Group B Streptococcus surface determinants of neonatal intestinal colonization and infection

Project Summary Group B Streptococcus (GBS; Streptococcus agalactiae) is a dominant cause of bacterial morbidity and mortality for newborns and infants in the United States and around the world. Globally, GBS sepsis and meningitis occur among approximately 400,000 young children annually, leading to 90,000 deaths. While a portion of these infections develop antenatally or during the birth process, a large percentage develop after the first week of life, which is termed “late-onset” GBS infection. In the United States, late-onset infection is now the most common presentation of GBS disease. Unlike early-onset infection (during the first week of life), late- onset infection is unaffected by perinatal administration of prophylactic antibiotics to the delivering mother. There is currently no effective, scalable strategy for preventing late-onset GBS infection. This proposal seeks to make fundamental discoveries about an essential and poorly understood first step in late-onset infection pathogenesis: colonization of the newborn intestine by GBS, which can then progress to transluminal invasion and systemic spread. Our central hypothesis is that GBS uses surface-trafficked proteins to bind to, persist on, and invade neonatal intestinal surfaces. Understanding these key GBS protein-host interactions would open avenues toward vaccine- or antibody-based therapies to interrupt initial neonatal GBS intestinal persistence. We will test our hypothesis using novel, highly efficient GBS genetic modification tools, including a system recently developed and validated by the PI for CRISPR/Cas-mediated GBS gene repression (CRISPRi), and developmentally appropriate human fetal tissue-derived enteroid and mouse models of neonatal intestinal colonization and infection. Our approaches will allow unprecedented, multidimensional interrogation of a set of 70 highly conserved, surface-trafficked GBS proteins to understand the role of each candidate protein in GBS-neonatal host interactions. The set of conserved, surface-trafficked GBS proteins we will examine includes known contributors to maternal, fetal, and neonatal GBS disease (such as the CovR/S signal transduction system) and many proteins whose roles in virulence have yet to be investigated. The unique, complementary capabilities of our multi-institutional consortium will permit unprecedented breadth and depth of investigation into a major cause of newborn illness and death.