Adaptive response of neonatal sepsis-derived Group B Streptococcus to bilirubin

Abstract

Hyperbilirubinemia is so common in newborns as to be termed physiological. The most common bacteria involved in early-onset neonatal sepsis are Streptococcus agalactiae, commonly called Group B Streptococcus (GBS). Whilst previous studies show bilirubin has antioxidant properties and is beneficial in endotoxic shock, little thought has been given to whether bilirubin might have antibacterial properties. In this study, we performed a transcriptomic and proteomic assessment of GBS cultured in the presence/absence of bilirubin. Our analysis revealed that increasing levels of bilirubin (>100 µmol/L) negatively correlated with GBS growth (18% reduction from 0–400 µmol/L on plate model, p < 0.001; 33% reduction from 0–100 µmol/L in liquid model, p = 0.02). Transcriptome analysis demonstrated 19 differentially expressed genes, almost exclusively up-regulated in the presence of bilirubin. Proteomic analysis identified 12 differentially expressed proteins, half over-expressed in the presence of bilirubin. Functional analysis using Gene Ontology and KEGG pathways18 revealed a differential expression of genes involved in transport and carbohydrate metabolism, suggesting bilirubin may impact on substrate utilisation. The data improve our understanding of the mechanisms modulating GBS survival in neonatal hyperbilirubinemia and suggest physiological jaundice may have an evolutionary role in protection against early-onset neonatal sepsis.

Liver Injury and Failure in Critical Illness

“…Recently, it has been shown that neonatal hyperbilirubinemia may protect newborns from Streptococcus agalactiae associated sepsis, thereby suggesting an evolutionary role of hyperbilirubinemia …”

“…agalactiae associated sepsis, thereby suggesting an evolutionary role of hyperbilirubinemia. (25) Heme degradation products Z-BOX A and B, which are elevated in cholestatic liver injury, show dose-dependent intrahepatic and extrahepatic cytotoxicity. (26) Collectively, impaired hepatobiliary transport and BA signaling contributes to cholestasis and may have widespread implications for control of metabolism, inflammation, gut integrity, and microbiota.…”

Infections of GBS's etiology and use of perinatal antibiotic prophylaxis

“…Analysis revealed that increasing levels of bilirubin negatively correlated with GBS growth [26]. Studies by Hijona et al seem to be optimistic.…”

Heme‐Derived Bilins

“…The PPARα mediated effects account for at least partly the anti‐obesity and anti‐diabetic effects of bilirubin . Bilirubin is also anti‐bacterial, and this property was recently shown to provide natural protection against prenatal sepsis …”

“…Also, being more hydrophilic than bilirubin IXα, the BVRB‐generated isomers are less capable of crossing the placental barrier contributing further to bilirubin accumulation (hyperbilirubinimea or jaundice) in the fetus and neonates ,. Such accumulation is speculated to have a protective role against streptococcal sepsis due to the antibacterial action of the bilirubins . Interestingly, BVRB is also expressed in hepatocellular carcinomas and prostate cancer cells…”