In this article, authors demonstrate that the intracellular pathogen Listeria monocytogenes modulates gene expression of the host by inducing histone modifications, via secretion of the virulence factor listeriolysin O (LLO). They found that LLO provokes the dephosphorylation of H3S10 and deacetylation of H4 in HeLa cells. As H3S10 dephosphorylation occurs early in infection, they hypothesized that the effect might occur by secretion of toxins. To this end, they evaluated several virulence factor mutants, and found that the ∆hly strain (LLO defective) had no effect on phospho- H3S10 levels, compared to the wild- type; complementation of the mutation restored the wild type phenotype. Later, when HeLa cells were treated with purified LLO, it was able to induce both H3S10 dephosphorylation and H4 deacetylation. Total levels of histone did not vary, meaning that bacteria did not induce histone degradation. The same effect was seen in other cell lines. As LLO is member of the CDC family of toxins, they evaluated other members of this group (Clostridium perfringens PFO and Streptococcus pneumoniae PLY) for the same effects, and found that both PFO and PLY induced similar levels of dephosphorylation, suggesting that this could be a property of the whole CDC family. They later observed (using microarrays and real time PCR) that the expression was being modulated by the infection: ~50 repressed and ~100 induced genes. phospho- H3S10 ChIP experiments confirmed that LLO treatment modulated the expression in these genes, and western blots showed that the same subset of genes were targeted for H4 modification. Interestingly, none of the up- regulated genes has known implications in the immune response; in contrast, some down- regulated genes are indeed involved in immune processes, meaning that Listeria might counteract the host immunity before invasion. Other assays using MAPK, PKC, and NF-kB pathways inhibitors, did not block the effect of LLO on H3S10, suggesting that H3S10 dephosphorylation must be induced through a pathway not yet described. The same results were seen for inhibitors to tyrosine kinases, serine/threonine kinases, and phosphatidyl- inositol kinases.
Epigenetic regulation by LLO is thus a so far unsuspected function for this key virulence factor [...]. LLO most likely activates a [yet unknown] signaling cascade.
epigenetics
