Targeted control of toxin production by a mobile genetic element in Streptococcus pneumoniae.

Streptococcus pneumoniae is a major human pathogen that can cause severe invasive diseases such as pneumonia, septicaemia and meningitis. Young children are at a particularly high risk, with an estimated half a million deaths worldwide in those under five attributable to invasive pneumococcal disease each year. The cytolytic toxin pneumolysin (Ply) is a primary virulence factor for this bacterium, yet despite its key role in pathogenesis, immune evasion, and transmission, the regulation of Ply production is not well defined. Using a genome-wide association approach we identified a large number of potential affectors of Ply activity, including a gene acquired horizontally on the antibiotic resistance conferring Integrative and Conjugative Element (ICE) ICESp23FST81. This gene encodes a novel modular protein, ZomB, which has an N-terminal UvrD-like helicase domain followed by two Cas4-like domains with potent ATP-dependent nuclease activity. We found the regulatory effect of ZomB to be specific for the ply operon, potentially mediated by its high affinity for the BOX repeats encoded therein. Using a murine model of pneumococcal colonisation, we further demonstrate that a ZomB mutant strain colonises both the upper respiratory tract and lungs at higher levels when compared to the wild type strain. While the antibiotic resistance conferring aspects of ICESp23FST81 is often credited with contributing to the success of the S. pneumoniae lineages that acquire it, its ability to control the expression of a major virulence factor implicated in bacterial transmission is also likely to have played an important role.