A Rationally Targeted Approach to Preventing GBS Infection

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PROJECT SUMMARY Dr. Thomas Hooven is a neonatologist and Assistant Professor of Pediatrics at Columbia University studying Streptococcus agalactiae (group B Streptococcus; GBS), the major infectious cause of neonatal morbidity and mortality. His research, under the mentorship of Dr. Adam Ratner, focuses on genes and gene networks that enable GBS to successfully colonize the maternal reproductive tract and to survive in amniotic fluid and blood during perinatal infection. Using a novel genome-wide screening technique based on next-generation sequencing of transposon-genome junctions from a saturated mutant library (Tn-seq), Dr. Hooven can accurately predict GBS genes whose protein products are necessary for bacterial growth under diverse experimental conditions. His proposed research seeks to use Tn-seq technology—in combination with ex vivo and in vivo models of colonization and invasion—to pinpoint surface-localized GBS proteins whose functions are essential for pathogenesis. Once validated by targeted knockout and antibody coincubation experiments, those proteins identified as essential for pathogenesis will be purified and tested as candidate vaccines to prevent vaginal colonization, ascending chorioamnionitis, and early-onset sepsis in clinically relevant mouse models. Recognizing that vaccine efficacy may depend on a combination of humoral and cellular immune mechanisms, this proposal also includes studies of opsonophagocytosis after antibody binding to candidate vaccine protein targets and T cell responses to immunization and vaginal colonization. By performing this research, Dr. Hooven will advance scientific understanding of GBS pathogenesis and bring society closer to a safe and effective vaccine to prevent devastating neonatal GBS infections. He will also expand his experimental repertoire through exposure to key methods in bioinformatics, immunology, molecular genetics, and vaccine development. This project will provide crucial training that will set the stage for his transition to becoming an independent investigator. Upon completion of the proposed research, Dr. Hooven will be ready to assume oversight of his own basic and translational research program aimed at advancing neonatal health through new insights into infection and new approaches toward its prevention and treatment.