Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Tara M. Randis, MS, MD

Co-Major Professor

Sophie E. Darch, Ph.D.

Committee Member

Burt Anderson, Ph.D.

Committee Member

Larry Dishaw, Ph.D.

Committee Member

Andreas Seyfang, Ph.D.

Keywords

GBS, neonatal sepsis, toxin, barrier disruption, microbiome, bacterial metabolites

Abstract

Group B Streptococcus (Streptococcus agalactiae; GBS) is a leading cause of neonatal sepsis worldwide. Intrapartum antibiotics in GBS-colonized mothers significantly reduced the incidence of early-onset sepsis occurring in the first week of life; however, there are currently no prophylactic interventions for late-onset sepsis, occurring within the first 3 months of life. GBS is a pathobiont that primarily colonizes the gastrointestinal tract and can cross the intestinal barrier via both the paracellular and transcellular routes, causing invasive disease. Neonatal susceptibility to GBS intestinal translocation is mediated by inadequate epithelial barrier function and microbiome immaturity; however, the mechanisms by which GBS exploits the immature host remain unclear.

β-hemolysin/cytolysin (βH/C) is a highly conserved, pore-forming, rhamnolipid toxin produced by GBS that contributes to the development of sepsis, pneumonia, meningitis, chorioamnionitis, and uropathogenesis. Rhamnolipid toxins can enhance intestinal paracellular translocation via disruption of epithelial tight junction proteins. GBS βH/C disrupts barriers in other tissues but, its role in disrupting the intestinal barrier remains unexplored. That is, βH/C is a key virulence factor that may contribute to intestinal barrier disruption and GBS translocation.

The microbiome is tightly linked to intestinal barrier function; indeed, the absence of keystone microbes, i.e., fiber degraders, contributes to a virulent uprising in pathobionts and bacterial translocation. These microbes metabolize dietary fiber into butyrate, a short-chain fatty acid that promotes and restores intestinal barrier function via tight junction protein modulation and direct antimicrobial activity. Maternal diet primes the neonatal intestinal environment and, more specifically, maternal butyrate treatment increases keystone microbes, butyrate production, and fortifies intestinal barrier integrity in offspring.

Despite the importance of the intestinal barrier function in protecting the host from enteric pathogens, its relevance to GBS late-onset sepsis is largely unexplored. Our objective was to determine βH/C-mediated effects on intestinal barrier function and the influence of maternal butyrate treatment on GBS disease in offspring. Our overriding hypothesis was that GBS invasive disease is driven by βH/C-mediated intestinal barrier disruption and that maternal butyrate treatment will bolster offspring intestinal barrier function and prevent GBS translocation.

Download

Share

COinS