Abstract
Streptococcus pneumoniae is the world's leading cause of pneumonia, bacteremia, meningitis and otitis media. A major pneumococcal virulence factor is the cholesterol-dependent cytolysin, which has the defining property of forming pores in cholesterol-containing membranes. In recent times a clinically significant and internationally successful serotype 1 ST306 clone has been found to express a non-cytolytic variant of Ply (Ply306). However, while the pneumococcus is a naturally transformable organism, strains of the ST306 clonal group have to date been virtually impossible to transform, severely restricting efforts to understand the role of non-cytolytic Ply in the success of this clone. In this study isogenic Ply mutants were constructed in the D39 background and for the first time in the ST306 background (A0229467) to enable direct comparisons between Ply variants for their impact on the immune response in a macrophage-like cell line. Strains that expressed cytolytic Ply were found to induce a significant increase in IL-1β release from macrophage-like cells compared to the non-cytolytic and Ply-deficient strains in a background-independent manner, confirming the requirement for pore formation in the Ply-dependent activation of the NLRP3 inflammasome. However, cytolytic activity in the D39 background was found to induce increased expression of the genes encoding GM-CSF (CSF2), p19 subunit of IL-23 (IL23A) and IFNβ (IFNB1) compared to non-cytolytic and Ply-deficient D39 mutants, but had no effect in the A0229467 background. The impact of Ply on the immune response to the pneumococcus is highly dependent on the strain background, thus emphasising the importance of the interaction between specific virulence factors and other components of the genetic background of this organism.
Highlights
Streptococcus pneumoniae is responsible for almost 1 million deaths in children under 5 years of age annually, and is the leading cause of diseases such as pneumonia, bacteremia, meningitis and otitis media
While the importance of Ply as a pneumococcal virulence factor has been known for decades, it is becoming increasingly clear that the role Ply plays in disease is more complex than originally thought
The apparent success of clonal types that express noncytolytic variants of Ply suggest that cytolytic activity may not be an essential property in certain contexts
Summary
Streptococcus pneumoniae (the pneumococcus) is responsible for almost 1 million deaths in children under 5 years of age annually, and is the leading cause of diseases such as pneumonia, bacteremia, meningitis and otitis media. The defining property of Ply is its ability to form pores in cholesterol-containing membranes, causing potent induction of inflammation and tissue damage [7,9,10,11,12,13]. Amongst a number of responses, pore formation activates the NLRP3 inflammasome, leading to Caspase-1 activation and subsequent processing and release of IL1b from immune cells [17]. There is some evidence to suggest that Ply-induced pore formation is responsible for potassium efflux and lysosomal destabilization that are detected either directly by NLRP3 or via intermediary factors leading to inflammasome assembly and Caspase-1 activation [17]. IL-1b release is indicative of Ply-dependent activation of the NLRP3 inflammasome [17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
