, several key defense molecules associated with GBS in other (non-UTI) infection models such as inducible nitric oxide synthase (iNOS) (78) and TNF-␣ (27) were not detected as significantly altered in expression in the bladder transcriptome.…”