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

dc.contributor.authorStevens, Emily J.
dc.contributor.authorMorse, Daniel J.
dc.contributor.authorBonini, Dora
dc.contributor.authorDuggan, Seana
dc.contributor.authorBrignoli, Tarcisio
dc.contributor.authorRecker, Mario
dc.contributor.authorLees, John A.
dc.contributor.authorCroucher, Nicholas J.
dc.contributor.authorBentley, Stephen
dc.contributor.authorWilson, Daniel J.
dc.contributor.authorEarle, Sarah G.
dc.contributor.authorDixon, Robert
dc.contributor.authorNobbs, Angela
dc.contributor.authorJenkinson, Howard
dc.contributor.authorvan Opijnen, Tim
dc.contributor.authorThibault, Derek
dc.contributor.authorWilkinson, Oliver J.
dc.contributor.authorDillingham, Mark S.
dc.contributor.authorCarlile, Simon
dc.contributor.authorMcLoughlin, Rachel M.
dc.contributor.authorMassey, Ruth C.
dc.contributor.funderBiotechnology and Biological Sciences Research Councilen
dc.contributor.funderWellcome Trusten
dc.contributor.funderMedical Research Councilen
dc.description.abstractStreptococcus 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 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) 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 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 ICESp23FST81 are 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.en
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council (SWBio DTP PhD funding); Medical Research Council (PhD funding); Wellcome Trust-funded Investigators (Grant reference numbers: 212258/Z/18/Z and 202846/Z/16/Z). D.J.W. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant 101237/Z/13/B) and is supported by a Big Data Institute Robertson Fellowshipen
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.identifier.citationStevens, E. J., Morse, D. J., Bonini, D., Duggan, S., Brignoli, T., Recker, M., Lees, J. A., Croucher, N. J., Bentley, S., Wilson, D. J., Earle, S. G., Dixon, R., Nobbs, A., Jenkinson, H., van Opijnen, T., Thibault, D., Wilkinson, O. J., Dillingham, M. S., Carlile, S., McLoughlin, R. M. and Massey, R. C. (2022) 'Targeted control of pneumolysin production by a mobile genetic element in Streptococcus pneumoniae', Microbial Genomics, 8(4), 000784 (14pp). doi: 10.1099/mgen.0.000784en
dc.identifier.journaltitleMicrobial Genomicsen
dc.publisherMicrobiology Societyen
dc.rights© 2021, the Authors. 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.en
dc.subjectStreptococcus pneumoniaeen
dc.subjectICE elementsen
dc.subjectPneumolysin regulationen
dc.subjectZomB proteinen
dc.titleTargeted control of pneumolysin production by a mobile genetic element in Streptococcus pneumoniaeen
dc.typeArticle (peer-reviewed)en
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