Abstract
Group B Streptococcus (GBS, S. agalactiae) is a human commensal and occasional pathogen that remains a leading cause of neonatal sepsis and meningitis with increasing disease burden in adult populations. Although programs for universal screening in pregnancy to guide intrapartum prophylaxis have reduced GBS invasive disease burden resulting from mother-to-newborn transfer during birth, better knowledge of disease mechanisms may elucidate new strategies to reduce antibiotic exposure. In our efforts to expand the knowledge base required for targeted anti-virulence therapies, we identified a GBS homolog for a recently identified virulence determinant of group A Streptococcus, S protein, and evaluated its role in GBS pathogenesis. A GBS S protein deletion mutant, Δess, showed altered cell-surface properties compared to the WT parent strain, including defective retention of its surface polysaccharide. Quantitative proteome analysis of enzymatically shaved surface epitopes of the GBS Δess mutant revealed a dysregulated cell surface virulome, with reduced abundance of several protein and glycoprotein components. The Δess mutant showed markedly attenuated virulence in a murine model of GBS systemic infection, with increased proteasome activity detected in the spleens of animals infected with the Δess mutant. These results expand the key roles S protein plays in streptococcal pathogenesis and introduces a new GBS virulence determinant and potential target for therapy development.
Highlights
Group B Streptococcus (GBS), or Streptococcus agalactiae, remains a major cause of neonatal morbidity and mortality across the globe
The S protein sequence from the virulent serotype V CNCTC 10/84 GBS strain was subjected to PSIBLAST, of which 29/43 sequences were attributed to Streptococcus agalactiae (GBS)
We characterized the GBS S protein homolog to a virulence determinant originally identified in group A Streptococcus (GAS)
Summary
Group B Streptococcus (GBS), or Streptococcus agalactiae, remains a major cause of neonatal morbidity and mortality across the globe. Universal maternal screening protocols and intrapartum antibiotic prophylaxis have made GBS-induced preterm birth and early onset GBS infection (i.e., infections that occur during the first week of life) less common (Renner et al, 2006; Seedat et al, 2019). Characterizing the S Protein of GBS are increasingly reported in scenarios where maternal prophylaxis is ineffective, such as in infants beyond the first week of life, pregnant women, and older or immunocompromised adults (Farley, 2001). One potential alternative approach to intrapartum use of antibiotics in GBS-colonized mothers is the use of pharmacological agents that target virulence factors. Despite over a century of investigation into GBS pathogenesis, only a small fraction of the genome has been characterized, with the majority of open reading frames still annotated as “uncharacterized,” or ascribed a putative function on the basis of sequence homology to known proteins in other species. Characterizing proteins of unknown function, especially those that are localized to the bacterial surface, is critical for identifying novel antivirulence targets or candidate vaccine antigens (Doro et al, 2009; Patras et al, 2018)
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