Abstract
The bacterial factors responsible for the variation in invasive potential between different clones and serotypes of Streptococcus pneumoniae are largely unknown. Therefore, the isolation of rare serotype 1 carriage strains in Indigenous Australian communities provided a unique opportunity to compare the genomes of non-invasive and invasive isolates of the same serotype in order to identify such factors. The human virulence status of non-invasive, intermediately virulent and highly virulent serotype 1 isolates was reflected in mice and showed that whilst both human non-invasive and highly virulent isolates were able to colonize the murine nasopharynx equally, only the human highly virulent isolates were able to invade and survive in the murine lungs and blood. Genomic sequencing comparisons between these isolates identified 8 regions >1 kb in size that were specific to only the highly virulent isolates, and included a version of the pneumococcal pathogenicity island 1 variable region (PPI-1v), phage-associated adherence factors, transporters and metabolic enzymes. In particular, a phage-associated endolysin, a putative iron/lead permease and an operon within PPI-1v exhibited niche-specific changes in expression that suggest important roles for these genes in the lungs and blood. Moreover, in vivo competition between pneumococci carrying PPI-1v derivatives representing the two identified versions of the region showed that the version of PPI-1v in the highly virulent isolates was more competitive than the version from the less virulent isolates in the nasopharyngeal tissue, blood and lungs. This study is the first to perform genomic comparisons between serotype 1 isolates with distinct virulence profiles that correlate between mice and humans, and has highlighted the important role that hypervariable genomic loci, such as PPI-1v, play in pneumococcal disease. The findings of this study have important implications for understanding the processes that drive progression from colonization to invasive disease and will help direct the development of novel therapeutic strategies.
Highlights
IntroductionStreptococcus pneumoniae (the pneumococcus) is a leading cause of bacterial pneumonia, invasive disease (bacteremia and meningitis [IPD]) and otitis media, and is responsible for .1 million deaths in children ,5 years of age annually [1]
Streptococcus pneumoniae is a leading cause of bacterial pneumonia, invasive disease and otitis media, and is responsible for .1 million deaths in children,5 years of age annually [1]
Whilst a number of potential virulence determinants such as the pilus encoded within the rlrA islet and the pneumococcal serine rich repeat protein (PsrP) have received particular attention, little consistency between the presence of specific virulence determinants and invasive potential has been found in large-scale comparisons [10,14,15,16,17,18,19,20,21]
Summary
Streptococcus pneumoniae (the pneumococcus) is a leading cause of bacterial pneumonia, invasive disease (bacteremia and meningitis [IPD]) and otitis media, and is responsible for .1 million deaths in children ,5 years of age annually [1]. Whilst serotype 1 isolates have a high invasive potential, commonly studied serotype 1 clones tend to cause less severe disease in both humans and mice when compared to certain other serotypes and clones that behave as opportunistic pathogens [4,6]. It is possible that such large-scale comparisons fail to take into account the significant differences in virulence that may exist within groups of isolates with apparently equivalent invasive potential, such as hypervirulent and moderately virulent serotype 1 clones [14]. The human virulence status of non-invasive and invasive serotype 1 isolates was confirmed in mouse models of infection, enabling these isolates to be grouped as non-invasive, intermediately virulent and highly virulent Using these virulence profiles as a basis, preliminary comparisons between the three virulence phenotypes were performed using comparative genomic hybridization (CGH), and generation genome sequencing technology. Of particular significance was that the highly virulent isolates harbored a version of the pneumococcal pathogenicity island 1 (PPI-1) that conferred greater competitiveness in vivo than the versions in less virulent isolates
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