Tripartite toxin-antitoxin system regulates the production and release of pneumolysin by Streptococcus pneumoniae

The production of toxins is critical to the success of bacteria, with their targets and outcomes varying widely. Pneumolysin (Ply), produced by the major human pathogen Streptococcus pneumoniae, is a cytolytic pore forming toxin that plays many diverse roles including inducing tissue damage and inflammation, evasion of many aspects of the human immune system, invasion of the bacteria into deeper tissue, and transmission to new hosts. Despite its importance, many aspects of the biology of this toxin have to date remained unknown, in particular, what role of the three other genes that form part of the ply operon play in Ply production. Here we demonstrate that these genes encode a complex regulatory system, that includes a putative membrane destabilising protein (PlyA) and a MazEF-like toxin-antitoxin system (PlyB and PlyC), the toxin of which (PlyC) destabilises the Ply transcript. We propose a tripartite model whereby when the operon reaches relatively high levels of expression PlyA destabilises the S. pneumoniae membrane creating a stress that triggers a necessary negative feedback loop which results in the degradation of the PlyB antitoxin, release of the PlyC toxin and degradation of the ply transcript, thereby providing a means by which Ply production can be tightly regulated. Given the importance of Ply to the ability of S. pneumoniae to cause infection, identifying the factors that result in the shutdown of Ply production and release by the bacteria would seem promising target for future therapeutic strategies.