Dataset Information

The Pneumococcal Alpha-Glycerophosphate Oxidase Enhances Nasopharyngeal Colonization through Binding to Host Glycoconjugates.

ABSTRACT: Streptococcus pneumoniae (the pneumococcus) is a major human pathogen, causing a broad spectrum of diseases including otitis media, pneumonia, bacteraemia and meningitis. Here we examined the role of a potential pneumococcal meningitis vaccine antigen, alpha-glycerophosphate oxidase (SpGlpO), in nasopharyngeal colonization. We found that serotype 4 and serotype 6A strains deficient in SpGlpO have significantly reduced capacity to colonize the nasopharynx of mice, and were significantly defective in adherence to human nasopharyngeal carcinoma cells in vitro. We also demonstrate that intranasal immunization with recombinant SpGlpO significantly protects mice against subsequent nasal colonization by wild type serotype 4 and serotype 6A strains. Furthermore, we show that SpGlpO binds strongly to lacto/neolacto/ganglio host glycan structures containing the GlcNAc?1-3Gal? disaccharide, suggesting that SpGlpO enhances colonization of the nasopharynx through its binding to host glycoconjugates. We propose that SpGlpO is a promising vaccine candidate against pneumococcal carriage, and warrants inclusion in a multi-component protein vaccine formulation that can provide robust, serotype-independent protection against all forms of pneumococcal disease.

SUBMITTER: Mahdi LK

PROVIDER: S-EPMC5405170 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Publications

The Pneumococcal Alpha-Glycerophosphate Oxidase Enhances Nasopharyngeal Colonization through Binding to Host Glycoconjugates.

Mahdi Layla K LK Higgins Melanie A MA Day Christopher J CJ Tiralongo Joe J Hartley-Tassell Lauren E LE Jennings Michael P MP Gordon David L DL Paton Adrienne W AW Paton James C JC Ogunniyi Abiodun D AD

EBioMedicine 20170303

Streptococcus pneumoniae (the pneumococcus) is a major human pathogen, causing a broad spectrum of diseases including otitis media, pneumonia, bacteraemia and meningitis. Here we examined the role of a potential pneumococcal meningitis vaccine antigen, alpha-glycerophosphate oxidase (SpGlpO), in nasopharyngeal colonization. We found that serotype 4 and serotype 6A strains deficient in SpGlpO have significantly reduced capacity to colonize the nasopharynx of mice, and were significantly defective ...[more]

PMID: 28330602

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Project description:Streptococcus pneumoniae has evolved versatile strategies to colonize the nasopharynx of humans. Colonization is facilitated by direct interactions with host cell receptors or via binding to components of the extracellular matrix. In addition, pneumococci hijack host-derived extracellular proteases such as the serine protease plasmin(ogen) for ECM and mucus degradation as well as colonization. S. pneumoniae expresses strain-dependent up to four serine proteases. In this study, we assessed the role of secreted or cell-bound serine proteases HtrA, PrtA, SFP, and CbpG, in adherence assays and in a mouse colonization model. We hypothesized that the redundancy of serine proteases compensates for the deficiency of a single enzyme. Therefore, double and triple mutants were generated in serotype 19F strain EF3030 and serotype 4 strain TIGR4. Strain EF3030 produces only three serine proteases and lacks the SFP encoding gene. In adherence studies using Detroit-562 epithelial cells, we demonstrated that both TIGR4Δcps and 19F mutants without serine proteases or expressing only CbpG, HtrA, or PrtA have a reduced ability to adhere to Detroit-562 cells. Consistent with these results, we show that the mutants of strain 19F, which preferentially colonizes mice, abrogate nasopharyngeal colonization in CD-1 mice after intranasal infection. The bacterial load in the nasopharynx was monitored for 14 days. Importantly, mutants showed significantly lower bacterial numbers in the nasopharynx two days after infection. Similarly, we detected a significantly reduced pneumococcal colonization on days 3, 7, and 14 post-inoculations. To assess the impact of pneumococcal serine proteases on acute infection, we infected mice intranasally with bioluminescent and invasive TIGR4 or isogenic triple mutants expressing only CbpG, HtrA, PrtA, or SFP. We imaged the acute lung infection in real-time and determined the survival of the mice. The TIGR4lux mutant expressing only PrtA showed a significant attenuation and was less virulent in the acute pneumonia model. In conclusion, our results showed that pneumococcal serine proteases contributed significantly to pneumococcal colonization but played only a minor role in pneumonia and invasive diseases. Because colonization is a prerequisite for invasive diseases and transmission, these enzymes could be promising candidates for the development of antimicrobials to reduce pneumococcal transmission.

Project description:Pneumococcal conjugate vaccine (PCV) immunization of children induces shifts in colonizing pneumococcal serotypes. This study evaluated the effect of infant vaccination with 7-valent PCV (PCV7) on vaccine serotype (VT) colonization and whether the increase in nonvaccine serotype (NVT) was due to either unmasking of previously low-density-colonizing serotypes or increase in acquisition of NVT. A multiplex quantitative PCR (qPCR) was used to evaluate VT and NVT nasopharyngeal colonization in archived swabs of PCV-vaccinated and PCV-unvaccinated African children at 9 and 15 to 16 months of age. Molecular qPCR clearly identified the vaccine effect typified by a decrease in VT colonization and an increase in NVT colonization. Serotype 19A was primarily responsible for the higher NVT carriage among PCV vaccinees at 9 months of age (53.4% difference; P = 0.021) and 16 months of age (70.7% difference; P < 0.001). Furthermore, the density of serotype 19A colonization was higher in PCV-vaccinated groups than in PCV-unvaccinated groups (3.76 versus 2.83 CFU/ml [P = 0.046], respectively, and 4.15 versus 3.04 CFU/ml [P = 0.013], respectively) at 9 and 16 months of age, respectively. Furthermore, serotype 19A was also more commonly reported as a primary isolate (by having the highest density among other cocolonizing serotypes identified in the sample) in PCV7-vaccinated children, while being equally a primary (46.2%) or nonprimary (53.8%) isolate in PCV-unvaccinated children. Molecular qPCR showed both serotype replacement and unmasking to be the cause for the increase in NVT colonization in PCV7-vaccinated children, as some serotypes were associated with an absolute increase in colonization (replacement), while others were associated with an increase in detection (unmasking). IMPORTANCE This study focused on evaluating the effect of infant vaccination with 7-valent pneumococcal conjugate vaccine (PCV7), using a multiplex qPCR method, on the density of serotype-specific nasopharyngeal colonization in order to delineate the relative role of serotype replacement versus unmasking as the cause for the increase in nonvaccine serotype colonization in PCV7-vaccinated children. This is pertinent in the context of the ongoing deployment of PCV immunization in children, with surveillance of colonization considered an early proxy for disease that might arise from nonvaccine serotypes, as well as the success of childhood vaccination on indirect effect in the community through the interruption of pneumococcal transmission from vaccinated young children.

Dataset Information

The Pneumococcal Alpha-Glycerophosphate Oxidase Enhances Nasopharyngeal Colonization through Binding to Host Glycoconjugates.

Publications

The Pneumococcal Alpha-Glycerophosphate Oxidase Enhances Nasopharyngeal Colonization through Binding to Host Glycoconjugates.

Similar Datasets

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