Bacterial infections of the pregnant uterus are major causes of preterm birth, stillbirth, maternal death, and childhood disability. Group B Streptococcus (GBS) is a major culprit, but advancing preventive and therapeutic strategies has been slowed by gaps in our understanding of the host-microbial interactions responsible for infection. Our long term vision is to reduce the burden of perinatal infections by defining molecular mechanisms of disease pathogenesis. The goal of this project is to newly identify host and bacterial determinants of invasive GBS infection. There is considerable variation in the ability of phylogenetically distinct GBS strains to cause disease in neonates and pregnant women, ranging from asymptomatic colonization to severe infection. The basis of these differences is unclear. Early stages in the interaction between GBS and maternal gestational tissues potentially determine the outcome of infection. New data suggest that both host and bacterial responses to initial contact vary significantly depending on the strain, yet this has received almost no attention in regards to maternal-fetal infection. Based on preliminary data from our groups and others, we hypothesize that (1) distinct virulence gene expression profiles in unique multilocus sequence types (STs) of GBS are triggered by contact with human gestational tissues, and (2) host immune responses to GBS are shaped by the virulence of the infecting ST. We propose to test these novel hypotheses through three Specific Aims that take advantage of collaborations among experts in microbial pathogenesis, reproductive biology, infectious diseases, and innate immunity.
The Aims are: (1) identify differences in global transcriptome remodeling of diverse GBS STs during infection of human placental macrophages and intact extraplacental gestational membranes; (2) define host immune responses to diverse GBS sequence types that mediate invasive vs. colonizing GBS phenotypes in human extraplacental gestational membranes; and (3) determine the extent to which placental macrophage behavior is influenced by GBS ST variation. These studies will shed new light on the pathogenesis of perinatal GBS infections, revealing novel targets that could be used to improve the health of mothers and children worldwide.

Public Health Relevance

Group B Streptococcus (GBS) is an important bacterial cause of invasive infections during pregnancy that leads to preterm birth, stillbirth, childhood disability, and maternal mortality. This project combines studies of bacterial pathogenesis and female reproductive tract immunology to better understand how GBS causes severe disease. These investigations will facilitate the development of novel preventive and therapeutic options against perinatal GBS infections, thereby improving the health of women and children worldwide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI100903-01
Application #
8507835
Study Section
Special Emphasis Panel (ZAI1-BDP-M (M1))
Program Officer
GU, Xin-Xing
Project Start
2012-08-01
Project End
2013-09-30
Budget Start
2012-08-01
Budget End
2013-09-30
Support Year
1
Fiscal Year
2012
Total Cost
$596,136
Indirect Cost
$132,380
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Boldenow, Erica; Hogan, Kelly A; Chames, Mark C et al. (2015) Role of cytokine signaling in group B Streptococcus-stimulated expression of human beta defensin-2 in human extraplacental membranes. Am J Reprod Immunol 73:263-72
Korir, Michelle L; Knupp, David; LeMerise, Kathryn et al. (2014) Association and virulence gene expression vary among serotype III group B streptococcus isolates following exposure to decidual and lung epithelial cells. Infect Immun 82:4587-95
Boldenow, E; Jones, S; Lieberman, R W et al. (2013) Antimicrobial peptide response to group B Streptococcus in human extraplacental membranes in culture. Placenta 34:480-5
Singh, Pallavi; Springman, A Cody; Davies, H Dele et al. (2012) Whole-genome shotgun sequencing of a colonizing multilocus sequence type 17 Streptococcus agalactiae strain. J Bacteriol 194:6005