Abstract
ABSTRACTNonencapsulated Streptococcus pneumoniae (NESp) is an emerging human pathogen that colonizes the nasopharynx and is associated with noninvasive diseases such as otitis media (OM), conjunctivitis, and nonbacteremic pneumonia. Since capsule expression was previously thought to be necessary for establishment of invasive pneumococcal disease (IPD), serotype-specific polysaccharide capsules are targeted by currently licensed pneumococcal vaccines. Yet, NESp expressing oligopeptide binding proteins AliC and AliD have been isolated during IPD. Thus, we hypothesize AliC and AliD are major NESp virulence determinants that facilitate persistence and development of IPD. Our study reveals that NESp expressing AliC and AliD have intensified virulence compared to isogenic mutants. Specifically, we demonstrate AliC and AliD enhance murine nasopharyngeal colonization and pulmonary infection and are required for OM in a chinchilla model. Furthermore, AliC and AliD increase pneumococcal survival in chinchilla whole blood and aid in resistance to killing by human leukocytes. Comparative proteome analysis revealed significant alterations in protein levels when AliC and AliD were absent. Virulence-associated proteins, including a pneumococcal surface protein C variant (CbpAC), were significantly downregulated, while starvation response indicators were upregulated in the double mutant relative to wild-type levels. We also reveal that differentially expressed CbpAC was essential for NESp adherence to epithelial cells, virulence during OM, reduction of C3b deposition on the NESp surface, and binding to nonspecific IgA. Altogether, the rise in NESp prevalence urges the need to understand how NESp establishes disease and persists in a host. This study highlights the roles of AliC, AliD, and CbpAC in the pathogenesis of NESp.
Highlights
IMPORTANCE Despite the effective, widespread use of licensed pneumococcal vaccines over many decades, pneumococcal infections remain a worldwide burden resulting in high morbidity and mortality
Biofilm formation and pneumococcal viability were quantified to determine whether the absence of AliC or AliD resulted in differences in community growth phenotypes (Fig. 1; see Fig. S1A in the supplemental material)
To investigate how nonencapsulated S. pneumoniae (NESp) survives in whole blood, we examined pneumococcal survival when exposed to human neutrophils, the most abundant immune cell in blood
Summary
IMPORTANCE Despite the effective, widespread use of licensed pneumococcal vaccines over many decades, pneumococcal infections remain a worldwide burden resulting in high morbidity and mortality. Pneumococcal vaccines do not prevent pneumococcal disease caused by nonencapsulated S. pneumoniae (NESp), as this subpopulation lacks capsule expression. Selective pressure against the polysaccharide capsule provided by current vaccines has likely driven the increase in NESp colonization and disease establishment. Extensive surveillance of invasive pneumococcal disease (IPD) isolates has revealed an association of invasive disease with NESp expressing oligopeptide binding proteins AliC and AliD despite the absence of a protective, antiphagocytic capsule thought to be necessary to establish IPD [12, 16,17,18,19,20]. The isolation of IPD-associated NESp expressing AliC and AliD from geographically distinct areas of isolation suggests that these oligopeptide binding proteins afford a selective advantage during invasive disease. AliC and AliD enhances the pathogenic potential of NESp by altering protein expression that aids in bacterial persistence
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