Group B Streptococcus (GBS) is a leading cause of infectious morbidity during infancy. Late-onset GBS infection (>7 days of age) typically manifests as sepsis, focal bone/soft tissue infections, or meningitis, all of which may be associated with significant long-term sequelae in survivors. In contrast to early-onset GBS infection, there are currently no effective strategies to reduce the incidence of late-onset GBS disease or to identify those infants who may be most at risk. We have developed a novel murine model of late-onset GBS infection that closely mimics the human disease state in which perinatally acquired GBS first colonizes the newborn intestinal tract and then transverses intestinal barriers to cause invasive disease.
In Aim 1 of this proposal, we will use our animal model to identify critical bacterial determinants underlying GBS colonization of the neonatal gastrointestinal tract and the progression from asymptomatic carriage to invasive disease using both targeted (isogenic in-frame deletion) and unbiased (transposon insertional mutant library, Tn-seq) approaches. In addition to specific bacterial factors, we hypothesize that the composition and diversity of the developing intestinal microbiota influences the likelihood of sustained GBS colonization in exposed infants. We will use next generation 16S rRNA sequencing to examine impact of general (alpha and beta diversity) and species-level (candidate interbacterial interactions) characteristics of the murine intestinal microbiome on the establishment of GBS carriage.
In Aim 2, we will determine the contribution of antibody-mediated protection against GBS colonization and late-onset disease. Using our animal model, we will determine the impact of active immunization strategies in vivo. At the conclusion of these aims, we will have defined the specific contributions of the host, pathogen and intestinal bacterial community to the pathogenesis of late-onset GBS infection. These data will provide much needed insight into the mechanisms of resistance to GBS colonization in exposed newborns and identify potential strategies to disrupt colonization in those infants most at risk for invasive disease.

Public Health Relevance

Group B Streptococcus (GBS) is a leading cause of late-onset (> 7 days of age) infection in infants and is associated with significant long-term disability in survivors. GBS first colonizes the gastrointestinal tract, and in some infants, it invades tissues and causes systemic infection. This project will use a novel animal model of GBS colonization to better understand the factors that contribute to the development of this important disease and develop new strategies for prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI127957-02
Application #
9391649
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
GU, Xin-Xing
Project Start
2016-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016