A Streptococcal Penicillin-Binding Protein Is Critical for Resisting Innate Airway Defenses in the Neonatal Lung

Abstract

Group B streptococcus (GBS) is a major cause of neonatal pneumonia. The early interactions between innate airway defenses and this pathogen are likely to be a critical factor in determining the outcome for the host. The surface-localized penicillin-binding protein (PBP)1a, encoded by ponA, is known to be an important virulence trait in a sepsis model of GBS infection that promotes resistance to neutrophil killing and more specifically to neutrophil antimicrobial peptides (AMPs). In this study, we used an aerosolization model to explore the role of PBP1a in evasion of innate immune defenses in the neonatal lung. The ponA mutant strain was cleared more rapidly from the lungs of neonatal rat pups compared with the wild-type strain, which could be linked to a survival defect in the presence of alveolar macrophages (AM). Rat AM were found to secrete β-defensin and cathelicidin AMP homologues, and the GBS ponA mutant was more susceptible than the wild-type strain to killing by these peptides in vitro. Collectively, our observations suggest that PBP1a-mediated resistance to AM AMPs promotes the survival of GBS in the neonatal lung. Additionally, AM are traditionally thought to clear bacteria through phagocytic uptake; our data indicate that secretion of AMPs may also participate in limiting bacterial replication in the airway.

The two-component response regulator LiaR regulates cell wall stress responses, pili expression and virulence in group B Streptococcus

“…As is true in Staphylococcus aureus, mutation of the dlt system results in alteration of surface-expressed LTA, an increase in the overall surface negative charge, and increased susceptibility of GBS to antimicrobial peptides (Poyart et al, 2003). Deletion of penicillin-binding protein 1A (product of the ponA gene) results in increased susceptibility of GBS to antimicrobial peptides and in decreased virulence in a rat model of GBS sepsis and pneumonia (Hamilton et al, 2006;Jones et al, 2007). Deletion of pilB, one of the GBS pilus-forming proteins, was shown to result in increased susceptibility to neutrophil and antimicrobial peptide killing, and decreased virulence in a mouse model of GBS sepsis (Maisey et al, 2008b).…”

Immune Activation and Suppression by Group B Streptococcus in a Murine Model of Urinary Tract Infection

“…Much of what is known about GBS virulence has been defined in animal models of systemic infection (18,20,23,25,28,46,47). GBS has also been described in animal models of localized colonization and infection, including vaginal (7,8), pulmonary (15,19,22), mammary (52), and orogastric (27) infection models. GBS can also cause cystitis and pyelonephritis (54,55), but the urinary tract is less well characterized as a site of GBS-host interactions.…”

Role of Toll-like receptor 2 in innate resistance to Group B Streptococcus

“…There appears to be functional redundancy in PBP activity such that inactivation of one PBP can often be compensated for by others [25][26][27][40][41][42][43]. We have previously shown that PBP1a is important for virulence of GBS in neonatal rat pups, both in an intraperitoneal sepsis model [21,22] and in lung colonization model [23].…”

“…We have previously shown that PBP1a, a surface-localized penicillin-binding protein encoded by ponA, plays an important role in the pathogenesis of GBS infection as a mutant lacking PBP1a is attenuated for virulence in a neonatal rat sepsis infection model [21,22] and cleared more rapidly from the lungs of neonatal rat pups in an aerosol infection model [23]. Additional characterization of the mutant revealed that PBP1a promotes resistance of GBS to killing by host innate immune antimicrobial peptides, which likely contributes to the virulence defect of this mutant [24].…”