Characterization of Interkingdom Synergy between Group B Streptococcus and Candida albicans - PROJECT SUMMARY Streptococcus agalactiae microbiota However, disease factor 30%. or Group B streptococcus (GBS) is a pathobiont that is often part of the normal found in the gastrointestinal (GI) tract and reproductive tract of healthy people. it onset ( LOD), which presents as meningitis. Maternal GBS colonization represents the most important r isk for adverse pregnancy outcomes and neonatal infections, worldwide range from 10- F female (FRT) is a major cause of serious invasive disease in neonates, including pneumonia, sepsis and late and carriage rates etal and neonatal infection can occur following i) ascending infection of the placental membranes in utero, ii) passage through the birth canal, by aspiration of infected vaginal fluids, or iii) colonization of the neonatal GI tract, which can occur during childbirth, or ingestion of infected breast milk postnatally. The fungus Candida albicans (Ca) is also a frequent inhabitant of the GI tract and FRT, with asymptomatic carriage rates of approximately 30% in women, and a higher prevalence often reported with age and in pregnancy. A growing body of evidence has identified C. albicans as an independent risk factor for vaginal colonization by GBS. However, surprisingly little is known about the cross-kingdom interactions that govern these bacterial- fungal associations within the GI and genital tract mucosa. We now have data using our mouse model of vaginal colonization that indicates co-colonization with Ca increases GBS vaginal persistence in vivo; however, the specific mechanism(s) for this synergy is unknown. We also show that Ca significantly enhances GBS attachment to vaginal mucosa using a newly developed multi-layered, highly differentiated human Vaginal Epithelial Cell-Air Liquid Interface (hVEC-ALI) model. Using triple RNA-sequencing during co-culture we have observed that Ca reprograms GBS transcription to induce adhesins and -hemolysin/cytolysin ( -h/c) that are requiredfor GBS colonization and virulence, and that Ca responds to GBS by upregulating genes involved in arginine biosynthesis and uptake. We hypothesize that a GBS-Ca direct physical interaction promotes this transcriptional remodeling to promote GBS host cell attachment, vaginal persistence, and ascending infection. Further, that Ca arginine biosynthesis promotes GBS survival and virulence potential. We will also explore the hypothesize that Ca will similarly promote GBS neonatal intestinal colonization which could impact LOD, and that GBS mucosal colonization can be Ca Als3-based vaccine. We will examine these hypotheses in the following aims: 1) Determine the consequence of Ca-induced transcriptional reprogramming to GBS vaginal colonization and disease, 2) Elucidate the role of Ca arginine biosynthesis to GBS-Ca synergy and vaginal persistence, 3) Examine the effect of Ca on GBS intestinal targeted by therapeutic intervention with a colonizationand LOD, and the potential for maternal vaccination in preventing cross-kingdom synergy.
