1887

Abstract

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 3–4 million cases of severe disease and between 300 000 and 500 000 deaths attributable to pneumococcal disease each year. The haemolytic 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) ICE23FST81. 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 operon, potentially mediated by its high affinity for the BOX repeats encoded therein. Using a murine model of pneumococcal colonization, we further demonstrate that a ZomB mutant strain colonizes both the upper respiratory tract and lungs at higher levels when compared to the wild-type strain. While the antibiotic resistance-conferring aspects of ICE23FST81 are often credited with contributing to the success of the 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.

Funding
This study was supported by the:
  • Wellcome Trust (Award 101237/Z/13/B)
    • Principle Award Recipient: DanielJ. Wilson
  • Wellcome Trust (Award 202846/Z/16/Z)
    • Principle Award Recipient: RachelM McLoughlin
  • Wellcome Trust (Award 212258/Z/18/Z)
    • Principle Award Recipient: RuthC Massey
  • Medical Research Foundation (Award DTP Studentship)
    • Principle Award Recipient: DoraBonini
  • Biotechnology and Biological Sciences Research Council (Award DTP Studentship)
    • Principle Award Recipient: EmilyJ Stevens
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2022-04-13
2022-07-06
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