Abstract
Group B Streptococcus (GBS) is the leading cause of neonatal pneumonia, septicemia, and meningitis. We have previously shown that in adult mice GBS glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an extracellular virulence factor that induces production of the immunosuppressive cytokine interleukin-10 (IL-10) by the host early upon bacterial infection. Here, we investigate whether immunity to neonatal GBS infection could be achieved through maternal vaccination against bacterial GAPDH. Female BALB/c mice were immunized with rGAPDH and the progeny was infected with a lethal inoculum of GBS strains. Neonatal mice born from mothers immunized with rGAPDH were protected against infection with GBS strains, including the ST-17 highly virulent clone. A similar protective effect was observed in newborns passively immunized with anti-rGAPDH IgG antibodies, or F(ab')2 fragments, indicating that protection achieved with rGAPDH vaccination is independent of opsonophagocytic killing of bacteria. Protection against lethal GBS infection through rGAPDH maternal vaccination was due to neutralization of IL-10 production soon after infection. Consequently, IL-10 deficient (IL-10−/−) mice pups were as resistant to GBS infection as pups born from vaccinated mothers. We observed that protection was correlated with increased neutrophil trafficking to infected organs. Thus, anti-rGAPDH or anti-IL-10R treatment of mice pups before GBS infection resulted in increased neutrophil numbers and lower bacterial load in infected organs, as compared to newborn mice treated with the respective control antibodies. We showed that mothers immunized with rGAPDH produce neutralizing antibodies that are sufficient to decrease IL-10 production and induce neutrophil recruitment into infected tissues in newborn mice. These results uncover a novel mechanism for GBS virulence in a neonatal host that could be neutralized by vaccination or immunotherapy. As GBS GAPDH is a structurally conserved enzyme that is metabolically essential for bacterial growth in media containing glucose as the sole carbon source (i.e., the blood), this protein constitutes a powerful candidate for the development of a human vaccine against this pathogen.
Highlights
Streptococcus agalactiae, named Group B Streptococcus (GBS), is a Gram-positive encapsulated commensal bacterium of the human intestine that colonizes the vagina of up to 30% of healthy women
We show that the high susceptibility of newborn mice to GBS infections is associated with their propensity to produce elevated amounts of immunosuppressive cytokine IL-10
We show that maternal vaccination with recombinant glyceraldehyde-3-phosphate dehydrogenase (GAPDH) confers robust protective immunity against lethal infection with a GBS hyper-virulent strain in mice offspring
Summary
Streptococcus agalactiae, named Group B Streptococcus (GBS), is a Gram-positive encapsulated commensal bacterium of the human intestine that colonizes the vagina of up to 30% of healthy women. This bacterium is the leading cause of neonatal pneumonia, septicemia, and meningitis [1,2,3,4]. Neonatal GBS infections are acquired through maternal transmission and may result in early-onset disease (EOD), which occurs within the first week of life, or in late-onset disease (LOD), that occurs after the first week and accounts for most meningitis cases and deaths [3,5,6]. Recent reports described the emergence of antibiotic-resistant GBS strains likely caused by the widespread use of IAP [11,12]
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