Whole-Genome Comparison Uncovers Genomic Mutations between Group B Streptococci Sampled from Infected Newborns and Their Mothers

Abstract

Streptococcus agalactiae (group B Streptococcus or GBS), a commensal of the human gut and genitourinary tract, is a leading cause of neonatal infections, in which vertical transmission from mother to child remains the most frequent route of contamination. Here, we investigated whether the progression of GBS from carriage to disease is associated with genomic adaptation. Whole-genome comparison of 47 GBS samples from 19 mother-child pairs uncovered 21 single nucleotide polymorphisms (SNPs) and seven insertions/deletions. Of the SNPs detected, 16 appear to have been fixed in the population sampled whereas five mutations were found to be polymorphic. In the infant strains, 14 mutations were detected, including two independently fixed variants affecting the covRS locus, which is known to encode a major regulatory system of virulence. A one-nucleotide insertion was also identified in the promoter region of the highly immunogenic surface protein Rib gene. Gene expression analysis after incubation in human blood showed that these mutations influenced the expression of virulence-associated genes. Additional identification of three mutated strains in the mothers' milk raised the possibility of the newborns also being a source of contamination for their mothers. Overall, our work showed that GBS strains in carriage and disease scenarios might undergo adaptive changes following colonization. The types and locations of the mutations found, together with the experimental results showing their phenotypic impact, suggest that those in a context of infection were positively selected during the transition of GBS from commensal to pathogen, contributing to an increased capacity to cause disease. IMPORTANCEGroup B Streptococcus (GBS) is a major pathogen responsible for neonatal infections. Considering that its colonization of healthy adults is mostly asymptomatic, the mechanisms behind its switch from a commensal to an invasive state are largely unknown. In this work, we compared the genomic profile of GBS samples causing infections in newborns with that of the GBS colonizing their mothers. Multiple mutations were detected, namely, within key virulence factors, including the response regulator CovR and surface protein Rib, potentially affecting the pathogenesis of GBS. Their overall impact was supported by differences in the expression of virulence-associated genes in human blood. Our results suggest that during GBS's progression to disease, particular variants are positively selected, contributing to the ability of this bacterium to infect its host. Streptococcus agalactiae, or group B Streptococcus (GBS), is currently regarded as one of the leading causes of neonatal sepsis and meningitis worldwide (1-4). Known as a commensal of the digestive and genitourinary tracts of 10 to 30% of the human population, GBS is also a significant source of disease in immunocompromised adults and in the elderly (4-7). Apart from causing human infections, GBS is an etiological agent of bovine mastitis and invasive disease in fish (8-10). F...

Maternal colonization with Streptococcus agalactiae and associated stillbirth and neonatal disease in coastal Kenya

“…Genetically divergent maternal-newborn dyads may reflect un-sampled variation in the mother, as only a single colony was sequenced in each case. Whilst adaptive mutations associated with disease progression have been reported elsewhere from the comparison of mother-newborn pairs,47 we were unable to find evidence for this in the current study, as all pairs involving invasive isolates were either genetically identical (0 SNVs), or divergent enough to argue against this. The findings show GBS infection occurs prior to delivery; supporting the need for IAP to be administered before delivery to be effective, and showing why antisepsis in active labour, for example vaginal chlorhexidine wipes, are ineffective in reducing neonatal EOD 8.…”

The cyl Genes Reveal the Biosynthetic and Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene

“…GBS strains lacking a functional CovR ( covR) cause significantly greater cytotoxicity in neutrophils compared to wildtype (WT) GBS and isogenic non-pigmented/non-hemolytic mutants due to enhanced production of Granadaene (Lamy et al, 2004;Jiang et al, 2005;Rajagopal et al, 2006;Boldenow et al, 2016). Furthermore, GBS strains lacking CovR have been identified and isolated from women in preterm labor (Whidbey et al, 2013) and from patients with other GBS infectious morbidities (Sendi et al, 2009;Lupo et al, 2014;Almeida et al, 2015Almeida et al, , 2017Whidbey et al, 2015a). We hypothesized that L. lactis pcylX-K, which lacks transcriptional repressors specific to the cyl operon, would induce neutrophil cytotoxicity similar to GBS covR.…”

Parallel Evolution of Group B Streptococcus Hypervirulent Clonal Complex 17 Unveils New Pathoadaptive Mutations

“…To obtain a detailed overview of the genomic diversity of CC17, we compiled all of the publicly available genomes belonging to CC17 as of May 2017 ( 8 , 15 , 17 – 20 ), together with a new panel of 45 strains, totaling a set of 626 GBS sequences (see Table S1 in the supplemental material). This comprises strains collected between 1955 and 2016 in Africa ( n = 359), Asia, ( n = 14), Europe ( n = 131), North America ( n = 95), and Australia ( n = 3), as well as others from unknown origins ( n = 24).…”