Lineage-encoded genomic determinants of neonatal invasive Group B Streptococcal disease

OBJECTIVES: Group B Streptococcus (GBS) is a leading cause of invasive infection in newborns and infants. Yet the genomic basis of invasiveness and disease severity remains incompletely defined. We aimed to identify bacterial genomic features associated with invasive GBS disease and to explore associations between bacterial genomics and severe clinical outcomes. METHODS: We performed PacBio long-read whole-genome sequencing of 381 GBS isolates, including 127 invasive isolates obtained from blood cultures of infants with GBS disease and 254 serotype-matched colonizing isolates obtained from rectovaginal swabs of pregnant women. Gene presence/absence and allele-level variation were analyzed for virulence, adhesion, hemolysis, regulatory, and antimicrobial resistance genes. Associations with invasive disease, life-threatening organ dysfunction (LTOD), and meningitis were assessed using univariable logistic regression with false discovery rate correction. Correlation matrices were constructed to identify lineage-associated genomic profiles. RESULTS: Invasive disease was strongly associated with clonal complex 17 (CC17), which accounted for 83/127 (65%) invasive isolates compared with 72/254 (28%) colonizing isolates. After correction for multiple testing, the presence of hylB, hvgA, and ermB was significantly associated with invasive disease, whereas pilus island 1 was negatively associated. Invasive isolates also carried CC17-associated allelic variants in genes involved in antimicrobial resistance, transcriptional regulation, virulence, and hemolysis, forming a tightly correlated genomic constellation. Among infants with invasive disease, 28/127 (22%) developed LTOD. Prematurity (17/28 vs 24/99), early-onset disease (14/28 vs 23/99), and lower birthweight were associated with LTOD, whereas no bacterial gene or allelic variant remained associated with severity after correction for multiple testing. No meningitis-specific genomic signatures were identified. CONCLUSIONS: Neonatal GBS invasiveness is primarily associated with a CC17-linked genomic profile comprising both specific virulence genes and lineage-associated allelic variants. In contrast, progression to life-threatening organ dysfunction appears to be driven predominantly by clinical factors rather than bacterial genomic variation.