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Updated: Sep 27, 2025
Constructing Mutants in Serotype 1 Streptococcus pneumoniae strain 519/43
Published on: September 11, 2020
Targeted control of pneumolysin production by a mobile genetic element in Streptococcus pneumoniae
Emily J Stevens1, Daniel J Morse1, Dora Bonini1
1School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK.
Insights
A novel protein, ZomB, regulates pneumolysin production in Streptococcus pneumoniae. This regulation impacts bacterial colonization, suggesting a role beyond antibiotic resistance for mobile genetic elements in pathogen success.
Area of Science:
- Microbiology
- Molecular Biology
- Genetics
Background:
- Streptococcus pneumoniae causes severe invasive diseases like pneumonia and meningitis, particularly in young children.
- Pneumolysin (Ply), a hemolytic toxin, is a key virulence factor, but its production regulation is poorly understood.
- Integrative and Conjugative Elements (ICEs) carrying antibiotic resistance genes are important for bacterial adaptation.
Purpose of the Study:
- To identify novel regulators of pneumolysin (Ply) production in Streptococcus pneumoniae.
- To investigate the role of a newly identified gene, ZomB, located on an ICE, in regulating Ply activity and bacterial pathogenesis.
Main Methods:
- Genome-wide association study to identify Ply activity affectors.
- Characterization of the ZomB protein, including its domains and nuclease activity.
- In vitro studies of ZomB's interaction with the ply operon.
- Murine model of pneumococcal colonization to assess the impact of ZomB deficiency.
Main Results:
- A novel gene, ZomB, located on ICESp23FST81, was identified as a specific regulator of the ply operon.
- ZomB possesses UvrD-like helicase and Cas4-like nuclease domains, with ATP-dependent activity.
- ZomB exhibits high affinity for BOX repeats within the ply operon, suggesting a mechanism of regulation.
- A ZomB mutant strain showed increased colonization levels in the upper respiratory tract and lungs of mice.
Conclusions:
- ZomB is a novel regulator of pneumolysin production in Streptococcus pneumoniae.
- The ICESp23FST81 element contributes to S. pneumoniae success not only through antibiotic resistance but also by regulating virulence factors like Ply.
- Understanding ZomB's regulatory role provides insights into pneumococcal pathogenesis and transmission dynamics.
Abstract:
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 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.
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