Histone modifications induced by a family of bacterial toxins

Abstract

Upon infection, pathogens reprogram host gene expression. In eukaryotic cells, genetic reprogramming is induced by the concerted activation/repression of transcription factors and various histone modifications that control DNA accessibility in chromatin. We report here that the bacterial pathogen Listeria monocytogenes induces a dramatic dephosphorylation of histone H3 as well as a deacetylation of histone H4 during early phases of infection. This effect is mediated by the major listerial toxin listeriolysin O in a pore-forming-independent manner. Strikingly, a similar effect also is observed with other toxins of the same family, such as Clostridium perfringens perfringolysin and Streptococcus pneumoniae pneumolysin. The decreased levels of histone modifications correlate with a reduced transcriptional activity of a subset of host genes, including key immunity genes. Thus, control of epigenetic regulation emerges here as an unsuspected function shared by several bacterial toxins, highlighting a common strategy used by intracellular and extracellular pathogens to modulate the host response early during infection.

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

“…Specifically, sublytic concentrations of ␣-toxin from S. aureus, streptolysin O from Streptococcus pyogenes, anthrolysin O from Bacillus anthracis, and pneumolysin from Streptococcus pneumoniae, have been shown to stimulate MAP kinase signaling (Ratner et al, 2006). In addition, pneumolysin, as well listeriolysin O from Listeria monocytogenes and perfringolysin from Clostridium perfringes, have been shown to induce histone modifications within target host cells (Hamon et al, 2007). Our results, coupled with these findings, indicate that modulation of host signaling cascades, rather than host cell lysis, may be the major physiological role for HlyA and other pore-forming toxins during the course of an infection.…”

Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3

“…A small pool of data suggests that the epigenetic circuits within a mammalian cell also respond to bacterial infections 10,11 . There are reports that show host cell signalling mediates changes in the epigenetic modifications at specific gene loci in response to bacterial infection 12,13 .…”

Listeria monocytogenesinduces host DNA damage and delays the host cell cycle to promote infection

“…33 Lm modifies host gene expression via 2 virulence factors, LntA and LLO. [20][21][22]34 LLO modulates host transcription from the extracellular milieu and is degraded once Lm escapes the vacuole, being unlikely to modify host histones from the cytoplasm. 20 Our data do not support a crucial role for LLO or any other bacterial secreted proteins acting from the extracellular milieu.…”

“…19 The interplay between Lm and the host cell cycle is understudied. Albeit Lm remains mostly cytosolic, it interferes with histone modifications 20,21 and chromatin-regulatory factors 22 to modulate host gene expression.…”