The Role of Secreted Bacterial Effectors in Intestinal Dysbiosis and Systemic Spread

About This Grant

PROJECT SUMMARY The intestinal microbiota is a complex community that modulates immune responses and host metabolism. However, colonization of this niche by pathobionts, particularly early in life, can perturb this homeostasis and cause intestinal damage and inflammation. Further, because the neonatal intestinal microbiota, immunity, and barriers are not fully developed, infants are particularly susceptible to pathogen barrier breach and systemic bloodstream infection. Group B Streptococcus (GBS) is one such pathobiont that colonizes the neonatal gastrointestinal tract following aspiration of infected amniotic fluid and/or breast milk. This intestinal colonization serves as a reservoir for “late-onset” GBS systemic disease (LOD), which presents at least one week following birth (typically as bacteremia and/or meningitis) and causes ~15% mortality regardless of antibiotic treatment. Despite this, the mechanisms underlying GBS infant intestinal colonization and resulting systemic neonatal disease remain largely unknown. Type VII secretion systems (T7SS) export effector proteins with functions in virulence, toxicity, or interbacterial killing, and we recently characterized this system in GBS. Our previous work showed that GBS T7SS and its effectors promote virulence in murine models of meningitis by pore-forming effectors as well as female genital tract colonization by toxin-mediated interbacterial competition and immune evasion. We recently found that GBS T7SS is also important for neonatal systemic infection stemming from intestinal colonization and that GBS T7SS effectors are toxic to intestinal epithelium. Based on these data, this proposal will investigate the role of the GBS T7SS in neonatal intestinal dysbiosis, including disruption of the microbiota, impairment of immune responses, barrier breakdown, and ultimately systemic bacterial spread/bacteremia. These questions will be addressed with human cohort data as well as in vitro and in vivo models of GBS intestinal colonization and systemic dissemination in the following aims: AIM 1: Investigate GBS perturbation of the intestinal microbiota during infant intestinal colonization. AIM 2: Evaluate anti-GBS mucosal immune responses during infant intestinal colonization. AIM 3: Determine mechanisms of GBS-mediated inflammation and barrier damage in intestinal epithelium in vitro and during infant intestinal colonization in vivo. This proposal will investigate the role of GBS T7SS effectors on newborn intestinal colonization and barrier loss, which may afford novel targets and alternative therapeutic strategies to treat and prevent neonatal infections.